Sample records for tamoxifen-induced hot flashes

  1. Hot flashes are not predictive for serum concentrations of tamoxifen and its metabolites

    PubMed Central

    2013-01-01

    Background Tamoxifen has dramatically reduced the recurrence and mortality rate of estrogen receptor positive breast cancer. However, the efficacy of tamoxifen varies between individuals and 40% of patients will have a recurrence despite adjuvant tamoxifen treatment. Factors that predict tamoxifen efficacy would be helpful for optimizing treatment. Serum concentrations of the active metabolite, endoxifen, may be positively related to treatment outcome. In addition, hot flashes are suggested to be positively associated with tamoxifen treatment outcome. Methods We investigated in a series of 109 patients whether the frequency and severity of hot flashes were related to concentrations of tamoxifen and its metabolites. A serum sample of all patients was analyzed for the concentration of tamoxifen, N-desmethyltamoxifen, endoxifen and 4-hydroxytamoxifen, as well as for estradiol concentrations and several single nucleotide polymorphisms in CYP2D6. Additionally, these patients completed a questionnaire concerning biometric data and treatment side effects. Results We found no evidence supporting an association between concentrations of tamoxifen or metabolites and either the frequency or severity of hot flashes in the covariate unadjusted analyses. However, including interactions with menopausal status and pre-treatment hot flash (PTHF) history indicated that post-menopausal women with PTHF experienced an increasing frequency of hot flashes with increasing serum concentrations of tamoxifen and its metabolites. This finding was not altered when adjusting for potential confounding factors (duration of tamoxifen treatment, CYP2D6 phenotype, estradiol serum concentration, age and body mass index). In addition we observed a positive association between body mass index and both hot flash frequency (p = 0.04) and severity (p < 0.0001). We also observed that patients with lower estradiol levels reported more severe hot flashes (p = 0.02). Conclusions No univariate

  2. CYP2D6 genotype in relation to hot flashes as tamoxifen side effect in a Dutch cohort of the tamoxifen exemestane adjuvant multinational (TEAM) trial.

    PubMed

    Dezentjé, Vincent O; Gelderblom, Hans; Van Schaik, Ron H N; Vletter-Bogaartz, Judith M; Van der Straaten, Tahar; Wessels, Judith A M; Kranenbarg, Elma Meershoek-Klein; Berns, Els M; Seynaeve, Caroline; Putter, Hein; Van de Velde, Cornelis J H; Nortier, Johan W R; Guchelaar, Henk-Jan

    2014-01-01

    In tamoxifen-treated breast cancer patients the occurrence of hot flashes may be associated with effective estrogen receptor antagonism dependent on genetic variations of metabolic enzymes and the estrogen receptor. Early breast cancer patients who were randomized to receive tamoxifen, followed by exemestane within the tamoxifen exemestane adjuvant multinational trial were genotyped for five CYP2D6 alleles. CYP2D6 genotypes and phenotypes were related to the occurrence of hot flashes as adverse event during the first year of tamoxifen use (primary aim) and the time to the occurrence of hot flashes as AE during the complete time on tamoxifen (secondary aim). In addition, exploratory analyses on 22 genetic variants of other metabolic enzymes and two common polymorphisms in the estrogen receptor-1 were performed. No association was found between the CYP2D6 genotype/phenotype or any other genetic variant and hot flashes during the first year. Only higher age was related to a lower incidence of hot flashes in the first year (adjusted odds ratio 0.94, 95 % CI 0.92-0.96; p < 0.001). The ESR1 PvuII XbaI CG haplotype was associated with the time to the occurrence of hot flashes during the complete time on tamoxifen (CG/CG vs. CG/other + other/other: adjusted hazard ratio 0.49, 95 % CI 0.25-0.97; p = 0.04). In conclusion, the CYP2D6 genotypes and phenotypes were not associated with the occurrence of hot flashes. Common polymorphisms in the estrogen receptor-1 might predict hot flashes as common tamoxifen side effect, although this finding needs replication.

  3. Metabolic Activity in the Insular Cortex and Hypothalamus Predicts Hot Flashes: An FDG-PET Study

    PubMed Central

    Deckersbach, Thilo; Lin, Nancy U.; Makris, Nikos; Skaar, Todd C.; Rauch, Scott L.; Dougherty, Darin D.; Hall, Janet E.

    2012-01-01

    Context: Hot flashes are a common side effect of adjuvant endocrine therapies (AET; leuprolide, tamoxifen, aromatase inhibitors) that reduce quality of life and treatment adherence in breast cancer patients. Because hot flashes affect only some women, preexisting neurobiological traits might predispose to their development. Previous studies have implicated the insula during the perception of hot flashes and the hypothalamus in thermoregulatory dysfunction. Objective: The aim of the study was to understand whether neurobiological factors predict hot flashes. Design: [18F]-Fluorodeoxyglucose (FDG) positron emission tomography (PET) brain scans coregistered with structural magnetic resonance imaging were used to determine whether metabolic activity in the insula and hypothalamic thermoregulatory and estrogen-feedback regions measured before and in response to AET predict hot flashes. Findings were correlated with CYP2D6 genotype because of CYP2D6 polymorphism associations with tamoxifen-induced hot flashes. Outcome Measures: We measured regional cerebral metabolic rate of glucose uptake (rCMRglu) in the insula and hypothalamus on FDG-PET. Results: Of 18 women without hot flashes who began AET, new-onset hot flashes were reported by 10 (55.6%) and were detected objectively in nine (50%) participants. Prior to the use of all AET, rCMRglu in the insula (P ≤ 0.01) and hypothalamic thermoregulatory (P = 0.045) and estrogen-feedback (P = 0.007) regions was lower in women who reported developing hot flashes. In response to AET, rCMRglu was further reduced in the insula in women developing hot flashes (P ≤ 0.02). Insular and hypothalamic rCMRglu levels were lower in intermediate than extensive CYP2D6 metabolizers. Conclusions: Trait neurobiological characteristics predict hot flashes. Genetic variability in CYP2D6 may underlie the neurobiological predisposition to hot flashes induced by AET. PMID:22723326

  4. Hot Flashes

    MedlinePlus

    ... report menopausal hot flashes than do women of European descent. Hot flashes are less common in women of Japanese and Chinese descent than in white European women. Complications Nighttime hot flashes (night sweats) can ...

  5. Acupuncture for the Treatment of Hot Flashes in Patients with Breast Cancer Receiving Antiestrogen Therapy: A Pilot Study in Korean Women

    PubMed Central

    Jeong, Young Ju; Park, Young Sun; Kwon, Hyo Jung; Shin, Im Hee; Bong, Jin Gu

    2013-01-01

    Abstract Objectives Antiestrogen therapy can cause vasomotor symptoms similar to those occurring during menopause, including hot flashes. Recent studies suggest that acupuncture is effective in reducing vasomotor symptoms in patients with breast cancer receiving tamoxifen. The purpose of this study was to assess the feasibility and safety of acupuncture for treatment of hot flashes in Korean patients with breast cancer receiving antiestrogen therapy. Design This was a prospective single-arm observational study using before and after measurements. Settings/location The study was located at the East–West Medical Center at Daegu Catholic University Medical Center, Daegu, Korea. Subjects The subjects were 10 patients with breast cancer who were undergoing antiestrogen therapy with tamoxifen or anastrozole and who were suffering from hot flashes. Interventions Acupuncture was administered 3 times a week for 4 consecutive weeks, for 20±5 minutes at each session. Outcome measures The outcome measure was severity of hot flashes assessed by visual analogue scale (VAS) and total hot flash score. Results During treatment, severity of hot flashes was reduced by 70%–95% in all patients. Acupuncture significantly alleviated severity of hot flashes assessed by a visual analogue scale (F=30.261; p<0.001) as well as the total hot flash score (F=21.698; p=0.006). Four (4) weeks after the final treatment, symptoms were not aggravated. Conclusions Acupuncture appeared to provide effective relief from hot flashes among Korean women receiving antiestrogen therapy after surgery for breast cancer, and the effects lasted for at least 1 month after termination of treatment. A randomized controlled prospective study with a larger sample size is required to clarify the role of acupuncture in the management of hot flashes in Korean patients with breast cancer. PMID:23383974

  6. Adverse Effects of Induced Hot Flashes on Objectively Recorded and Subjectively Reported Sleep: Results of a Gonadotropin-Releasing Hormone Agonist Experimental Protocol

    PubMed Central

    Joffe, Hadine; White, David P.; Crawford, Sybil L.; McCurnin, Kristin E.; Economou, Nicole; Connors, Stephanie; Hall, Janet E.

    2013-01-01

    Objectives The impact of hot flashes on sleep is of great clinical interest, but results are inconsistent, especially when both hot flashes and sleep are measured objectively. Using objective and subjective measurements, we examined the impact of hot flashes on sleep by inducing hot flashes with a gonadotropin-releasing hormone agonist (GnRHa). Methods The GnRHa leuprolide was administered to 20 healthy premenopausal volunteers without hot flashes or sleep disturbances. Induced hot flashes were assessed objectively (skin-conductance monitor) and subjectively (daily diary) during one-month follow-up. Changes from baseline in objective (actigraphy) and subjective sleep quality (Pittsburgh Sleep Quality Index [PSQI]) were compared between women who did and did not develop objective hot flashes, and, in parallel analyses, subjective hot flashes. Results New-onset hot flashes were recorded in 14 (70%) and reported by 14 (70%) women (80% concordance). Estradiol was universally suppressed. Objective sleep efficiency worsened in women with objective hot flashes and improved in women without objective hot flashes (median decrease 2.6%, increase 4.2%, p=0.005). Subjective sleep quality worsened more in those with than without subjective hot flashes (median increase PSQI 2.5 vs. 1.0, p=0.03). Objective hot flashes were not associated with subjective sleep quality, nor were subjective symptoms linked to objective sleep measures. Conclusions This experimental model of induced hot flashes demonstrates a causal relationship between hot flashes and poor sleep quality. Objective hot flashes result in worse objective sleep efficiency, while subjective hot flashes worsen perceived sleep quality. PMID:23481119

  7. Informing hot flash treatment decisions for breast cancer survivors: a systematic review of randomized trials comparing active interventions.

    PubMed

    Johns, Claire; Seav, Susan M; Dominick, Sally A; Gorman, Jessica R; Li, Hongying; Natarajan, Loki; Mao, Jun James; Irene Su, H

    2016-04-01

    Patient-centered decision making about hot flash treatments often incorporates a balance of efficacy and side effects in addition to patient preference. This systematic review examines randomized controlled trials (RCTs) comparing at least two non-hormonal hot flash treatments in breast cancer survivors. In July 2015, PubMed, SCOPUS, CINAHL, Cochrane, and Web of Science databases were searched for RCTs comparing active, non-hormonal hot flash treatments in female breast cancer survivors. Thirteen trials were included after identifying 906 potential studies. Four trials were dose comparison studies of pharmacologic treatments citalopram, venlafaxine, gabapentin, and paroxetine. Hot flash reduction did not differ by tamoxifen or aromatase inhibitor use. Citalopram 10, 20, and 30 mg daily had comparable outcomes. Venlafaxine 75 mg daily improved hot flashes without additional side effects from higher dosing. Gabapentin 900 mg daily improved hot flashes more than 300 mg. Paroxetine 10 mg daily had fewer side effects than 20 mg. Among four trials comparing different pharmacologic treatments, venlafaxine alleviated hot flash symptoms faster than clonidine; participants preferred venlafaxine over gabapentin. Five trials compared pharmacologic to non-pharmacologic treatments. Acupuncture had similar efficacy to venlafaxine and gabapentin but may have longer durability after completing treatment and fewer side effects. We could not perform a pooled meta-analysis because outcomes were not reported in comparable formats. Clinical trial data on non-hormonal hot flash treatments provide comparisons of hot flash efficacy and other patient important outcomes to guide clinical management. Clinicians can use the information to help patients select hot flash interventions.

  8. Menopausal hot flashes: Randomness or rhythmicity

    NASA Astrophysics Data System (ADS)

    Kronenberg, Fredi

    1991-10-01

    Menopausal hot flashes are episodes of flushing, increased heart rate, skin blood flow and skin temperature, and a sensation of heat. The thermoregulatory and cardiovascular concomitants of hot flashes are associated with peaks in the levels of various hormones and neurotransmitters in the peripheral circulation. Although hot flashes affect about 75% of women, and are the primary reason that women at menopause seek medical attention, the mechanism of hot flashes is still not understood. Hot flashes vary in frequency and intensity both within and between individuals, and have been thought of as occurring randomly. Yet, some women report that their hot flashes are worse at a particular time of day or year. Initial examination of subjects' recordings of their hot flashes showed diurnal patterns of hot flash occurrence. There also seems to be a diurnal rhythm of hot flash intensity. Continuous physiological monitoring of hot flashes is facilitating the analysis of these patterns, which is revealing circadian and ultradian periodicities. The occurrence of hot flashes can be modulated by external and internal factors, including ambient temperature and fever. Rhythms of thermoregulatory and endocrine functions also may influence hot flash patterns. Examination of the interrelationships between the various systems of the body involved in hot flashes, and a multidisciplinary approach to the analysis of hot flash patterns, will aid our understanding of this complex phenomenon.

  9. Anxiogenic CO2 Stimulus Elicits Exacerbated Hot Flash-like Responses in a Rat Menopause Model and Hot Flashes in Menopausal Women

    PubMed Central

    Federici, Lauren M.; Roth, Sarah Dorsey; Krier, Connie; Fitz, Stephanie D.; Skaar, Todd; Shekhar, Anantha; Carpenter, Janet S.; Johnson, Philip L.

    2016-01-01

    Objective Since longitudinal studies determined that anxiety is a strong risk factor for hot flashes, we hypothesized that an anxiogenic stimulus that signals air hunger (hypercapnic, normoxic gas) would trigger an exacerbated hot flash-associated increase in tail skin temperature (TST) in a rat ovariectomy (OVEX) model of surgical menopause and hot flashes in symptomatic menopausal women. We also assessed TST responses in OVEX serotonin transporter (SERT)+/− rats that models a common polymorphism that is associated with increased climacteric symptoms in menopausal women and increases in anxiety traits. Methods OVEX and sham-OVEX rats (initial experiment) and wildtype and SERT+/− OVEX rats (subsequent experiment) were exposed to a 5 min infusion of 20%CO2 normoxic gas while measuring TST. Menopausal women were given brief 20% and 35%CO2 challenges, and hot flashes were self-reported and objectively verified. Results Compared to controls, OVEX rats had exacerbated increases in TST, and SERT+/− OVEX rats had prolonged TST increases following CO2. Most women reported mild/moderate hot flashes after CO2 challenges, and the hot flash severity to CO2 was positively correlated with daily hot flash frequency. Conclusions The studies demonstrate that this anxiogenic stimulus is capable of inducing cutaneous vasomotor responses in OVEX rats, and eliciting hot flashes in menopausal women. In rats, the severity of the response was mediated by loss of ovarian function and increased anxiety traits (SERT+/−), and, in women, by daily hot flash frequency. These findings may provide insights into anxiety related triggers and genetic risk factors for hot flashes in thermoneutral environments. PMID:27465717

  10. Menopausal Hot Flashes and White Matter Hyperintensities

    PubMed Central

    Thurston, Rebecca C.; Aizenstein, Howard J.; Derby, Carol A.; Sejdić, Ervin; Maki, Pauline M.

    2015-01-01

    Objective Hot flashes are the classic menopausal symptom. Emerging data links hot flashes to cardiovascular disease (CVD) risk, yet how hot flashes are related to brain health is poorly understood. We examined the relationship between hot flashes - measured via physiologic monitor and self-report - and white matter hyperintensities (WMH) among midlife women. Methods Twenty midlife women ages 40-60 without clinical CVD, with their uterus and both ovaries, and not taking hormone therapy were recruited. Women underwent 24 hours of ambulatory physiologic and diary hot flash monitoring to quantify hot flashes; magnetic resonance imaging to assess WMH burden; 72 hours of actigraphy and questionnaires to quantify sleep; and a blood draw, questionnaires, and physical measures to quantify demographics and CVD risk factors. Test of a priori hypotheses regarding relations between physiologically-monitored and self-reported wake and sleep hot flashes and WMH were conducted in linear regression models. Results More physiologically-monitored hot flashes during sleep were associated with greater WMH, controlling for age, race, and body mass index [beta(standard error)=.0002 (.0001), p=.03]. Findings persisted controlling for sleep characteristics and additional CVD risk factors. No relations were observed for self-reported hot flashes. Conclusions More physiologically-monitored hot flashes during sleep were associated with greater WMH burden among midlife women free of clinical CVD. Results suggest that relations between hot flashes and CVD risk observed in the periphery may extend to the brain. Future work should consider the unique role of sleep hot flashes in brain health. PMID:26057822

  11. Measuring hot flash phenomenonology using ambulatory prospective digital diaries

    PubMed Central

    Fisher, William I.; Thurston, Rebecca C.

    2016-01-01

    Objective This study provides the description, protocol, and results from a novel prospective ambulatory digital hot flash phenomenon diary. Methods This study included 152 midlife women with daily hot flashes who completed an ambulatory electronic hot flash diary continuously for the waking hours of 3 consecutive days. In this diary, women recorded their hot flashes and accompanying characteristics and associations as the hot flashes occurred. Results Self-reported hot flash severity on the digital diaries indicated that the majority of hot flashes were rated as mild (41.3%) or moderate (43.7%). Severe (13.1%) and very severe (1.8%) hot flashes were less common. Hot flash bother ratings were rated as mild (43%), or moderate (33.5%), with fewer hot flashes reported bothersome (17.5%) or very bothersome (6%). The majority of hot flashes were reported as occurring on the on the face (78.9%), neck (74.7%), and chest (61.3%). Prickly skin was reported concurrently with 32% of hot flashes, 7% with anxiety and 5% with nausea. A novel finding, 38% of hot flashes were accompanied by a premonitory aura. Conclusion A prospective electronic digital hot flash diary allows for a more precise quantitation of hot flashes while overcoming many of the limitations of commonly employed retrospective questionnaires and paper diaries. Unique insights into the phenomenology, loci and associated characteristics of hot flashes were obtained using this device. The digital hot flash phenomenology diary is recommended for future ambulatory studies of hot flashes as a prospective measure of the hot flash experience. PMID:27404030

  12. Measuring hot flash phenomenonology using ambulatory prospective digital diaries.

    PubMed

    Fisher, William I; Thurston, Rebecca C

    2016-11-01

    This study provides the description, protocol, and results from a novel prospective ambulatory digital hot flash phenomenon diary. This study included 152 midlife women with daily hot flashes who completed an ambulatory electronic hot flash diary continuously for the waking hours of three consecutive days. In this diary, women recorded their hot flashes and accompanying characteristics and associations as the hot flashes occurred. Self-reported hot flash severity on the digital diaries indicated that the majority of hot flashes were rated as mild (41.3%) or moderate (43.7%). Severe (13.1%) and very severe (1.8%) hot flashes were less common. Hot flash bother ratings were rated as mild (43%), or moderate (33.5%), with fewer hot flashes reported bothersome (17.5%) or very bothersome (6%). The majority of hot flashes were reported as occurring on the face (78.9%), neck (74.7%), and chest (61.3%). Of all reported hot flashes, 32% occurred concurrently with prickly skin, 7% with anxiety, and 5% with nausea. A novel finding from the study was that 38% of hot flashes were accompanied by a premonitory aura. A prospective electronic digital hot flash diary allows for a more precise quantitation of hot flashes while overcoming many of the limitations of commonly used retrospective questionnaires and paper diaries. Unique insights into the phenomenology, loci, and associated characteristics of hot flashes were obtained using this device. The digital hot flash phenomenology diary is recommended for future ambulatory studies of hot flashes as a prospective measure of the hot flash experience.

  13. Menopausal hot flashes and insulin resistance.

    PubMed

    Tuomikoski, Pauliina; Ylikorkala, Olavi; Mikkola, Tomi S

    2012-10-01

    Recent data have indicated that menopausal hot flashes may be a determinant for cardiovascular health. Therefore, we studied the impact of hot flashes on insulin resistance, one of the most powerful markers of cardiovascular health, in recently postmenopausal women. We studied 143 recently postmenopausal (amenorrhea 6-36 mo) healthy and normal-weight women without previous hormone therapy use. The women prospectively recorded the number and severity of hot flashes for 2 weeks, and a validated total symptom score, the hot flash weekly weighted score, was calculated for each woman. Insulin resistance was assessed from fasting blood levels of glucose and insulin with the homeostasis model assessment. In 12 women, the assessment of insulin (n = 11) or glucose (n = 1) failed, and they were excluded from further analysis. Thus, hot flashes were absent in 19, mild in 32, moderate in 27, and severe in 53 women. The levels of glucose or insulin, or HOMA showed no differences between these groups, nor was insulin resistance related to the number or severity of hot flashes or to the levels of C-reactive protein or sex hormone-binding globulin. Overall, insulin resistance showed a positive association with body mass index (mean difference, 0.058; 95% CI, 0.015-0.102; P = 0.009) and a negative association with level of estradiol (mean difference, -0.002; 95% CI, -0.003 to -0.001; P = 0.009). Insulin resistance may not be involved in hot flash-related changes in cardiovascular health. However, because of the small sample size, these findings need to be interpreted with caution.

  14. Abdominal adiposity and hot flashes among midlife women.

    PubMed

    Thurston, Rebecca C; Sowers, MaryFran R; Sutton-Tyrrell, Kim; Everson-Rose, Susan A; Lewis, Tené T; Edmundowicz, Daniel; Matthews, Karen A

    2008-01-01

    Two competing hypotheses suggest how adiposity may affect menopausal hot flashes. The "thin hypothesis" asserts that aromatization of androgens to estrogens in body fat should be associated with decreased hot flashes. Conversely, thermoregulatory models argue that body fat should be associated with increased hot flashes. The study objective was to examine associations between abdominal adiposity and hot flashes, including the role of reproductive hormones in these associations. The Study of Women's Health Across the Nation Heart Study (2001-2003) is an ancillary study to the Study of Women's Health Across the Nation, a community-based cohort study. Participants were 461 women (35% African American, 65% white) ages 45 to 58 years with an intact uterus and at least one ovary. Measures included a computed tomography scan to assess abdominal adiposity; reported hot flashes over the previous 2 weeks; and a blood sample for measurement of follicle-stimulating hormone, estradiol, and sex hormone-binding globulin-adjusted estradiol (free estradiol index). Associations were evaluated within multivariable logistic and linear regression models. Every 1-SD increase in total (odds ratio [OR]=1.28; 95% CI: 1.06-1.55) and subcutaneous (OR=1.30; 95% CI: 1.07-1.58) abdominal adiposity was associated with increased odds of hot flashes in age- and site-adjusted models. Visceral adiposity was not associated with hot flashes. Associations were not reduced when models included reproductive hormone concentrations. Increased abdominal adiposity, particularly subcutaneous adiposity, is associated with increased odds of hot flashes, favoring thermoregulatory models of hot flashes. Body fat may not protect women from hot flashes as once thought.

  15. Daily Physical Activity and Hot Flashes in the Study of Women's Health Across the Nation FLASHES Study

    PubMed Central

    Gibson, Carolyn; Matthews, Karen; Thurston, Rebecca

    2014-01-01

    Objective To examine the role of physical activity in menopausal hot flashes. Competing models conceptualize physical activity as a risk or protective factor for hot flashes. Few studies have examined this relationship prospectively using physiologic measures of hot flashes and physical activity. Design Over two 48 hour-periods, 51 participants wore a physiologic hot flash monitor and activity monitor, and reported their hot flashes in an electronic diary. Physiologic hot flashes, reported hot flashes and reported hot flashes without physiological corroboration were related to activity changes using hierarchical generalized linear modeling, adjusting for potential confounders. Setting Community. Patients Midlife women. Interventions None. Main Outcome Measures Physiologically-detected hot flashes and reported hot flashes with and without physiologic corroboration. Results Hot flash reports without physiologic corroboration were more likely after activity increases (OR 1.04, 95% CI: 1.00-1.10, p=.01), particularly among women with higher levels of depressive symptoms (interaction p=.02). No other types of hot flashes were related to physical activity. Conclusion Acute increases in physical activity were associated with increased reporting of hot flashes lacking physiologic corroboration, particularly among women with depressive symptoms. Clinicians should consider the role of symptom perception and reporting in relations between physical activity and hot flashes. PMID:24491454

  16. Hot flashes in breast cancer survivors: Frequency, severity and impact.

    PubMed

    Chang, Hao-Yuan; Jotwani, Aparna C; Lai, Yeur-Hur; Jensen, Mark P; Syrjala, Karen L; Fann, Jesse R; Gralow, Julie

    2016-06-01

    To (1) determine the frequency and severity of hot flashes, (2) examine the associations between hot flash frequency and severity and quality of life, and (3) identify the predictors of hot flash activity in breast cancer survivors. The study used a cross-sectional design and mailed survey of 253 breast cancer survivors recruited from a cancer wellness clinic. Participants provided information regarding cancer history, hot flashes, pain intensity, sleep problems, physical functioning, and psychological functioning. About half of the survivors reported at least one hot flash in the past 24 h (45%) or past week (52%). The average frequency of hot flashes was 1.9 in the past 24 h and 1.8 in the past week. Hot flash severity was usually mild or asymptomatic. However, participants with hot flashes reported significantly more sleep problems and higher pain severity than those reporting no hot flashes. Moreover, the severity of hot flashes was associated with more sleep problems, higher pain severity, and more psychological dysfunction. History of hormonal suppression therapy and younger age predicted hot flash activity in the study sample. In breast cancer survivors, hot flashes are common and are associated with unpleasant symptoms and poor quality of life. Research is needed to determine if treatments that reduce the frequency and severity of hot flashes in breast cancer survivors also result in improvements in symptoms such as sleep problems, pain, and psychological dysfunction. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Hot flashes in breast cancer survivors: Frequency, severity and impact

    PubMed Central

    Chang, Hao-Yuan; Jotwani, Aparna C.; Lai, Yeur-Hur; Jensen, Mark P.; Syrjala, Karen L.; Fann, Jesse R.; Gralow, Julie

    2018-01-01

    Purposes To (1) determine the frequency and severity of hot flashes, (2) examine the associations be- tween hot flash frequency and severity and quality of life, and (3) identify the predictors of hot flash activity in breast cancer survivors. Methods The study used a cross-sectional design and mailed survey of 253 breast cancer survivors recruited from a cancer wellness clinic. Participants provided information regarding cancer history, hot flashes, pain intensity, sleep problems, physical functioning, and psychological functioning. Results About half of the survivors reported at least one hot flash in the past 24 h (45%) or past week (52%). The average frequency of hot flashes was 1.9 in the past 24 h and 1.8 in the past week. Hot flash severity was usually mild or asymptomatic. However, participants with hot flashes reported significantly more sleep problems and higher pain severity than those reporting no hot flashes. Moreover, the severity of hot flashes was associated with more sleep problems, higher pain severity, and more psychological dysfunction. History of hormonal suppression therapy and younger age predicted hot flash activity in the study sample. Conclusions In breast cancer survivors, hot flashes are common and are associated with unpleasant symptoms and poor quality of life. Research is needed to determine if treatments that reduce the frequency and severity of hot flashes in breast cancer survivors also result in improvements in symptoms such as sleep problems, pain, and psychological dysfunction. PMID:27065357

  18. Hot Flashes and Quality of Life Among Breast Cancer Patients

    DTIC Science & Technology

    2006-08-01

    hot flashes, 40.7% report at baseline, having used HRT and 26.8% used exercise to control hot flashes. The 12-month data indicates that 26.5% of the...entire sample who are experiencing hot flashes, tried or are using some form of HRT to control hot flashes with exercise still the most frequently...used approach to manage hot flashes with 44.2% of sample currently exercising . 15. SUBJECT TERMS Breast Cancer, Hot Flashes, Quality of Life

  19. Physiologically assessed hot flashes and endothelial function among midlife women.

    PubMed

    Thurston, Rebecca C; Chang, Yuefang; Barinas-Mitchell, Emma; Jennings, J Richard; von Känel, Roland; Landsittel, Doug P; Matthews, Karen A

    2017-08-01

    Hot flashes are experienced by most midlife women. Emerging data indicate that they may be associated with endothelial dysfunction. No studies have tested whether hot flashes are associated with endothelial function using physiologic measures of hot flashes. We tested whether physiologically assessed hot flashes were associated with poorer endothelial function. We also considered whether age modified associations. Two hundred seventy-two nonsmoking women reporting either daily hot flashes or no hot flashes, aged 40 to 60 years, and free of clinical cardiovascular disease, underwent ambulatory physiologic hot flash and diary hot flash monitoring; a blood draw; and ultrasound measurement of brachial artery flow-mediated dilation to assess endothelial function. Associations between hot flashes and flow-mediated dilation were tested in linear regression models controlling for lumen diameter, demographics, cardiovascular disease risk factors, and estradiol. In multivariable models incorporating cardiovascular disease risk factors, significant interactions by age (P < 0.05) indicated that among the younger tertile of women in the sample (age 40-53 years), the presence of hot flashes (beta [standard error] = -2.07 [0.79], P = 0.01), and more frequent physiologic hot flashes (for each hot flash: beta [standard error] = -0.10 [0.05], P = 0.03, multivariable) were associated with lower flow-mediated dilation. Associations were not accounted for by estradiol. Associations were not observed among the older women (age 54-60 years) or for self-reported hot flash frequency, severity, or bother. Among the younger women, hot flashes explained more variance in flow-mediated dilation than standard cardiovascular disease risk factors or estradiol. Among younger midlife women, frequent hot flashes were associated with poorer endothelial function and may provide information about women's vascular status beyond cardiovascular disease risk factors and estradiol.

  20. Hot Flashes and Carotid Intima Media Thickness among Midlife Women

    PubMed Central

    Thurston, Rebecca C.; Sutton-Tyrrell, Kim; Everson-Rose, Susan A.; Hess, Rachel; Powell, Lynda H.; Matthews, Karen A.

    2010-01-01

    Objective Emerging evidence suggests associations between menopausal hot flashes and cardiovascular risk. Whether hot flashes are associated with intima media thickness (IMT) or IMT changes over time is unknown. We hypothesized that reported hot flashes would be associated with greater IMT cross-sectionally and with greater IMT progression over two years. Methods Participants were 432 women ages 45-58 at baseline participating in SWAN Heart, an ancillary study to the Study of Women's Health Across the Nation. Measures at the SWAN Heart baseline and follow-up visit two years later included a carotid artery ultrasound, reported hot flashes (past two weeks: none, 1-5, ≥6 days), and a blood sample for measurement of estradiol. Results Women reporting hot flashes ≥6 days in the prior two weeks had significantly higher IMT than women without hot flashes at baseline (mean difference(SE), mm =0.02(0.01), p=0.03) and follow-up (mean difference(SE), mm =0.02(0.01), p=0.04) visits, controlling for demographic factors and cardiovascular risk factors. Reporting hot flashes at both study visits was associated with higher follow-up IMT relative to reporting hot flashes at neither visit (mean difference(SE), mm=0.03(0.01), p=0.03). Associations between hot flashes and IMT largely remained after adjusting for estradiol. An interaction between hot flashes and obesity status was observed (p=0.05) such that relations between hot flashes and IMT were observed principally among overweight/obese women. Hot flashes were not associated with IMT progression. Conclusions These findings provided some indication that women reporting hot flashes ≥6 days in the prior two weeks may have higher IMT than women without hot flashes, particularly for women who are overweight or obese. Further work should determine whether hot flashes mark adverse underlying vascular changes. PMID:21242820

  1. Are menopausal hot flashes an evolutionary byproduct of postpartum warming?

    PubMed

    Sievert, Lynnette Leidy; Masley, Allison

    2015-04-01

    Hot flashes are commonly associated with menopause, and some researchers have questioned whether the widespread phenomenon may somehow be adaptive. It has been hypothesized that hot flashes were selected to occur during the hypoestrogenic postpartum period as a mechanism to warm infants. The purpose of this study was to test whether postpartum hot flashes are similar to hot flashes associated with menopause and whether postpartum hot flashes are concordant with breast-feeding episodes. Women who gave birth within the past year (n = 20) and a comparison group of women who had not given birth in the past 2 years (n = 14) participated in interviews and anthropometric measures. All wore ambulatory skin conductance monitors for a mean of 6.5 hours during afternoons and early evenings. New mothers also recorded breast-feeding episodes. Objectively measured and subjectively reported hot flashes were compared between groups and in relation to breast-feeding and other variables. Age of infants ranged from 4 days to 11 months. New mothers were more likely to report feeling warmer than the comparison group (100% vs 7%) but were not significantly more likely to demonstrate hot flashes (35% vs 50%) or to report hot flashes (30% vs 21%) during the study period. Of 75 breast-feeding episodes, only 4% were concurrent with an objective hot flash, and only 9% were concurrent with a subjective hot flash. This study does not support the hypothesis that menopausal-like hot flashes evolved to warm infants during the postpartum period.

  2. Menopausal Hot Flashes and Carotid Intima Media Thickness Among Midlife Women.

    PubMed

    Thurston, Rebecca C; Chang, Yuefang; Barinas-Mitchell, Emma; Jennings, J Richard; Landsittel, Doug P; Santoro, Nanette; von Känel, Roland; Matthews, Karen A

    2016-12-01

    There has been a longstanding interest in the role of menopause and its correlates in the development of cardiovascular disease (CVD) in women. Menopausal hot flashes are experienced by most midlife women; emerging data link hot flashes to CVD risk indicators. We tested whether hot flashes, measured via state-of-the-art physiologic methods, were associated with greater subclinical atherosclerosis as assessed by carotid ultrasound. We considered the role of CVD risk factors and estradiol concentrations in these associations. A total of 295 nonsmoking women free of clinical CVD underwent ambulatory physiologic hot flash assessments; a blood draw; and carotid ultrasound measurement of intima media thickness and plaque. Associations between hot flashes and subclinical atherosclerosis were tested in regression models controlling for CVD risk factors and estradiol. More frequent physiologic hot flashes were associated with higher carotid intima media thickness (for each additional hot flash: β [SE]=0.004 [0.001]; P=0.0001; reported hot flash: β [SE]=0.008 [0.002]; P=0.002, multivariable) and plaque (eg, for each additional hot flash, odds ratio [95% confidence interval] plaque index ≥2=1.07 [1.003-1.14]; P=0.04, relative to no plaque, multivariable] among women reporting daily hot flashes; associations were not accounted for by CVD risk factors or by estradiol. Among women reporting hot flashes, hot flashes accounted for more variance in intima media thickness than most CVD risk factors. Among women reporting daily hot flashes, frequent hot flashes may provide information about a woman's vascular status beyond standard CVD risk factors and estradiol. Frequent hot flashes may mark a vulnerable vascular phenotype among midlife women. © 2016 American Heart Association, Inc.

  3. Menopausal Hot Flashes and Carotid Intima Media Thickness among Midlife Women

    PubMed Central

    Thurston, Rebecca C.; Chang, Yuefang; Barinas-Mitchell, Emma; Jennings, J. Richard; Landsittel, Doug P.; Santoro, Nanette; von Känel, Roland; Matthews, Karen A.

    2016-01-01

    Background and Purpose There has been a longstanding interest in the role of menopause and its correlates in the development of cardiovascular disease (CVD) in women. Menopausal hot flashes are experienced by most midlife women; emerging data link hot flashes to CVD risk indicators. We tested whether hot flashes, measured via state-of-the-art physiologic methods, were associated with greater subclinical atherosclerosis as assessed by carotid ultrasound. We considered the role of CVD risk factors and estradiol concentrations in these associations. Methods 295 nonsmoking women free of clinical CVD underwent ambulatory physiologic hot flash assessments; a blood draw; and carotid ultrasound measurement of IMT and plaque. Associations between hot flashes and subclinical atherosclerosis were tested in regression models controlling for CVD risk factors and estradiol. Results More frequent physiologic hot flashes were associated with higher carotid intima media thickness [IMT; for each additional hot flash: beta (standard error)=.004(.001), p=.0001; reported hot flash: beta (standard error)=.008(.002), p=.002, multivariable] and plaque [e.g., for each additional hot flash, odds ratio (95% confidence interval) plaque index ≥2=1.07(1.003–1.14, p=.04), relative to no plaque, multivariable] among women reporting daily hot flashes; associations were not accounted for by CVD risk factors or by estradiol. Among women reporting hot flashes, hot flashes accounted for more variance in IMT than most CVD risk factors. Conclusions Among women reporting daily hot flashes, frequent hot flashes may provide information about a woman’s vascular status beyond standard CVD risk factors and estradiol. Frequent hot flashes may mark a vulnerable vascular phenotype among midlife women. PMID:27834746

  4. Uridine prevents tamoxifen-induced liver lipid droplet accumulation

    PubMed Central

    2014-01-01

    Background Tamoxifen, an agonist of estrogen receptor, is widely prescribed for the prevention and long-term treatment of breast cancer. A side effect of tamoxifen is fatty liver, which increases the risk for non-alcoholic fatty liver disease. Prevention of tamoxifen-induced fatty liver has the potential to improve the safety of long-term tamoxifen usage. Methods Uridine, a pyrimidine nucleoside with reported protective effects against drug-induced fatty liver, was co-administered with tamoxifen in C57BL/6J mice. Liver lipid levels were evaluated with lipid visualization using coherent anti-Stokes Raman scatting (CARS) microscopy, biochemical assay measurement of triacylglyceride (TAG), and liquid chromatography coupled with mass spectrometry (LC-MS) measurement of membrane phospholipid. Blood TAG and cholesterol levels were measured. Mitochondrial respiration of primary hepatocytes in the presence of tamoxifen and/or uridine was evaluated by measuring oxygen consumption rate with an extracellular flux analyzer. Liver protein lysine acetylation profiles were evaluated with 1D and 2D Western blots. In addition, the relationship between endogenous uridine levels, fatty liver, and tamoxifen administration was evaluated in transgenic mice UPase1−/−and UPase1-TG. Results Uridine co-administration prevented tamoxifen-induced liver lipid droplet accumulation in mice. The most prominent effect of uridine co-administration with tamoxifen was the stimulation of liver membrane phospholipid biosynthesis. Uridine had no protective effect against tamoxifen-induced impairment to mitochondrial respiration of primary hepatocytes or liver TAG and cholesterol export. Uridine had no effect on tamoxifen-induced changes to liver protein acetylation profile. Transgenic mice UPase1−/−with increased pyrimidine salvage activity were protected against tamoxifen-induced liver lipid droplet accumulation. In contrast, UPase1-TG mice with increased pyrimidine catabolism activity had

  5. Uridine prevents tamoxifen-induced liver lipid droplet accumulation.

    PubMed

    Le, Thuc T; Urasaki, Yasuyo; Pizzorno, Giuseppe

    2014-05-23

    Tamoxifen, an agonist of estrogen receptor, is widely prescribed for the prevention and long-term treatment of breast cancer. A side effect of tamoxifen is fatty liver, which increases the risk for non-alcoholic fatty liver disease. Prevention of tamoxifen-induced fatty liver has the potential to improve the safety of long-term tamoxifen usage. Uridine, a pyrimidine nucleoside with reported protective effects against drug-induced fatty liver, was co-administered with tamoxifen in C57BL/6J mice. Liver lipid levels were evaluated with lipid visualization using coherent anti-Stokes Raman scatting (CARS) microscopy, biochemical assay measurement of triacylglyceride (TAG), and liquid chromatography coupled with mass spectrometry (LC-MS) measurement of membrane phospholipid. Blood TAG and cholesterol levels were measured. Mitochondrial respiration of primary hepatocytes in the presence of tamoxifen and/or uridine was evaluated by measuring oxygen consumption rate with an extracellular flux analyzer. Liver protein lysine acetylation profiles were evaluated with 1D and 2D Western blots. In addition, the relationship between endogenous uridine levels, fatty liver, and tamoxifen administration was evaluated in transgenic mice UPase1-/-and UPase1-TG. Uridine co-administration prevented tamoxifen-induced liver lipid droplet accumulation in mice. The most prominent effect of uridine co-administration with tamoxifen was the stimulation of liver membrane phospholipid biosynthesis. Uridine had no protective effect against tamoxifen-induced impairment to mitochondrial respiration of primary hepatocytes or liver TAG and cholesterol export. Uridine had no effect on tamoxifen-induced changes to liver protein acetylation profile. Transgenic mice UPase1-/-with increased pyrimidine salvage activity were protected against tamoxifen-induced liver lipid droplet accumulation. In contrast, UPase1-TG mice with increased pyrimidine catabolism activity had intrinsic liver lipid droplet

  6. Cardiac autonomic function and hot flashes among perimenopausal and postmenopausal women.

    PubMed

    Gibson, Carolyn J; Mendes, Wendy Berry; Schembri, Michael; Grady, Deborah; Huang, Alison J

    2017-07-01

    Abnormalities in autonomic function are posited to play a pathophysiologic role in menopausal hot flashes. We examined relationships between resting cardiac autonomic activity and hot flashes in perimenopausal and postmenopausal women. Autonomic function was assessed at baseline and 12 weeks among perimenopausal and postmenopausal women (n = 121, mean age 53 years) in a randomized trial of slow-paced respiration for hot flashes. Pre-ejection period (PEP), a marker of sympathetic activation, was measured with impedance cardiography. Respiratory sinus arrhythmia (RSA), a marker of parasympathetic activation, was measured with electrocardiography. Participants self-reported hot flash frequency and severity in 7-day symptom diaries. Analysis of covariance models were used to relate autonomic function and hot flash frequency and severity at baseline, and to relate changes in autonomic function to changes in hot flash frequency and severity over 12 weeks, adjusting for age, body mass index, and intervention assignment. PEP was not associated with hot flash frequency or severity at baseline or over 12 weeks (P > 0.05 for all). In contrast, there was a trend toward greater frequency of moderate-to-severe hot flashes with higher RSA at baseline (β = 0.43, P = 0.06), and a positive association between change in RSA and change in frequency of moderate-to-severe hot flashes over 12 weeks (β = 0.63, P = 0.04). Among perimenopausal and postmenopausal women with hot flashes, variations in hot flash frequency and severity were not explained by variations in resting sympathetic activation. Greater parasympathetic activation was associated with more frequent moderate-to-severe hot flashes, which may reflect increased sensitivity to perceiving hot flashes.

  7. Effect of Escitalopram on Hot Flash Interference: A Randomized, Controlled Trial

    PubMed Central

    Carpenter, Janet S.; Guthrie, Katherine A.; Larson, Joseph C.; Freeman, Ellen W.; Joffe, Hadine; Reed, Susan D.; Ensrud, Kristine E.; LaCroix, Andrea Z.

    2012-01-01

    Objectives To estimate the effect of escitalopram 10–20 mg/day versus placebo for reducing hot flash interference in daily life and understand correlates and predictors of reductions in hot flash interference, a key measure of quality of life. Design Multi-site, randomized, double-blind, placebo-controlled clinical trial. Patients 205 midlife women (46% African-American) who met criteria participated. Setting MsFLASH clinical sites in Boston, Indianapolis, Oakland, and Philadelphia. Intervention After baseline, women were randomized to 1 pill of escitalopram 10 mg/day (n=104) or placebo (n=101) with follow-up at 4- and 8-weeks. At week 4, those not achieving 50% fewer hot flashes were increased to 2 pills daily (20 mg/day or 2 placebo pills). Main outcome measures The Hot Flash Related Daily Interference Scale; Correlates were variables from hot flash diaries; Predictors were baseline demographics, clinical variables, depression, anxiety, sleep quality, and hot flashes. Results Compared to placebo, escitalopram significantly reduced hot flash interference by 6.0 points at week 4 and 3.4 points at week 8 more than placebo (p=0.012). Reductions in hot flash interference correlated with changes in hot flash diary variables. However, baseline variables did not significantly predict reductions in hot flash interference. Conclusions Escitalopram 10–20mg/day for 8 weeks improves women’s quality of life and this benefit did not vary by demographic, clinical, mood, sleep, or hot flash variables. PMID:22480818

  8. Understanding the complex relationships underlying hot flashes: a Bayesian network approach.

    PubMed

    Smith, Rebecca L; Gallicchio, Lisa M; Flaws, Jodi A

    2018-02-01

    The mechanism underlying hot flashes is not well-understood, primarily because of complex relationships between and among hot flashes and their risk factors. We explored those relationships using a Bayesian network approach based on a 2006 to 2015 cohort study of hot flashes among 776 female residents, 45 to 54 years old, in the Baltimore area. Bayesian networks were fit for each outcome (current hot flashes, hot flashes before the end of the study, hot flash severity, hot flash frequency, and age at first hot flashes) separately and together with a list of risk factors (estrogen, progesterone, testosterone, body mass index and obesity, race, income level, education level, smoking history, drinking history, and activity level). Each fitting was conducted separately on all women and only perimenopausal women, at enrollment and 4 years after enrollment. Hormone levels, almost always interrelated, were the most common variable linked to hot flashes; hormone levels were sometimes related to body mass index, but were not directly related to any other risk factors. Smoking was also frequently associated with increased likelihood of severe symptoms, but not through an antiestrogenic pathway. The age at first hot flashes was related only to race. All other factors were either not related to outcomes or were mediated entirely by race, hormone levels, or smoking. These models can serve as a guide for design of studies into the causal network underlying hot flashes.

  9. Kappa Agonists as a Novel Therapy for Menopausal Hot Flashes

    PubMed Central

    Oakley, Amy E.; Steiner, Robert A.; Chavkin, Charles; Clifton, Donald K.; Ferrara, Laura K.; Reed, Susan D.

    2015-01-01

    Objective Postmenopausal hot flash etiology is poorly understood, making it difficult to develop and target ideal therapies. A network of hypothalamic estrogen-sensitive neurons producing Kisspeptin, Neurokinin B, and Dynorphin (KNDy neurons), located adjacent to the thermoregulatory center, regulate pulsatile secretion of GnRH and LH. Dynorphin may inhibit this system by binding kappa opioid receptors within the vicinity of KNDy neurons. We hypothesize that hot flashes are reduced by KNDy neuron manipulation. Methods A double-blind, cross-over, placebo-controlled pilot study evaluated the effect of a kappa agonist (KA).Hot flash frequency was the primary outcome. Twelve healthy postmenopausal women with moderate-severe hot flashes, ages 48-60 years, were randomized. Eight women with sufficient baseline hot flashes for statistical analysis completed all 3 interventions: placebo, standard Pentazocine/Naloxone (50/0.5 mg) or low-dose Pentazocine/Naloxone (25/0.25 mg). In an inpatient research setting, each participant received the 3 interventions, in randomized order, on 3 separate days. On each day, an intravenous catheter was inserted for luteinizing hormone (LH) blood sampling, and skin conductance and Holter monitors were placed. Subjective hot flash frequency and severity were recorded. Results Mean hot flash frequency 2-7 hours following therapy initiation was lower than that for placebo (KA standard-dose: 4.75 ± 0.67; KA low-dose: 4.50 ± 0.57; and placebo: 5.94 ± 0.78 hot flashes/5 hours; p =0.025). Hot flash intensity did not vary between interventions. LH pulsatility mirrored objective hot flashes in some, but not all women. Conclusions This pilot suggests that kappa agonists may affect menopausal vasomotor symptoms. PMID:25988798

  10. Phthalate metabolite levels and menopausal hot flashes in midlife women.

    PubMed

    Ziv-Gal, Ayelet; Gallicchio, Lisa; Chiang, Catheryne; Ther, Sara N; Miller, Susan R; Zacur, Howard A; Dills, Russell L; Flaws, Jodi A

    2016-04-01

    During the menopausal transition, a woman's reproductive capacity declines, her hormone milieu changes, and her risk of hot flashes increases. Exposure to phthalates, which can be found in personal care products, can also result in altered reproductive function. Here, we investigated the associations between phthalate metabolite levels and midlife hot flashes. Eligible women (45-54 years of age) provided detailed information on hot flashes history and donated urine samples (n=195). Urinary phthalate metabolite levels were measured by HPLC-MS/MS. A higher total sum of phthalate metabolites commonly found in personal care products was associated with an increased risk of ever experiencing hot flashes (odds ratio (OR)=1.45; 95% confidence interval (CI)=1.07-1.96), hot flashes in the past 30days (OR=1.43; 95%CI=1.04-1.96), and more frequent hot flashes (OR=1.47; 95%CI=1.06-2.05). These data suggest that some phthalate exposures from personal care products are associated with menopausal hot flashes in women. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Phthalate metabolite levels and menopausal hot flashes in midlife women

    PubMed Central

    Ziv-Gal, Ayelet; Gallicchio, Lisa; Chiang, Catheryne; Ther, Sara N.; Miller, Susan R.; Zacur, Howard A.; Dills, Russell L.; Flaws, Jodi A.

    2016-01-01

    During the menopausal transition, a woman’s reproductive capacity declines, her hormone milieu changes, and her risk of hot flashes increases. Exposure to phthalates, which can be found in personal-care products, can also result in altered reproductive function. Here, we investigated the associations between phthalate metabolite levels and midlife hot flashes. Eligible women (45–54 years of age) provided detailed information on hot flashes history and donated urine samples (n=195). Urinary phthalate metabolite levels were measured by HPLC-MS/MS. A higher total sum of phthalate metabolites commonly found in personal-care products was associated with an increased risk of ever experiencing hot flashes (odds ratio (OR)=1.45; 95% confidence interval (CI)= 1.07–1.96), hot flashes in the past 30 days (OR=1.43; 95%CI=1.04–1.96), and more frequent hot flashes (OR=1.47; 95%CI=1.06–2.05). These data suggest that some phthalate exposures from personal care products are associated with menopausal hot flashes in women. PMID:26867866

  12. Adiposity and hot flashes in midlife women: a modifying role of age.

    PubMed

    Thurston, Rebecca C; Santoro, Nanette; Matthews, Karen A

    2011-10-01

    The nature of the relationship between adiposity and hot flashes has been debated, but it has not been examined using physiological measures of hot flashes. We examined associations between body size/composition and physiologically assessed hot flashes among women with hot flashes. A subcohort of women in the Study of Women's Health Across the Nation (n = 52; 25 African-American and 27 non-Hispanic Caucasian; ages, 54 to 63 yr) who reported hot flashes, had their uterus and ovaries, and were not taking medications impacting hot flashes were recruited in 2008-2009. Women completed anthropometric measures [bioimpedance analysis of total percentage of body fat, body mass index (BMI), waist circumference], a blood draw (estradiol, SHBG, FSH, dehydroepiandrosterone sulfate), and 4 d of ambulatory sternal skin conductance monitoring with diary (physiological and reported hot flashes, respectively). Associations between anthropometrics and hot flashes were estimated with generalized estimating equations with covariates age, race, and anxiety. Higher BMI (odds ratio, 0.97; 95% confidence interval, 0.94-0.99; P < 0.05) and waist circumference (odds ratio, 0.98; 95% confidence interval, 0.97-0.99; P < 0.01) were associated with fewer physiological hot flashes. Interactions by age (P < 0.05) indicated that inverse associations of body fat, BMI, and waist circumference with hot flashes were most apparent among the oldest women in the sample. Estradiol and SHBG reduced but did not eliminate age-related variations in relations between body size/composition and hot flashes. Higher adiposity was associated with fewer physiological hot flashes among older women with hot flashes. A modifying role of age must be considered in understanding the role of adiposity in hot flashes.

  13. History of hot flashes and aortic calcification among postmenopausal women.

    PubMed

    Thurston, Rebecca C; Kuller, Lewis H; Edmundowicz, Daniel; Matthews, Karen A

    2010-03-01

    Menopausal hot flashes are considered largely a quality-of-life issue. However, emerging research also links hot flashes to cardiovascular risk. In some investigations, this risk is particularly apparent among women using hormone therapy. The aim of this study was to determine whether a longer history of reported hot flashes over the study period was associated with greater aortic and coronary artery calcification. Interactions with hormone therapy use were examined in an exploratory fashion. Participants included 302 women participating in the Healthy Women Study, a longitudinal study of cardiovascular risk during perimenopause and postmenopause, which was initiated in 1983. Hot flashes (any/none) were assessed when women were 1, 2, 5, and 8 years postmenopausal. Electron beam tomography measures of coronary artery calcification and aortic calcification were completed in 1997-2004. Associations between the number of visits with report of hot flashes, divided by the number of visits attended, and aortic or coronary artery calcification (transformed) were examined in linear regression models. Interactions by hormone therapy use were evaluated. Among women using hormone therapy, a longer history of reported hot flashes was associated with increased aortic calcification, controlling for traditional cardiovascular risk factors (b = 2.87, SE = 1.21, P < 0.05). There were no significant associations between history of hot flashes and coronary artery calcification. Among postmenopausal women using hormone therapy, a longer history of reported hot flashes measured prospectively was associated with increased aortic calcification, controlling for traditional cardiovascular risk factors. Hot flashes may signal adverse cardiovascular changes among certain postmenopausal women.

  14. Magnitude of the impact of hot flashes on sleep in perimenopausal women

    PubMed Central

    de Zambotti, Massimiliano; Colrain, Ian M.; Javitz, Harold S.; Baker, Fiona C.

    2014-01-01

    Objective To quantify the impact of objectively-recorded hot flashes on objective sleep in perimenopausal women. Design Cross-sectional study. Participants underwent 1–5 laboratory-based polysomnographic recordings for a total of 63 nights, including sternal skin conductance measures, from which 222 hot flashes were identified according to established criteria. Data were analyzed with hierarchical mixed-effect models and Spearman correlations. Setting Sleep laboratory. Patients 34 perimenopausal women (Age±SD:50.4±2.7y). Intervention None. Main Outcome Measures Perceived and polysomnographic sleep measures (sleep quality, amount of wake after sleep onset and number of awakenings). Subjective (frequency and bother) and objective (frequency and amount of hot flash-associated wake time) hot flash measures. Results Women had an average of 3.5 (95%CI:2.8–4.2, range=1– 9) objective hot flashes per night. 69.4% of hot flashes were associated with an awakening. Hot flash-associated wake time per night was, on average, 16.6 min (95%CI:10.8–22.4), which accounted for 27.2% (SD 27.1) of total wakefulness per night. Hot flash-associated wake, but not frequency, was negatively associated with sleep efficiency and positively associated with wake after sleep onset. Also, self-reported wakefulness correlated with hot flash-associated wake, suggesting that women’s estimates of wakefulness are influenced by the amount of time spent awake in association with hot flashes during the night. More perceived and bothersome hot flashes correlated with more perceived wakefulness and awakenings and more objective hot flash-associated wake time and hot flash frequency. Conclusions The presence of physiological hot flashes accounts for a significant proportion of total objective wakefulness during the night in perimenopausal women. PMID:25256933

  15. Adiposity and Hot Flashes in Midlife Women: A Modifying Role of Age

    PubMed Central

    Santoro, Nanette; Matthews, Karen A.

    2011-01-01

    Background: The nature of the relationship between adiposity and hot flashes has been debated, but it has not been examined using physiological measures of hot flashes. We examined associations between body size/composition and physiologically assessed hot flashes among women with hot flashes. Methods: A subcohort of women in the Study of Women's Health Across the Nation (n = 52; 25 African-American and 27 non-Hispanic Caucasian; ages, 54 to 63 yr) who reported hot flashes, had their uterus and ovaries, and were not taking medications impacting hot flashes were recruited in 2008–2009. Women completed anthropometric measures [bioimpedance analysis of total percentage of body fat, body mass index (BMI), waist circumference], a blood draw (estradiol, SHBG, FSH, dehydroepiandrosterone sulfate), and 4 d of ambulatory sternal skin conductance monitoring with diary (physiological and reported hot flashes, respectively). Associations between anthropometrics and hot flashes were estimated with generalized estimating equations with covariates age, race, and anxiety. Results: Higher BMI (odds ratio, 0.97; 95% confidence interval, 0.94–0.99; P < 0.05) and waist circumference (odds ratio, 0.98; 95% confidence interval, 0.97–0.99; P < 0.01) were associated with fewer physiological hot flashes. Interactions by age (P < 0.05) indicated that inverse associations of body fat, BMI, and waist circumference with hot flashes were most apparent among the oldest women in the sample. Estradiol and SHBG reduced but did not eliminate age-related variations in relations between body size/composition and hot flashes. Conclusion: Higher adiposity was associated with fewer physiological hot flashes among older women with hot flashes. A modifying role of age must be considered in understanding the role of adiposity in hot flashes. PMID:21778220

  16. Behavioral weight loss for the management of menopausal hot flashes: a pilot study.

    PubMed

    Thurston, Rebecca C; Ewing, Linda J; Low, Carissa A; Christie, Aimee J; Levine, Michele D

    2015-01-01

    Although adiposity has been considered to be protective against hot flashes, newer data suggest positive relationships between hot flashes and adiposity. No studies have been specifically designed to test whether weight loss reduces hot flashes. This pilot study aimed to evaluate the feasibility, acceptability, and initial efficacy of behavioral weight loss in reducing hot flashes. Forty overweight or obese women with hot flashes (≥ 4 hot flashes/d) were randomized to either behavioral weight loss intervention or wait-list control. Hot flashes were assessed before and after intervention via physiologic monitoring, diary, and questionnaire. Comparisons of changes in hot flashes and anthropometrics between conditions were performed via Wilcoxon tests. Study retention (83%) and intervention satisfaction (93.8%) were high. Most women (74.1%) reported that hot flash reduction was a major motivator for losing weight. Women randomized to the weight loss intervention lost more weight (-8.86 kg) than did women randomized to control (+0.23 kg; P < 0.0001). Women randomized to weight loss also showed greater reductions in questionnaire-reported hot flashes (2-wk hot flashes, -63.0) than did women in the control group (-28.0; P = 0.03)-a difference not demonstrated in other hot flash measures. Reductions in weight and hot flashes were significantly correlated (eg, r = 0.47, P = 0.006). This pilot study shows a behavioral weight loss program that is feasible, acceptable, and effective in producing weight loss among overweight or obese women with hot flashes. Findings indicate the importance of a larger study designed to test behavioral weight loss for hot flash reduction. Hot flash management could motivate women to engage in this health-promoting behavior.

  17. Genetic polymorphisms, hormone levels, and hot flashes in midlife women.

    PubMed

    Schilling, Chrissy; Gallicchio, Lisa; Miller, Susan R; Langenberg, Patricia; Zacur, Howard; Flaws, Jodi A

    2007-06-20

    Hot flashes disrupt the lives of millions of women each year. Although hot flashes are a public health concern, little is known about risk factors that predispose women to hot flashes. Thus, the objective of this study was to examine whether sex steroid hormone levels and genetic polymorphisms in hormone biosynthesis and degradation enzymes are associated with the risk of hot flashes. In a cross-sectional study design, midlife women aged 45-54 years (n=639) were recruited from Baltimore and its surrounding counties. Participants completed a questionnaire and donated a blood sample for steroid hormone analysis and genotyping. The associations between genetic polymorphisms and hormone levels, as well as the associations between genetic polymorphisms, hormone levels, and hot flashes were examined using statistical models. A polymorphism in CYP1B1 was associated with lower dehydroepiandrosterone-sulfate (DHEA-S) and progesterone levels, while a polymorphism in CYP19 (aromatase) was associated with higher testosterone and DHEA-S levels. Lower progesterone and sex hormone binding globulin levels, lower free estradiol index, and a higher ratio of total androgens to total estrogens were associated with the experiencing of hot flashes. A polymorphism in CYP1B1 and a polymorphism in 3betaHSD were both associated with hot flashes. Some genetic polymorphisms may be associated with altered levels of hormones in midlife women. Further, selected genetic polymorphisms and altered hormone levels may be associated with the risk of hot flashes in midlife women.

  18. Brain blood flow and cardiovascular responses to hot flashes in postmenopausal women

    PubMed Central

    Lucas, Rebekah A. I.; Ganio, Matthew S.; Pearson, James; Crandall, Craig G.

    2012-01-01

    Objective This study tested two related hypotheses: 1) that brain blood flow is reduced during the postmenopausal hot flash; and, 2) the magnitude of this reduction in brain blood flow is greater during hot flashes where blood pressure is reduced. Methods Eleven healthy, normotensive, postmenopausal women rested in a temperature-controlled laboratory (~25°C) for approximately 120 minutes while waiting for a hot flash to occur. The onset of a hot flash was objectively identified by an abrupt increase in sternal sweat rate (capacitance hygrometry). Middle cerebral artery blood velocity (MCAv, transcranial Doppler) and mean arterial pressure (Finometer®) were measured continuously. Each hot flash was divided into 8 equal segments and the segment with the largest reduction in MCAv and mean arterial pressure identified for each hot flash. Results Twenty-five hot flashes occurred during the experimental sessions (lasting 6.2 ± 2.8 min, 3 ± 1 hot flashes per participant). Seventy-six percent of hot flashes were accompanied by a clear reduction (greater than 5%) in brain blood flow. For all hot flashes, the average maximum decrease in MCAv was 12 ± 9% (7 ± 6 cm.s−1). This value did not correlate with corresponding changes in mean arterial pressure (R=0.36). Conclusion These findings demonstrate that hot flashes are often accompanied by clear reductions in brain blood flow that do not correspond with acute reductions in mean arterial blood pressure. PMID:23435027

  19. How self-reported hot flashes may relate to affect, cognitive performance and sleep.

    PubMed

    Regestein, Quentin; Friebely, Joan; Schiff, Isaac

    2015-08-01

    To explain the controversy about whether midlife women who self-report hot flashes have relatively increased affective symptoms, poor cognitive performance or worse sleep. Retrospective data from 88 women seeking relief from bothersome day and night hot flashes were submitted to mixed linear regression modeling to find if estimated hot flashes, as measured by Women's Health Questionnaire (WHQ) items, or diary-documented hot flashes recorded daily, were associated with each other, or with affective, cognitive or sleep measures. Subjects averaged 6.3 daytime diary-documented hot flashes and 2.4 nighttime diary-documented hot flashes per 24h. Confounder-controlled diary-documented hot flashes but not estimated hot flashes were associated with increased Leeds anxiety scores (F=4.9; t=2.8; p=0.01) and Leeds depression scores (3.4; 2.5; 0.02), decreased Stroop Color-Word test performance (9.4; 3.5; 0.001), increased subjective sleep disturbance (effect size=0.83) and increased objective sleep disturbance (effect size=0.35). Hot flash effects were small to moderate in size. Univariate but not multivariate analyses revealed that all hot flash measures were associated with all affect measures. Different measures of hot flashes associated differently with affect, cognition and sleep. Only nighttime diary-document hot flash consistently correlated with any affect measures in multivariate analyses. The use of differing measures for hot flashes, affect, cognition and sleep may account for the continually reported inconsistencies in menopause study outcomes. This problem impedes forging a consensus on whether hot flashes correlate with neuropsychological symptoms. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  20. Behavioral Weight Loss for the Management of Menopausal Hot Flashes: A Pilot Study

    PubMed Central

    Thurston, Rebecca C.; Ewing, Linda J.; Low, Carissa A.; Christie, Aimee J.; Levine, Michele D.

    2014-01-01

    Objective Although adiposity has been considered protective against hot flashes, newer data suggest positive relations between flashes and adiposity. No studies have been specifically designed to test whether weight loss reduces hot flashes. This pilot study aimed to evaluate the feasibility, acceptability, and initial efficacy of behavioral weight loss to reduce hot flashes. Methods Forty overweight/obese women with hot flashes (≥4/day) were randomized to a behavioral weight loss intervention or to wait list control. Hot flashes were assessed pre- and post-intervention via physiologic monitor, diary, and questionnaire. Comparisons of changes in hot flashes and anthropometrics between conditions were tested via Wilcoxon tests. Results Study retention (83%) and intervention satisfaction (93.8%) were high. Most women (74.1%) reported that hot flash reduction was a main motivator to lose weight. Women randomized to the weight loss intervention lost more weight (-8.86 kg) than did women randomized to control (+0.23 kg, p<.0001). Women randomized to weight loss also showed greater reductions in questionnaire-reported hot flashes (2-week hot flashes: −63.0) than did women in the control (−28.0, p=.03), a difference not demonstrated in other hot flash measures. Reductions in weight and hot flashes were significantly correlated (e.g., r=.47, p=.006). Conclusions This pilot study showed a behavioral weight loss program to be feasible, acceptable, and effective in producing weight loss among overweight/obese women with hot flashes. Findings indicate the importance of a larger study designed to test behavioral weight loss for hot flash reduction. Hot flash management could motivate women to engage in this health-promoting behavior. PMID:24977456

  1. Sternal skin conductance: a reasonable surrogate for hot flash measurement?

    PubMed

    Pachman, Deirdre R; Loprinzi, Charles L; Novotny, Paul J; Satele, Daniel V; Linquist, Breanna M; Wolf, Sherry; Barton, Debra L

    2013-11-01

    This study aims to examine the accuracy of a new sternal skin conductance (SSC) device in measuring hot flashes and to assess the acceptability of the device by women. Three small descriptive pilot studies were performed using two sequential prototypes of the SSC device developed by an engineering device company in the Midwest. The devices were worn either in a monitored setting for 24 hours or in an ambulatory setting for 5 weeks. During the study period, women recorded hot flashes in a prospective hot flash diary and answered questions about the acceptability of wearing the SSC device. The first prototype was not able to collect any analyzable skin conductance data owing to various malfunction issues, including poor conductance and battery failure. However, 16 women wore the device for 5 weeks and reported that wearing the device was acceptable, although 31% stated that it interfered with daily activities. Hot flash data from the second prototype revealed a 24% concordance rate between self-reported and device-recorded hot flashes. Findings from these studies support discordance between device-recorded and self-reported hot flashes. In addition, the studies reveal further limitations of SSC monitoring, including difficulties with data collection and lack of consistency in interpretation. Based on these results and other recent trials identifying issues with SSC methodology, it is time to find a better physiologic surrogate measure for hot flashes.

  2. Expectancy after the first treatment and response to acupuncture for menopausal hot flashes.

    PubMed

    Ee, Carolyn C; Thuraisingam, Sharmala; Pirotta, Marie V; French, Simon D; Xue, Charlie C; Teede, Helena J

    2017-01-01

    Evidence on the impact of expectancy on acupuncture treatment response is conflicting. This secondary analysis of a randomized sham-controlled trial on acupuncture for menopausal hot flashes investigated whether treatment expectancy score was associated with hot flash score at end-of-treatment. Secondary analyses investigated whether there were associations between other pre-specified factors and hot flash score. Women experiencing moderately-severe hot flashes were randomized to receive 10 sessions of real or sham acupuncture over eight weeks. Hot flash score was collected using a seven-day hot flash diary, and expectancy using the modified Credibility and Expectancy Questionnaire immediately after the first treatment. Linear mixed-effects models with random intercepts were used to identify associations between expectancy score and hot flash score at end-of-treatment. Regression was also used to identify associations between pre-specified factors of interest and hot flash score. Because there was no difference between real and sham acupuncture for the primary outcome of hot flash score, both arms were combined in the analysis. 285 women returned the Credibility and Expectancy Questionnaire, and 283 women completed both expectancy measures. We found no evidence for an association between expectancy and hot flash score at end-of-treatment for individual cases in either acupuncture or sham group. Hot flash scores at end-of-treatment were 8.1 (95%CI, 3.0 to 13.2; P = 0.002) points lower in regular smokers compared to those who had never smoked, equivalent to four fewer moderate hot flashes a day. In our study of acupuncture for menopausal hot flashes, higher expectancy after the first treatment did not predict better treatment outcomes. Future research may focus on other determinants of outcomes in acupuncture such as therapist attention. The relationship between smoking and hot flashes is poorly understood and needs further exploration.

  3. Perceived control and hot flashes in treatment-seeking breast cancer survivors and menopausal women.

    PubMed

    Carpenter, Janet S; Wu, Jingwei; Burns, Debra S; Yu, Menggang

    2012-01-01

    Lower perceived control over hot flashes has been linked to fewer coping strategies, more catastrophizing, and greater hot flash severity and distress in midlife women, yet this important concept has not yet been studied in breast cancer survivors. The aim of this study was to explore perceived control over hot flashes and hot flashes in breast cancer survivors compared with midlife women without cancer. Ninety-nine survivors and 138 midlife women completed questionnaires and a prospective, electronic hot flash diary. All data were collected at a baseline assessment before randomization in a behavioral intervention study. Both groups had moderate perceived control over hot flashes. Control was not significantly related to hot flash frequency but was significantly related to hot flash severity, bother, and interference in both groups. A significantly stronger association between control and hot flash interference was found for survivors than for midlife women. Survivors using hot flash treatments perceived less control than did survivors not using hot flash treatments, whereas the opposite was true in midlife women. Findings extend our knowledge of perceived control over hot flashes in both survivors and midlife women. Findings emphasize the importance of continued menopausal symptom assessment and management, support the importance of continuing nursing care even for survivors who are already using hot flash treatment, and suggest that nursing interventions aimed at improving perceived control over hot flashes may be more helpful for survivors than for midlife women.

  4. A pilot study of magnetic therapy for hot flashes after breast cancer.

    PubMed

    Carpenter, Janet S; Wells, Nancy; Lambert, Beth; Watson, Peggy; Slayton, Tami; Chak, Bapsi; Hepworth, Joseph T; Worthington, W Bradley

    2002-04-01

    The purpose of this randomized placebo-controlled crossover pilot study was to evaluate the effectiveness and acceptability of magnetic therapy for hot flashes among breast cancer survivors. Participants completed a 24-hour baseline hot-flash monitoring session, wore the magnetic devices or placebo for 3 days, completed an after-treatment hot-flash monitoring session, experienced a 10-day washout period, and then crossed over to the opposite study arm. Magnetic devices and placebos were placed on 6 acupressure sites corresponding to hot-flash relief. Complete data were available from 11 survivors of breast cancer. Results indicated magnetic therapy was no more effective than placebo in decreasing hot-flash severity, and contrary to expectations, placebo was significantly more effective than magnets in decreasing hot-flash frequency, bother, interference with daily activities, and overall quality of life. Implications for clinical practice and future research include the need to explore alternative interventions aimed at alleviating hot flashes in this population.

  5. Sternal Skin Conductance: A reasonable surrogate for Hot Flash Measurement?

    PubMed Central

    Pachman, Deirdre R.; Loprinzi, Charles L.; Novotny, Paul J; Satele, Daniel V; Linquist, Breanna M.; Wolf, Sherry; Barton, Debra L.

    2013-01-01

    Objective The aim of this study was to examine the accuracy of a new sternal skin conductance (SSC) device for the measurement of hot flashes, and secondly, to assess the acceptability of the device by women. Methods Three small descriptive pilot studies were performed utilizing two sequential prototypes of the SSC device developed by an engineering device company in the Midwest. The devices were worn either in a monitored setting for 24 hours or in an ambulatory setting for 5 weeks. During the study period, women recorded hot flashes in a prospective hot flash diary and also answered questions about the acceptability of wearing the SSC device. Results The first prototype was not able to collect any analyzable skin conductance data due to various malfunction issues; including poor conductance and battery failure. However, 16 patients did wear the device for 5 weeks and reported that wearing the device was acceptable, although 31% stated that it did interfere with daily activities. Hot flash data from the second prototype revealed a concordance rate between patient reported and device recorded hot flashes of 24%. Conclusions Findings from these studies support the discordance between SSC recorded and patient reported hot flashes. In addition, the studies reveal further limitations of SSC monitoring, including difficulties with data collection and lack of consistency in interpretation. Based on these results and other recent trials identifying issues with SSC methodology, it is time to find a better physiologic surrogate measure for hot flashes. PMID:23571528

  6. Hot flashes and midlife symptoms in relation to levels of salivary cortisol.

    PubMed

    Gerber, Linda M; Sievert, Lynnette L; Schwartz, Joseph E

    2017-02-01

    This study examined the relationship between salivary cortisol levels and hot flashes during midlife. Previous studies have shown that cortisol levels increase with hot flashes in the laboratory, and higher cortisol levels have been associated with more severe hot flashes. Salivary cortisol levels were also examined in relation to total number of midlife symptoms. Women aged 40-60 years (n=109) reported the presence or absence of 23 symptoms, including hot flashes, during the previous 2 weeks. Salivary samples were collected at waking, 30min after waking, 1h before bedtime, and at bedtime. The cortisol awakening response (CAR), cortisol daily decline (CDD), log transformed salivary cortisol levels at each time point, and mean cortisol levels were compared by hot flash report using t-tests. Logistic regression analyses were performed to assess the association between each cortisol measure and the presence or absence of hot flashes, after controlling for potential covariates. Salivary cortisol levels were not significantly associated with hot flashes or sum of symptoms. Hot flash report did not differentiate women who had a positive CAR from those who did not, or women who showed strong CDD from those who did not. Symptomatic women - defined by hot flash report or symptom total - were not found to have higher salivary cortisol levels. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  7. Hot Flashes and Night Sweats (PDQ®)—Patient Version

    Cancer.gov

    Hot flashes and night sweats can be a side effect of cancer or its treatment and can occur in both women and men. Learn more about hot flashes and night sweats and ways to treat them in this expert-reviewed summary.

  8. Risk Factors for Extended Duration and Timing of Peak Severity of Hot Flashes

    PubMed Central

    Gallicchio, Lisa; Miller, Susan R.; Zacur, Howard A.; Flaws, Jodi A.

    2016-01-01

    Objective To identify risk factors associated with the duration of hot flashes and the time of peak hot flash severity in mid-life women. Methods A cohort of 647 women reporting hot flashes were followed for 1–7 years, with survey data and hormone measurements. Survival analysis determined the association of risk factors with the duration of hot flashes. Linear regression determined the association of risk factors with the time of peak severity. Final models were determined through stepwise model selection. Results Average hot flash duration was 2.5 years (range: 1–33), with peak severity on average at 2.96 years (range: 1–20). Duration of hot flashes was associated with race, education, menopause status, smoking history, BMI, alcohol consumption, leisure activity levels, and levels of estradiol and progesterone. In the final model, only race, alcohol consumption, leisure activity, and menopause were retained. White women had significantly shorter hot flash durations than non-white women. Women consuming at least 12 alcoholic drinks in the previous year had a significantly shorter duration of hot flashes with a smaller effect of hot flash duration on increasing in time to peak severity compared to those who consumed less than 12 alcoholic drinks in that year. Higher serum progesterone levels were associated with later peak severity if the duration of the hot flashes was less than 2 years and an earlier peak severity otherwise. Conclusions These results suggest that some behaviors (such as moderate alcohol consumption) are associated with shorter durations of hot flashes, and that progesterone was associated with the dynamics of hot flash severity. PMID:27149066

  9. Levetiracetam for the treatment of hot flashes: a phase II study.

    PubMed

    Thompson, Susan; Bardia, Aditya; Tan, Angelina; Barton, Debra L; Kottschade, Lisa; Sloan, Jeff A; Christensen, Brad; Smith, DeAnne; Loprinzi, Charles L

    2008-01-01

    The objectives of this pilot trial were to assess the potential efficacy and safety of levetiracetam for the treatment of hot flashes, a major cause of morbidity among breast cancer survivors. Women, aged 18 years or more, with a history of breast cancer or those who wished to avoid estrogen because of a perceived increased risk of breast cancer, who were experiencing bothersome hot flashes (more than or equal to 14 times per week, for more than or equal to 1 month before study entry), were included. During the baseline week, general demographic characteristics, hot flash information, and quality of life data were obtained. At the beginning of week 2, patients were started on levetiracetam for a total of 4 weeks. Information about hot flashes, quality of life, and toxicity were collected during these 4 weeks and compared with the baseline week. After treatment with levetiracetam for 4 weeks (N = 19), mean hot flash scores (frequency times mean severity) were reduced by 57%, and mean hot flash frequencies were reduced by 53%, compared to the baseline week; both these reductions were greater than what would be expected with a placebo (20-25% reduction). There were significant improvements in abnormal sweating (p = 0.004), hot flash distress (p = 0.0002), and satisfaction of hot flash control (p = 0.0001), when comparing data from the fourth week of treatment to the baseline week. Twenty-nine percent of the subjects did not complete the study because of treatment-related adverse events, with the most frequently reported side effects being somnolence, fatigue, and dizziness, usually with mild to moderate intensity. The results of this pilot trial suggest that levetiracetam might be an effective therapy for the treatment of hot flashes. Further data are needed to test this hypothesis, evaluating the efficacy and toxicity of this agent.

  10. Oxidative stress contributes to the tamoxifen-induced killing of breast cancer cells: implications for tamoxifen therapy and resistance

    PubMed Central

    Bekele, Raie T.; Venkatraman, Ganesh; Liu, Rong-Zong; Tang, Xiaoyun; Mi, Si; Benesch, Matthew G. K.; Mackey, John R.; Godbout, Roseline; Curtis, Jonathan M.; McMullen, Todd P. W.; Brindley, David N.

    2016-01-01

    Tamoxifen is the accepted therapy for patients with estrogen receptor-α (ERα)-positive breast cancer. However, clinical resistance to tamoxifen, as demonstrated by recurrence or progression on therapy, is frequent and precedes death from metastases. To improve breast cancer treatment it is vital to understand the mechanisms that result in tamoxifen resistance. This study shows that concentrations of tamoxifen and its metabolites, which accumulate in tumors of patients, killed both ERα-positive and ERα-negative breast cancer cells. This depended on oxidative damage and anti-oxidants rescued the cancer cells from tamoxifen-induced apoptosis. Breast cancer cells responded to tamoxifen-induced oxidation by increasing Nrf2 expression and subsequent activation of the anti-oxidant response element (ARE). This increased the transcription of anti-oxidant genes and multidrug resistance transporters. As a result, breast cancer cells are able to destroy or export toxic oxidation products leading to increased survival from tamoxifen-induced oxidative damage. These responses in cancer cells also occur in breast tumors of tamoxifen-treated mice. Additionally, high levels of expression of Nrf2, ABCC1, ABCC3 plus NAD(P)H dehydrogenase quinone-1 in breast tumors of patients at the time of diagnosis were prognostic of poor survival after tamoxifen therapy. Therefore, overcoming tamoxifen-induced activation of the ARE could increase the efficacy of tamoxifen in treating breast cancer. PMID:26883574

  11. Therapeutic options for the management of hot flashes in breast cancer survivors: an evidence-based review.

    PubMed

    Bordeleau, Louise; Pritchard, Kathleen; Goodwin, Pamela; Loprinzi, Charles

    2007-02-01

    Women with breast cancer may experience treatment-induced menopausal symptoms or natural menopause. Menopausal symptoms, particularly hot flashes, are reported at a high frequency in this group and tend to be more severe, distressing, and of greater duration than in controls. Because of the contribution of sex hormones to breast cancer, the use of hormonal agents for the control of hot flashes is problematic in these women. Safer nonhormonal alternatives are recommended for this patient group. This was a systematic review of the therapeutic options for the treatment of hot flashes in breast cancer survivors. MEDLINE was searched from 1990 to July 2006 using the disease-specific term breast neoplasms and the subheadings menopause and hot flashes. EMBASE was searched from 1990 to March 2006 using the disease-specific subject headings breast tumor/ breast cancer and menopause and the key word hot flashes. The reference lists of the identified articles and relevant review articles were examined for additional publications. Pertinent articles and abstracts of large randomized controlled trials focusing on the treatment of hot flashes in breast cancer survivors were selected for review. Pilot studies were excluded. A number of nonpharmacologic approaches are available for the treatment of hot flashes in breast cancer survivors, although they appear to be of limited effectiveness. Complementary alternative medicine therapies and vitamin E have been found to have modest effectiveness at best, and data on their long-term safety are not available. Centrally active agents such as the antidepressants venlafaxine and paroxetine and the anti seizure agent gabapentin have shown clinical effectiveness and appear to be reasonably well tolerated in this population. Centrally active agents (eg, venlafaxine, paroxetine, gabapentin) are regarded as the most promising nonhormonal treatments for hot flashes in breast cancer survivors. Nonpharmacologic and complementary alternative

  12. Serum leptin levels, hormone levels, and hot flashes in midlife women.

    PubMed

    Alexander, Carolyn; Cochran, Chrissy J; Gallicchio, Lisa; Miller, Susan R; Flaws, Jodi A; Zacur, Howard

    2010-08-01

    To examine the associations between serum leptin levels, sex steroid hormone levels, and hot flashes in normal weight and obese midlife women. Cross-sectional study. University clinic. 201 Caucasian, nonsmoking women aged 45 to 54 years with a body mass index of <25 kg/m2 or >or=30 kg/m2. Questionnaire, fasting blood samples. Serum leptin and sex steroid hormone levels. Correlation and regression models were performed to examine associations between leptin levels, hormone levels, and hot flashes. Leptin levels were associated with BMI, with "ever experiencing hot flashes" (questionnaire), with hot flashes within the last 30 days, and with duration of hot flashes (>1 year, P=.03). Leptin was positively correlated with testosterone, free testosterone index, and free estrogen index and inversely associated with levels of sex hormone-binding globulin. In women with a body mass index>or=30 kg/m2, leptin levels no longer correlated with testosterone levels. Serum leptin levels are associated with the occurrence and duration of hot flashes in midlife women; however, no correlation was found between leptin and serum estradiol. Copyright (c) 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  13. Risk Factors, Pathophysiology, and Treatment of Hot Flashes in Cancer

    PubMed Central

    Fisher, William I.; Johnson, Aimee K.; Elkins, Gary R.; Otte, Julie L.; Burns, Debra S.; Yu, Menggang; Carpenter, Janet S.

    2012-01-01

    Hot flashes are prevalent and severe symptoms that can interfere with mood, sleep, and quality of life for women and men with cancer. The purpose of this article is to review existing literature on the risk factors, pathophysiology, and treatment of hot flashes in persons with cancer. Electronic searches were conducted to identify relevant, English-language literature published through June 15, 2012. Results indicated that risk factors for hot flashes in cancer include patient-related factors (eg, age, race/ethnicity, educational level, smoking history, cardiovascular risk including BMI, and genetics) and disease-related factors (eg, cancer diagnosis, and dose/type of treatment). In addition, although the pathophysiology of hot flashes has remained elusive, these symptoms are likely attributable to disruptions in thermoregulation and neurochemicals. Therapies that have been offered or tested fall into 4 broad categories: pharmacological, nutraceutical, surgical, and complementary/behavioral strategies. The evidence base for this broad range of therapies varies, with some treatments not yet having been fully tested or showing equivocal results. The evidence base surrounding all therapies is evaluated to enhance hot flash treatment decision making by clinicians and patients. PMID:23355109

  14. Clinical Hypnosis in the Treatment of Post-Menopausal Hot Flashes: A Randomized Controlled Trial

    PubMed Central

    Elkins, Gary R.; Fisher, William I.; Johnson, Aimee K.; Carpenter, Janet S.; Keith, Timothy Z.

    2012-01-01

    Objective The use of estrogen and progesterone to manage vasomotor symptoms (i.e., hot flashes, night sweats) has declined due to concerns over their risks and there is an increased interest in alternate, effective, and low-risk treatments. This study reports the results of a randomized, controlled trial of clinical hypnosis in treating vasomotor symptoms among post-menopausal women. Methods Randomized, single-blind, controlled, clinical trial involving 187 post-menopausal women reporting a minimum of seven hot flashes per day, or at least 50 hot flashes a week at baseline between December 2008 and April 2012. Eligible participants received five weekly sessions of either clinical hypnosis or structured-attention control. Primary outcomes were hot flash frequency (subjectively and physiologically recorded) and hot flash score assessed by daily diaries at weeks 2–6, and 12. Secondary outcomes included measures of hot flash related daily interference, sleep quality and treatment satisfaction. Results In a modified intent-to-treat analysis that included all randomized participants that provided data, reported subjective hot flash frequency from baseline to week 12 showed a mean reduction of 55.82 hot flashes for the clinical hypnosis intervention (74.16%), versus a 12.89 hot flash reduction (17.13%) for the control (p<.001, 95% CI, 36.15–49.67). Mean reduction in hot flash score was 18.83 (80.32%) for the clinical hypnosis intervention as compared to 3.53 (15.38%) for the control (p<.001, 95% CI, 12.60–17.54). At 12 week follow-up, the mean reduction in physiologically monitored hot flashes was 5.92 (56.86%) for clinical hypnosis and .88 (9.94%) for the control (p<.001, 95% CI, 2.00–5.46). Secondary outcomes were significantly improved compared to control at 12 week follow-up in hot flash related interference (p<.001, 95% CI, 2.74–4.02), sleep quality (p<.001, 95% CI, 3.65–5.84), and treatment satisfaction (p<.001, 95% CI, 7.79–8.59). Conclusion Compared

  15. Moclobemide in the treatment of hot flashes in postmenopausal women.

    PubMed

    Tarim, Ebru; Bagis, Tayfun; Kilicdag, Esra; Erkanli, Serkan; Aslan, Erdogan; Kuscu, Esra

    2002-01-01

    This randomized, prospective, double-blind study evaluated the efficacy and tolerability of moclobemide, a reversible, selective inhibitor of monoamine oxidase-A, in reducing the frequency and severity of hot flashes. Thirty postmenopausal women were enrolled, and 28 were allocated to 5 weeks of treatment with moclobemide 150 mg (group 1, n = 10), moclobemide 300 mg (group 2, n = 11), or placebo (group 3, n = 9). Data on hot flashes were recorded in a daily diary. Mean reductions in the hot flash severity score were 24.4% in the placebo group, 69.8% in group 1, and 35.0% in group 2. This large difference suggests that the beneficial effects were not due to a placebo effect. Moclobemide may be a new nonhormonal option for reducing the incidence, severity, and duration of hot flashes in postmenopausal women who do not wish to take estrogen or have contraindications to its use.

  16. Efficacy of a biobehavioral intervention for hot flashes: a randomized controlled pilot study.

    PubMed

    Barton, Debra L; Schroeder, Kelliann C Fee; Banerjee, Tanima; Wolf, Sherry; Keith, Timothy Z; Elkins, Gary

    2017-07-01

    The need for effective nonhormonal treatments for hot flash management without unwanted side effects continues. The primary aim of this pilot study was to evaluate the effect of combining a nonhormonal pharmacologic agent with a behavioral treatment for hot flash reduction. Seventy-one postmenopausal women were randomized to one of four groups: venlafaxine 75 mg + hypnosis (VH) versus venlafaxine 75 mg + sham hypnosis (VSH) versus a placebo pill + hypnosis (PH) versus placebo pill + sham hypnosis (PSH). Women recorded hot flash severity and frequency in a daily diary, in real time. The intrapatient difference in hot flash score (frequency × severity) at 8 weeks was analyzed using a General Estimating Equation model, using VSH as the referent arm, controlling for baseline hot flashes. The active arms including PH or VH were not statistically significantly different than VSH (P = 0.34, P = 0.05, respectively). Women in each active arm reported hot flash reductions of about 50%, with the PSH group reporting a 25% reduction. Women receiving the PSH reported statistically significantly smaller reductions in hot flash score than women in the referent VSH arm (P = 0.001). There were no significant negative side effects during the course of the study. Hypnosis alone reduced hot flashes equal to venlafaxine alone, but the combination of hypnosis and venlafaxine did not reduce hot flashes more than either treatment alone. More research is needed to clarify whether combining hypnosis with a different antidepressant would provide synergistic benefits.

  17. Hot flash report and measurement among Bangladeshi migrants, their London neighbors, and their community of origin.

    PubMed

    Sievert, L L; Begum, K; Sharmeen, T; Murphy, L; Whitcomb, B W; Chowdhury, O; Muttukrishna, S; Bentley, G R

    2016-12-01

    To examine hot flashes in relation to climate and activity patterns, and to compare subjective and objective hot flashes among Bangladeshi immigrants to London, their white London neighbors, and women still living in their community of origin, Sylhet, Bangladesh ("sedentees"). Ninety-five women, aged 40-55, wore the Biolog ambulatory hot flash monitor. Objective measurements and subjective hot flash reports were examined in relation to demographic, reproductive, anthropometric, and lifestyle variables; temperature and humidity at 12:00 and 18:00; and time spent on housework and cooking. Concordance of objective and subjective hot flashes was assessed by Kappa statistics and by sensitivity of hot flash classification. During the study period, Bangladeshi sedentees reported more subjective hot flashes (p < .05), but there was no difference in number of objective hot flashes. White Londoners were more likely to describe hot flashes on their face and neck compared to Bangladeshis (p < .05). Sedentees were more likely to describe hot flashes on their feet (p < .05). Postmenopausal status, increasing parity, and high levels of housework were significant determinants of subjective hot flashes, while ambient temperature and humidity were not. Measures of subjective/objective concordance were low but similar across groups (10-20%). The proportion of objective hot flashes that were also self-reported was lowest among immigrants. Hot flashes were not associated with warmer temperatures, but were associated with housework and with site-specific patterns of cooking. The number of objective hot flash measures did not differ, but differences in subjective experience suggest the influence of culture. © 2016 Wiley Periodicals, Inc.

  18. Pilot evaluation of hypnosis for the treatment of hot flashes in breast cancer survivors.

    PubMed

    Elkins, Gary; Marcus, Joel; Stearns, Vered; Hasan Rajab, M

    2007-05-01

    This single arm, pilot study investigated the use of hypnosis to reduce hot flashes in 16 breast cancer survivors. Each patient provided baseline data and received 4 weekly sessions of hypnosis that followed a standardized transcript. Patients were also instructed in self-hypnosis. Throughout the clinical care, patients completed daily diaries of the frequency and severity of their hot flashes. Patients also completed baseline and post-treatment ratings of the degree to which hot flashes interfered with daily activities and quality of life. Results indicated a 59% decrease in total daily hot flashes and a 70% decrease in weekly hot flash scores from their baselines. There was also a significant decrease in the degree to which hot flashes interfered with daily activities for all measures including work, social activities, leisure activities, sleep, mood, concentration, relations with others, sexuality, enjoyment of life, and overall quality of life. This pilot study suggests that clinical hypnosis may be an effective non-hormonal and non-pharmacological treatment for hot flashes. A randomized, controlled clinical trial is planned to more definitively elucidate the efficacy and applicability of hypnosis for reducing hot flashes.

  19. Continuous transdermal nitroglycerin therapy for menopausal hot flashes: a single-arm, dose-escalation trial.

    PubMed

    Huang, Alison J; Cummings, Steven R; Schembri, Michael; Vittinghoff, Eric; Ganz, Peter; Grady, Deborah

    2016-03-01

    To describe the efficacy and tolerability of continuous nitroglycerin for treatment of hot flashes. Perimenopausal and postmenopausal women reporting at least seven hot flashes per day were recruited into a single-arm, dose-escalation trial of continuous transdermal nitroglycerin. Participants were started on a generic 0.1 mg/hour nitroglycerin patch applied daily without patch-free periods. During 4 weeks, participants escalated dosage weekly to 0.2, 0.4, or 0.6 mg/hour as tolerated, then discontinued nitroglycerin during the final week. Changes in hot flash frequency and severity were assessed using symptom diaries. Paired t tests examined change in outcomes between baseline and maximal-dose therapy and after discontinuation of nitroglycerin. Of the 19 participants, mean age was 51.4 (±4.3) years. Women reported an average 10.6 (±3.0) hot flashes and 7.1 (±3.8) moderate-to-severe hot flashes per day at baseline. Eleven women escalated to 0.6 mg/hour, three to 0.4 mg/hour, two to 0.2 mg/hour, and one remained on 0.1 mg/hour nitroglycerin. Two discontinued nitroglycerin before the first outcomes assessment. Among the remaining 17 women, the average daily frequency of hot flashes decreased by 54% and the average frequency of moderate-to-severe hot flashes decreased by 69% from baseline to maximum-dose therapy (P < 0.001 for both). After discontinuing nitroglycerin, participants reported an average 23% increase in frequency of any hot flashes (P = 0.041) and 96% increase in moderate-to-severe hot flashes (P < 0.001). Continuous nitroglycerin may substantially and reversibly decrease hot flash frequency and severity. If confirmed in a randomized blinded trial, it may offer a novel nonhormonal hot flash treatment.

  20. Continuous Transdermal Nitroglycerin Therapy for Menopausal Hot Flashes: A Single-Arm Dose-Escalation Trial

    PubMed Central

    Huang, Alison J.; Cummings, Steven R.; Schembri, Michael; Vittinghoff, Eric; Ganz, Peter; Grady, Deborah

    2015-01-01

    Objective To describe the efficacy and tolerability of continuous nitroglycerin for treatment of hot flashes. Methods Peri- and postmenopausal women reporting at least 7 hot flashes per day were recruited into a single-arm, dose-escalation trial of continuous transdermal nitroglycerin. Participants were started on a generic 0.1 mg/hr nitroglycerin patch applied daily without patch-free periods. Over four weeks, participants escalated dosage weekly to 0.2, 0.4, or 0.6 mg/hr as tolerated, then discontinued nitroglycerin during the final week. Changes in hot flash frequency and severity were assessed using symptom diaries. Paired t-tests examined change in outcomes between baseline and maximal-dose therapy as well as after discontinuation of nitroglycerin. Results Of the 19 participants, mean age was 51.4 (±4.3) years. Women reported an average 10.6 (±3.0) hot flashes and 7.1 (±3.8) moderate-to-severe hot flashes per day at baseline. Eleven women escalated to 0.6 mg/hr, three to 0.4 mg/hr, two to 0.2 mg/hr, and one remained on 0.1 mg/hr nitroglycerin. Two discontinued nitroglycerin before the first outcomes assessment. Among the remaining 17 women, the average daily frequency of hot flashes decreased by 54% and the average frequency of moderate-to-severe hot flashes decreased by 69% from baseline to maximum-dose therapy (P<0.001 for both). After discontinuing nitroglycerin, participants reported an average 23% increase in frequency of any hot flashes (P=0.041) and 96% increase in moderate-to-severe hot flashes (P<0.001). Conclusions Continuous nitroglycerin may substantially and reversibly decrease hot flash frequency and severity. If confirmed in a randomized blinded trial, it may offer a novel non-hormonal hot flash treatment. PMID:26263283

  1. Behavioral Treatment of Menopausal Hot Flashes: Evaluation by Objective Methods.

    ERIC Educational Resources Information Center

    Germaine, Leonard M.; Freedman, Robert R.

    1984-01-01

    Used latency to hot flash onset under heat stress to evaluate the effects of relaxation treatment or a control procedure in 14 menopausal women. Following treatment, the latency to hot flash onset during heat stress was increased in relaxation subjects. Reported symptom frequency was significantly reduced in relaxation subjects. (BH)

  2. Phase II evaluation of S-adenosyl-L-methionine (SAMe) for the treatment of hot flashes.

    PubMed

    Kadakia, Kunal C; Loprinzi, Charles L; Atherton, Pamela J; Fee-Schroeder, Kelliann C; Sood, Amit; Barton, Debra L

    2016-03-01

    Hot flashes are a significant source of symptom burden that negatively impacts quality of life (QOL). For women who have contraindications to, or are unwilling to consider, estrogens or antidepressants for bothersome hot flashes, there are limited effective pharmacologic or complementary and alternative medicines. This single-arm phase II trial studied the efficacy of S-adenosyl-L-methionine (SAMe) for the treatment of hot flashes. Eligible women were required to have reported ≥14 hot flashes per week for ≥1 month. The patients were treated with SAMe at a dose of 400 mg twice daily to evaluate whether a reduction in hot flash score appeared to be better than the historical placebo response of approximately 25%. The women kept a daily hot flash diary during a baseline week and then daily during weeks 2-7. The primary endpoint was the change from baseline to week 7 in hot flash score and hot flash frequency. Secondary endpoints included toxicity analyses and the effect of SAMe on QOL. From October 28, 2010 to January 30, 2012, 43 women were treated with SAMe. The decrease in mean percent of baseline hot flash score and frequency was 35.4 and 32.6%, respectively. When compared to the historical placebo response of 25%, the effect of SAMe on hot flash score was not statistically significant (p = 0.09). Treatment was well tolerated with expected grade 1/2 gastrointestinal toxicity and no negative effect on QOL. The use of SAMe does not appear to significantly reduce hot flashes more than would be expected with a placebo.

  3. Acupuncture as treatment of hot flashes and the possible role of calcitonin gene-related Peptide.

    PubMed

    Spetz Holm, Anna-Clara E; Frisk, Jessica; Hammar, Mats L

    2012-01-01

    The mechanisms behind hot flashes in menopausal women are not fully understood. The flashes in women are probably preceded by and actually initiated by a sudden downward shift in the set point for the core body temperature in the thermoregulatory center that is affected by sex steroids, β-endorphins, and other central neurotransmitters. Treatments that influence these factors may be expected to reduce hot flashes. Since therapy with sex steroids for hot flashes has appeared to cause a number of side effects and risks and women with hot flashes and breast cancer as well as men with prostate cancer and hot flashes are prevented from sex steroid therapy there is a great need for alternative therapies. Acupuncture affecting the opioid system has been suggested as an alternative treatment option for hot flashes in menopausal women and castrated men. The heat loss during hot flashes may be mediated by the potent vasodilator and sweat gland activator calcitonin gene-related peptide (CGRP) the concentration of which increases in plasma during flashes in menopausal women and, according to one study, in castrated men with flushes. There is also evidence for connections between the opioid system and the release of CGRP. In this paper we discuss acupuncture as a treatment alternative for hot flashes and the role of CGRP in this context.

  4. Support Vector Machines to improve physiologic hot flash measures: application to the ambulatory setting.

    PubMed

    Thurston, Rebecca C; Hernandez, Javier; Del Rio, Jose M; De La Torre, Fernando

    2011-07-01

    Most midlife women have hot flashes. The conventional criterion (≥2 μmho rise/30 s) for classifying hot flashes physiologically has shown poor performance. We improved this performance in the laboratory with Support Vector Machines (SVMs), a pattern classification method. We aimed to compare conventional to SVM methods to classify hot flashes in the ambulatory setting. Thirty-one women with hot flashes underwent 24 h of ambulatory sternal skin conductance monitoring. Hot flashes were quantified with conventional (≥2 μmho/30 s) and SVM methods. Conventional methods had low sensitivity (sensitivity=.57, specificity=.98, positive predictive value (PPV)=.91, negative predictive value (NPV)=.90, F1=.60), with performance lower with higher body mass index (BMI). SVMs improved this performance (sensitivity=.87, specificity=.97, PPV=.90, NPV=.96, F1=.88) and reduced BMI variation. SVMs can improve ambulatory physiologic hot flash measures. Copyright © 2010 Society for Psychophysiological Research.

  5. Hot flashes, core body temperature, and metabolic parameters in breast cancer survivors.

    PubMed

    Carpenter, Janet S; Gilchrist, Janet M; Chen, Kong; Gautam, Shiva; Freedman, Robert R

    2004-01-01

    To examine core body temperature, energy expenditure, and respiratory quotient among breast cancer survivors experiencing hot flashes and compare these data to published studies from healthy women. In an observational study, nine breast cancer survivors with daily hot flashes who met specified criteria spent 24 hours in a temperature- and humidity-controlled whole-room indirect calorimeter (ie, metabolic room). Demographic and disease/treatment information were obtained and the following were measured: hot flashes via sternal skin conductance monitoring (sampled every second); core body temperature via an ingested radiotelemetry pill (sampled every 10 seconds); and energy expenditure and respiratory quotient via a whole-room indirect calorimeter (calculated every minute). Circadian analysis of core temperature indicated wide variability with disrupted circadian rhythm noted in all women. Core temperature began to rise 20 minutes pre-flash to 7 minutes pre-flash (0.09 degrees C increase). Increases in energy expenditure and respiratory quotient increased with each hot flash. Findings are comparable to published data from healthy women and warrant replication in larger, more diverse samples of women treated for breast cancer.

  6. Black cohosh (Cimicifuga racemosa) in tamoxifen-treated breast cancer patients with climacteric complaints - a prospective observational study.

    PubMed

    Rostock, Matthias; Fischer, Julia; Mumm, Andreas; Stammwitz, Ute; Saller, Reinhard; Bartsch, Hans Helge

    2011-10-01

    The antihormonal therapy of breast cancer patients with the antiestrogen tamoxifen often induces or aggravates menopausal complaints. As estrogen substitution is contraindicated, herbal alternatives, e.g. extracts of black cohosh are often used. A prospective observational study was carried out in 50 breast cancer patients with tamoxifen treatment. All patients had had surgery, most of them had undergone radiation therapy (87%) and approximately 50% had received chemotherapy. Every patient was treated with an isopropanolic extract of black cohosh (1-4 tablets, 2.5 mg) for 6 months. Patients recorded their complaints before therapy and after 1, 3, and 6 months of therapy using the menopause rating scale (MRS II). The reduction of the total MRS II score under black cohosh treatment from 17.6 to 13.6 was statistically significant. Hot flashes, sweating, sleep problems, and anxiety improved, whereas urogenital and musculoskeletal complaints did not change. In all, 22 patients reported adverse events, none of which were linked with the study medication; 90% reported the tolerability of the black cohosh extract as very good or good. Black cohosh extract seems to be a reasonable treatment approach in tamoxifen treated breast cancer patients with predominantly psychovegetative symptoms.

  7. Circulating interleukin-8 and tumor necrosis factor-α are associated with hot flashes in healthy postmenopausal women.

    PubMed

    Huang, Wan-Yu; Hsin, I-Lun; Chen, Dar-Ren; Chang, Chia-Chu; Kor, Chew-Teng; Chen, Ting-Yu; Wu, Hung-Ming

    2017-01-01

    Hot flashes have been postulated to be linked to systemic inflammation. This study aimed to investigate the relationship between hot flashes, pro-inflammatory factors, and leukocytes in healthy, non-obese postmenopausal women. In this cross-sectional study, a total of 202 women aged 45-60 years were stratified into one of four groups according to their hot-flash status: never experienced hot flashes (Group N), mild hot flashes (Group m), moderate hot flashes (Group M), and severe hot flashes (Group S). Variables measured in this study included clinical parameters, hot flash experience, leukocytes, and fasting plasma levels of nine circulating cytokines/chemokines measured by using multiplex assays. Multiple linear regression analysis was used to evaluate the associations of hot flashes with these pro-inflammatory factors. The study was performed in a hospital medical center. The mean values of leukocyte number were not different between these four groups. The hot flash status had a positive tendency toward increased levels of circulating IL-6 (P-trend = 0.049), IL-8 (P-trend < 0.001), TNF-α (P-trend = 0.008), and MIP1β (P-trend = 0.04). Multivariate linear regression analysis revealed that hot-flash severity was significantly associated with IL-8 (P-trend < 0.001) and TNFα (P-trend = 0.007) among these nine cytokines/chemokines after adjustment for age, menopausal duration, BMI and FSH. Multivariate analysis further revealed that severe hot flashes were strongly associated with a higher IL-8 (% difference, 37.19%; 95% confidence interval, 14.98,63.69; P < 0.001) and TNFα (51.27%; 6.64,114.57; P < 0.05). The present study provides evidence that hot flashes are associated with circulating IL-8 and TNF-α in healthy postmenopausal women. It suggests that hot flashes might be related to low-grade systemic inflammation.

  8. Circulating interleukin-8 and tumor necrosis factor-α are associated with hot flashes in healthy postmenopausal women

    PubMed Central

    Huang, Wan-Yu; Hsin, I-Lun; Chen, Dar-Ren; Chang, Chia-Chu; Kor, Chew-Teng; Chen, Ting-Yu

    2017-01-01

    Introduction Hot flashes have been postulated to be linked to systemic inflammation. This study aimed to investigate the relationship between hot flashes, pro-inflammatory factors, and leukocytes in healthy, non-obese postmenopausal women. Participants and design In this cross-sectional study, a total of 202 women aged 45–60 years were stratified into one of four groups according to their hot-flash status: never experienced hot flashes (Group N), mild hot flashes (Group m), moderate hot flashes (Group M), and severe hot flashes (Group S). Variables measured in this study included clinical parameters, hot flash experience, leukocytes, and fasting plasma levels of nine circulating cytokines/chemokines measured by using multiplex assays. Multiple linear regression analysis was used to evaluate the associations of hot flashes with these pro-inflammatory factors. Settings The study was performed in a hospital medical center. Results The mean values of leukocyte number were not different between these four groups. The hot flash status had a positive tendency toward increased levels of circulating IL-6 (P-trend = 0.049), IL-8 (P-trend < 0.001), TNF-α (P-trend = 0.008), and MIP1β (P-trend = 0.04). Multivariate linear regression analysis revealed that hot-flash severity was significantly associated with IL-8 (P-trend < 0.001) and TNFα (P-trend = 0.007) among these nine cytokines/chemokines after adjustment for age, menopausal duration, BMI and FSH. Multivariate analysis further revealed that severe hot flashes were strongly associated with a higher IL-8 (% difference, 37.19%; 95% confidence interval, 14.98,63.69; P < 0.001) and TNFα (51.27%; 6.64,114.57; P < 0.05). Conclusion The present study provides evidence that hot flashes are associated with circulating IL-8 and TNF-α in healthy postmenopausal women. It suggests that hot flashes might be related to low-grade systemic inflammation. PMID:28846735

  9. RISK OF LONG TERM HOT FLASHES AFTER NATURAL MENOPAUSE: EVIDENCE FROM THE PENN OVARIAN AGING COHORT

    PubMed Central

    Freeman, Ellen W.; Sammel, Mary D.; Sanders, Richard J.

    2015-01-01

    Objectives To estimate the risk of hot flashes relative to natural menopause and evaluate associations of hormone levels, behavioral and demographic variables with the risk of hot flashes following menopause. Methods Annual assessments of 255 women who were premenopausal at baseline and reached natural menopause during 16 years of follow-up. Results The prevalence of moderate/severe hot flashes increased in each premenopausal year, reaching a peak of 46% in the first two years after the final menstrual period (FMP). Hot flashes decreased slowly following menopause and did not return to premenopausal levels until 9 years after FMP. The mean duration of moderate/severe hot flashes after FMP was 4.6 (SD2.9) years (4.9, SD3.1 years for any hot flashes). One-third of women at 10 or more years following menopause continued to experience moderate/severe hot flashes. African American women (obese and non-obese) and obese white women had significantly greater risk of hot flashes compared to non-obese white women (interaction P=0.01). In multivariable analysis, increasing FSH levels before FMP (P<0.001), decreasing estradiol (OR 0.87, 95% CI: 0.78–0.96, P=0.008), and increasing anxiety (OR 1.05, 95% CI: 1.03–1.06, P<0.001) were significant risk factors for hot flashes, while higher education levels were protective (OR 0.66, 95% CI: 0.47–0.91, P=0.011). Conclusions Moderate/severe hot flashes continued on average for nearly 5 years following menopause; more than one- third of women observed for 10 or more years following menopause had moderate/severe hot flashes. Continuation of hot flashes for more than 5 years following menopause underscores the importance of determining individual risk/benefit when selecting hormone or non-hormonal therapy for menopausal symptoms. PMID:24473530

  10. Circulating leptin and adiponectin are associated with insulin resistance in healthy postmenopausal women with hot flashes.

    PubMed

    Huang, Wan-Yu; Chang, Chia-Chu; Chen, Dar-Ren; Kor, Chew-Teng; Chen, Ting-Yu; Wu, Hung-Ming

    2017-01-01

    Hot flashes have been postulated to be linked to the development of metabolic disorders. This study aimed to evaluate the relationship between hot flashes, adipocyte-derived hormones, and insulin resistance in healthy, non-obese postmenopausal women. In this cross-sectional study, a total of 151 women aged 45-60 years were stratified into one of three groups according to hot-flash status over the past three months: never experienced hot flashes (Group N), mild-to-moderate hot flashes (Group M), and severe hot flashes (Group S). Variables measured in this study included clinical parameters, hot flash experience, fasting levels of circulating glucose, lipid profiles, plasma insulin, and adipocyte-derived hormones. Multiple linear regression analysis was used to evaluate the associations of hot flashes with adipocyte-derived hormones, and with insulin resistance. The study was performed in a hospital medical center. The mean (standard deviation) of body-mass index was 22.8(2.7) for Group N, 22.6(2.6) for Group M, and 23.5(2.4) for Group S, respectively. Women in Group S displayed statistically significantly higher levels of leptin, fasting glucose, and insulin, and lower levels of adiponectin than those in Groups M and N. Multivariate linear regression analysis revealed that hot-flash severity was significantly associated with higher leptin levels, lower adiponectin levels, and higher leptin-to-adiponectin ratio. Univariate linear regression analysis revealed that hot-flash severity was strongly associated with a higher HOMA-IR index (% difference, 58.03%; 95% confidence interval, 31.00-90.64; p < 0.001). The association between hot flashes and HOMA-IR index was attenuated after adjusting for leptin or adiponectin and was no longer significant after simultaneously adjusting for leptin and adiponectin. The present study provides evidence that hot flashes are associated with insulin resistance in postmenopausal women. It further suggests that hot flash association with

  11. Circulating leptin and adiponectin are associated with insulin resistance in healthy postmenopausal women with hot flashes

    PubMed Central

    Huang, Wan-Yu; Chang, Chia-Chu; Chen, Dar-Ren; Kor, Chew-Teng; Chen, Ting-Yu; Wu, Hung-Ming

    2017-01-01

    Introduction Hot flashes have been postulated to be linked to the development of metabolic disorders. This study aimed to evaluate the relationship between hot flashes, adipocyte-derived hormones, and insulin resistance in healthy, non-obese postmenopausal women. Participants and design In this cross-sectional study, a total of 151 women aged 45–60 years were stratified into one of three groups according to hot-flash status over the past three months: never experienced hot flashes (Group N), mild-to-moderate hot flashes (Group M), and severe hot flashes (Group S). Variables measured in this study included clinical parameters, hot flash experience, fasting levels of circulating glucose, lipid profiles, plasma insulin, and adipocyte-derived hormones. Multiple linear regression analysis was used to evaluate the associations of hot flashes with adipocyte-derived hormones, and with insulin resistance. Settings The study was performed in a hospital medical center. Results The mean (standard deviation) of body-mass index was 22.8(2.7) for Group N, 22.6(2.6) for Group M, and 23.5(2.4) for Group S, respectively. Women in Group S displayed statistically significantly higher levels of leptin, fasting glucose, and insulin, and lower levels of adiponectin than those in Groups M and N. Multivariate linear regression analysis revealed that hot-flash severity was significantly associated with higher leptin levels, lower adiponectin levels, and higher leptin-to-adiponectin ratio. Univariate linear regression analysis revealed that hot-flash severity was strongly associated with a higher HOMA-IR index (% difference, 58.03%; 95% confidence interval, 31.00–90.64; p < 0.001). The association between hot flashes and HOMA-IR index was attenuated after adjusting for leptin or adiponectin and was no longer significant after simultaneously adjusting for leptin and adiponectin. Conclusion The present study provides evidence that hot flashes are associated with insulin resistance in

  12. Beneficial role of tamoxifen in isoproterenol-induced myocardial infarction.

    PubMed

    Rayabarapu, Nihar; Patel, Bhoomika M

    2014-10-01

    ER-α and ER-β agonist 17β-estradiol is reported to attenuate cardiac hypertrophy. Tamoxifen is a selective estrogen receptor modulator. Hence, the objective of this study was to investigate the effects of tamoxifen in myocardial infarction. For this, tamoxifen was administered to Sprague-Dawley rats for 1-14 days, and isoproterenol (ISO) (100 mg·(kg body mass)(-1)·day(-1)) was administered subcutaneously on the 13th and 14th days of the study in order to induce myocardial infarction, after which, various biochemical, cardiac, and morphometric parameters were evaluated. ISO produced significant dyslipidemia, hypertension, bradycardia, oxidative stress, and an increase in serum cardiac markers. Treatment with tamoxifen significantly controlled dyslipidemia, hypertension, bradycardia, oxidative stress, and reduced serum cardiac markers. The ISO control rats exhibited significant increases in the infarct size of the left ventricle (LV), LV cavity area, cardiac and LV hypertrophic indices, LV-wall thickness, cardiomyocyte diameter, and area. Treatment with tamoxifen significantly reduced infarction as well as hypertrophic and morphometric parameters. ISO also produced significant increases in the LV collagen level, decreases in Na(+)K(+) ATPase activity, and a reduction in the rate of pressure development and decay, which were prevented by tamoxifen treatment. The protective effect of tamoxifen on myocardial infarct was further confirmed by histopathological examination. Our data thus suggest that tamoxifen exerts beneficial effects in ISO-induced myocardial infarction.

  13. Biochemical markers for cardiovascular disease in recently postmenopausal women with or without hot flashes.

    PubMed

    Tuomikoski, Pauliina; Mikkola, Tomi S; Hämäläinen, Esa; Tikkanen, Matti J; Turpeinen, Ursula; Ylikorkala, Olavi

    2010-01-01

    Menopausal hot flashes may affect vascular function and perhaps explain conflicting data on cardiovascular disease (CVD) between observational and randomized hormone therapy (HT) studies. We prospectively assessed hot flash status in recently postmenopausal women and related it to a number of biochemical vascular surrogate markers for CVD. Healthy, nonsmoking women (n = 150) exhibiting a broad range (no, mild, moderate, severe) of hot flashes and an onset of menopause within the previous 0.5 to 3 years were studied with laboratory tests for lipids, lipoproteins, apolipoproteins, high-sensitivity C-reactive protein, and sex hormone-binding globulin. Apart from marked differences in hot flashes, the groups showed comparable levels of estrone, estradiol, or free estradiol index. The levels of total cholesterol (3.7-9.1 mmol/L) were similar between the groups (P = 0.744), and hypercholesterolemia (>6.5 mmol/L) was encountered equally often (P = 0.699). No difference was seen in high-, low-, or very low-density lipoproteins, triglycerides, apolipoprotein A-1, apolipoprotein B (or their ratio), or lipoprotein(a) between the groups. The levels of sex hormone-binding globulin and high-sensitivity C-reactive protein correlated negatively with each other (r = -0.204; P = 0.013) but showed no dependence on hot flashes (P = 0.531 and P = 0.215, respectively). No baseline difference in lipid or nonlipid CVD risk factors was observed between women with hot flashes (potential HT users) and women with no or mild hot flashes (potential HT nonusers). This may imply that hot flash status per se cannot explain the difference between observational and randomized trials.

  14. 2. SECTIONAL BOILER '#4 IDEAL RED FLASH.' Hot Springs ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    2. SECTIONAL BOILER '#4 IDEAL RED FLASH.' - Hot Springs National Park, Bathhouse Row, Ozark Bathhouse: Mechanical & Piping Systems, State Highway 7, 1 mile north of U.S. Highway 70, Hot Springs, Garland County, AR

  15. The Association between Body Mass Index and Hot Flash in Midlife Women: A Meta-analysis.

    PubMed

    Shobeiri, Fatemeh; Jenabi, Ensiyeh; Poorolajal, Jalal; Hazavehei, Seyyed Mohammad Mahdi

    2016-04-01

    The association between body mass index (BMI) and hot flash risk has not been specifically clarifies yet. This meta-analysis was, therefore, conducted to estimate the association between overweight and obesity and hot flash risk. We searched PubMed, Web of Science, and Scopus for observational studies addressing the association between BMI and hot flash until August 2015. Data were independently extracted and analyzed using 95% odds ratio (OR), and confidence intervals (CI) based on the random-effects models. We identified 2,244 references and conducted seven studies with 4,219 participants. The association between hot flash and overweight was estimated 1.13 (95% CI: 0.97-1.32) and that of obesity was estimated 1.79 (95% CI: 1.52-2.11). No evidence of heterogeneity and publication bias was observed. This meta-analysis demonstrated that, though not to a great extent, obesity does increase the risk of hot flash. The findings from this meta-analysis indicated that obesity is associated with an increased risk of hot flash. Further large prospective cohort studies are required to provide convincing evidence as to whether or not BMI is associated with an increased risk of hot flashes.

  16. Omega-3 free fatty acids inhibit tamoxifen-induced cell apoptosis.

    PubMed

    Wu, Shufan; Guo, Yang; Wu, Yikuan; Zhu, Shenglong; He, Zhao; Chen, Yong Q

    2015-04-03

    Fish oil, which contains omega-3 fatty acids mainly in the form of triglycerides, has benefits for reducing breast cancer risk, similar to tamoxifen action. However, it remains to be elucidated whether the combination of omega-3 free fatty acid (ω-3FFA) with tamoxifen leads to improved treatment in breast cancer. In this study, we observed that ω-3FFA induces MCF-7 cell apoptosis to suppress cell growth. The treatment of breast cancer cells with ω-3FFA attenuated tamoxifen-induced cell apoptosis. ω-3FFA and tamoxifen significantly increased Erk1/2 and Akt phosphorylation levels in a dose and time dependent manner. Compared to ω-3FFA alone, the combination of tamoxifen with ω-3FFA significantly increased Erk1/2 and Akt phosphorylation levels. Because Erk1/2 and Akt activation has been linked to tamoxifen-related anti-estrogen resistance in breast cancer patients, these results indicate that ω-3FFA may interfere with the effects of tamoxifen in the prevention of breast cancer risk. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Hypnosis for Hot Flashes and Associated Symptomsin Women with Breast Cancer.

    PubMed

    Roberts, R Lynae; Na, Hyeji; Yek, Ming Hwei; Elkins, Gary

    2017-10-01

    Women with breast cancer experience a host of physical and psychological symptoms, including hot flashes, sleep difficulties, anxiety, and depression. Therefore, treatment for women with breast cancer should target these symptoms and be individualized to patients' specific presentations. The current article reviews the common symptoms associated with breast cancer in women, then examines clinical hypnosis as a treatment for addressing these symptoms and improving the quality of life of women with breast cancer. Clinical hypnosis is an effective, nonpharmaceutical treatment for hot flashes and addressing many symptoms typically experienced by breast cancer patients. A case example is provided to illustrate the use of clinical hypnosis for the treatment of hot flashes with a patient with breast cancer.

  18. ANXIETY AS A RISK FACTOR FOR MENOPAUSAL HOT FLASHES: EVIDENCE FROM THE PENN OVARIAN AGING COHORT

    PubMed Central

    Freeman, Ellen W.; Sammel, Mary D.

    2016-01-01

    Objective The aim of this study was to identify temporal associations of anxiety dimensions with menopausal hot flashes in women progressing through the menopause transition. We hypothesized that associations of both somatic and affective dimensions of anxiety with hot flashes increased in the menopause transition, and that somatic anxiety was an independent risk factor for menopausal hot flashes. Methods Hot flashes, anxiety symptoms, hormone levels and other psychosocial variables were assessed annually for 14 years of follow-up. The 233 women were premenopausal at baseline and continued through one year or more after the final menstrual period. Anxiety dimensions were assessed with the Zung Anxiety Scale (ZAS), a validated measure of affective anxiety and somatic anxiety. Summed item scores were divided by the number of items rated, so that ranges of the two dimensions were comparable. Results Seventy-two percent of the sample reported moderate/severe hot flashes during the 14-year interval. There was no significant interaction between anxiety dimensions and menopausal stages. However, when adjusted for menopausal stage, the magnitude of association between somatic anxiety and hot flashes dramatically increased (OR 3.03, 95% CI: 2.12, 4.32, P<0.001), while the association between affective anxiety and hot flashes increased to a lesser extent (OR 1.27, 95% CI: 1.03, 1.57, P=0.024). Women with high levels of somatic anxiety (top third of the sample) had the greatest risk of hot flashes (P<0.001). When the anxiety dimensions were considered in combination, the additive effect of high affective anxiety symptoms was minimal, with no significant difference between the group with high affective/low somatic symptoms and the low symptom group in incident hot flashes at each menopausal stage (P=0.54). In multivariable analysis, somatic anxiety increased the risk of hot flashes more than 3 times (OR 3.13, 95% CI: 2.16, 4.53, P<0.001), but affective anxiety was not

  19. The efficacy of Iranian herbal medicines in alleviating hot flashes: A systematic review

    PubMed Central

    Ghazanfarpour, Masumeh; Sadeghi, Ramin; Abdolahian, Somayeh; Latifnejad Roudsari, Robab

    2016-01-01

    Background: Hot flashes are the most common symptoms experienced by women around the time of menopause. Many women are interested in herbal medicines because of fear of side effects of hormone therapy. Objective: The aim of this systematic review was to assess the effectiveness of Iranian herbal medicines in alleviating hot flashes. Materials and Methods: MEDLINE (1966 to January 2015), Scopus (1996 to January 2015), and Cochrane Central Register of Controlled Trials (The Cochrane Library, issue 1, 2015) were searched along with, SID, Iran Medex, Magiran, Medlib and Irandoc. Nineteen randomized controlled trials met the inclusion criteria. Results: Overall, studies showed that Anise (Pimpinella anisum), licorice (Glycyrrhizaglabra), Soy, Black cohosh, Red clover, Evening primrose, Flaxseed, Salvia officinalis, Passiflora، itex Agnus Castus, Piascledine (Avacado plus soybean oil), St. John's wort (Hypericum perforatum), and valerian can alleviate the side effects of hot flashes. Conclusion: This research demonstrated the efficacy of herbal medicines in alleviating hot flashes, which are embraced both with people and health providers of Iran Therefore, herbal medicine can be seen as an alternative treatment for women experiencing hot flashes. PMID:27294213

  20. Risk of long-term hot flashes after natural menopause: evidence from the Penn Ovarian Aging Study cohort.

    PubMed

    Freeman, Ellen W; Sammel, Mary D; Sanders, Richard J

    2014-09-01

    This study aims to estimate the risk of hot flashes relative to natural menopause and to evaluate the associations of hormone levels, behavioral variables, and demographic variables with the risk of hot flashes after menopause. We performed annual assessment of 255 women who were premenopausal at baseline and reached natural menopause within 16 years of follow-up. The prevalence of moderate/severe hot flashes increased in each premenopausal year, reaching a peak of 46% in the first 2 years after the final menstrual period (FMP). Hot flashes decreased slowly after menopause and did not return to premenopausal levels until 9 years after the FMP. The mean (SD) duration of moderate/severe hot flashes after the FMP was 4.6 (2.9) years (for any hot flashes, 4.9 [3.1] y). One third of women at 10 years or more after menopause continued to experience moderate/severe hot flashes. African-American women (obese and nonobese) and obese white women had significantly greater risks of hot flashes compared with nonobese white women (interaction, P = 0.01). In multivariable analysis, increasing follicle-stimulating hormone levels before the FMP (P < 0.001), decreasing estradiol (odds ratio, 0.87; 95% CI, 0.78-0.96; P = 0.008), and increasing anxiety (odds ratio, 1.05; 95% CI, 1.03-1.06; P < 0.001) were significant risk factors for hot flashes, whereas higher education levels were protective (odds ratio, 0.66; 95% CI, 0.47-0.91; P = 0.011). Moderate/severe hot flashes continue, on average, for nearly 5 years after menopause; more than one third of women observed for 10 years or more after menopause have moderate/severe hot flashes. Continuation of hot flashes for more than 5 years after menopause underscores the importance of determining individual risks/benefits when selecting hormone or nonhormone therapy for menopausal symptoms.

  1. The Role of Serotonin in Hot Flashes after Breast Cancer

    DTIC Science & Technology

    2009-03-01

    physiological mechanisms involved in hot flashes c.fter breast cancer will enable us to develop more targeted behavioral and/or pharmacological therapi ...s to be used in lieu of, or in addition to, currently available therapies so that we can eradicate hot flashes and improve the quality of life for...flavorings were most palatable - chocolate mint and orange. We rejected a lemon flavoring as being unpalatable. We eliminated the mid-day snack per

  2. Daidzein-rich isoflavone aglycones are potentially effective in reducing hot flashes in menopausal women.

    PubMed

    Khaodhiar, Lalita; Ricciotti, Hope A; Li, Linglin; Pan, Weijun; Schickel, Mary; Zhou, Jinrong; Blackburn, George L

    2008-01-01

    The aim of this study was to determine the effect of DRIs on hot flash symptoms in menopausal women. This was a randomized, double-blind, placebo-controlled trial of menopausal women, aged 38 to 60 years, who experienced 4 to 14 hot flashes per day. After a 1-week run-in period, a total of 190 menopausal women were randomized to receive a placebo or 40 or 60 mg/day of a DRI for 12 weeks. The primary outcome was the mean changes from baseline to week 12 in the frequency of hot flashes recorded in the participant diary. The secondary outcomes included changes in quality of life and hormonal profiles. A total of 147 women (77%) completed the study. It was found that 40 and 60 mg of DRI improved hot flash frequency and severity equally. At 8 weeks hot flash frequency was reduced by 43% in the 40-mg DRI group and by 41% in the 60-mg DRI group, compared with 32% in the placebo group (P = not significant vs placebo). The corresponding numbers for 12 weeks were 52%, 51%, and 39%, respectively (P = 0.07 and 0.09 vs placebo). When comparing the two treatment groups with the placebo group, there were significant reductions in mean daily hot flash frequency. The supplement (either 40 or 60 mg) reduced hot flash frequency by 43% at 8 weeks (P = 0.1) and 52% at 12 weeks (P = 0.048) but did not cause any significant changes in endogenous sex hormones or thyroid hormones. Menopausal quality of life improved in all three groups, although there were no statistically significant differences between groups. DRI supplementation may be an effective and acceptable alternative to hormone treatment for menopausal hot flashes.

  3. Diurnal rhythm and concordance between objective and subjective hot flashes: the Hilo Women's Health Study.

    PubMed

    Sievert, Lynnette L; Reza, Angela; Mills, Phoebe; Morrison, Lynn; Rahberg, Nichole; Goodloe, Amber; Sutherland, Michael; Brown, Daniel E

    2010-01-01

    The aims of this study were to test for a diurnal pattern in hot flashes in a multiethnic population living in a hot, humid environment and to examine the rates of concordance between objective and subjective measures of hot flashes using ambulatory and laboratory measures. Study participants aged 45 to 55 years were recruited from the general population of Hilo, HI. Women wore a Biolog hot flash monitor (UFI, Morro Bay, CA), kept a diary for 24 hours, and also participated in 3-hour laboratory measures (n = 199). Diurnal patterns were assessed using polynomial regression. For each woman, objectively recorded hot flashes that matched subjective experience were treated as true-positive readings. Subjective hot flashes were considered the standard for computing false-positive and false-negative readings. True-positive, false-positive, and false-negative readings were compared across ethnic groups by chi analyses. Frequencies of sternal, nuchal, and subjective hot flashes peaked at 1500 +/- 1 hours with no difference by ethnicity. Laboratory results supported the pattern seen in ambulatory monitoring. Sternal and nuchal monitoring showed the same frequency of true-positive measures, but nonsternal electrodes picked up more false-positive readings. Laboratory monitoring showed very low frequencies of false negatives. There were no ethnic differences in the frequency of true-positive or false-positive measures. Women of European descent were more likely to report hot flashes that were not objectively demonstrated (false-negative measures). The diurnal pattern and peak in hot flash occurrence in the hot humid environment of Hilo were similar to results from more temperate environments. Lack of variation in sternal versus nonsternal measures and in true-positive measures across ethnicities suggests no appreciable effect of population variation in sweating patterns.

  4. Hot Flashes and Panic Attacks: A Comparison of Symptomatology, Neurobiology, Treatment, and a Role for Cognition

    ERIC Educational Resources Information Center

    Hanisch, Laura J.; Hantsoo, Liisa; Freeman, Ellen W.; Sullivan, Gregory M.; Coyne, James C.

    2008-01-01

    Despite decades of research, the causal mechanisms of hot flashes are not adequately understood, and a biopsychosocial perspective on hot flashes remains underdeveloped. This article explores overlooked parallels between hot flashes and panic attacks within 5 areas: course and symptomatology, physiological indicators, neurocircuitry and…

  5. Current alcohol use is associated with a reduced risk of hot flashes in midlife women.

    PubMed

    Schilling, Chrissy; Gallicchio, Lisa; Miller, Susan R; Babus, Janice K; Lewis, Lynn M; Zacur, Howard; Flaws, Jodi A

    2005-01-01

    To examine the relation between current alcohol use, estradiol, estrone, and testosterone levels, and hot flashes in midlife women using a case-control study design. Cases were midlife women (45-54 years) who reported ever experiencing hot flashes. Controls were midlife women (45-54 years) who reported never experiencing hot flashes. Each participant completed a questionnaire and provided a blood sample that was used to measure estradiol, estrone, and testosterone levels by enzyme-linked immunosorbent assay. The results indicate that current alcohol use (at least one day per month) was significantly associated with a reduced risk of hot flashes compared to non-use of alcohol, independent of age and smoking habits. The hot flashes experienced by current alcohol users were less severe and less frequent than those experienced by non-users of alcohol. Further, current alcohol users had similar levels of estradiol, estrone, and testosterone compared to non-users of alcohol. These data suggest that current alcohol use is associated with a reduced risk of any, severe, and frequent hot flashes in midlife women by a mechanism that may not include changes in sex steroid hormone levels.

  6. Association between polycystic ovary syndrome and hot flash presentation during the midlife period.

    PubMed

    Yin, Ophelia; Zacur, Howard A; Flaws, Jodi A; Christianson, Mindy S

    2018-06-01

    Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in reproductive-aged women; however, the impact of PCOS on menopausal symptoms remains poorly understood. This study aims to determine the influence of PCOS on hot flash presentation in midlife women. Participants were recruited from the Midlife Women's Health Study involving 780 women aged 45 to 54 years. All women completed detailed questionnaires on hot flash symptoms. Between June 2014 and March 2015, participants were screened for history of PCOS based on the Rotterdam criteria. Fisher's exact tests and Wilcoxon rank-sum tests were used for analysis. Multivariate logistic regression was performed to identify factors associated with hot flashes at midlife. In all, 453 women (69%) consented to the telephone interview and 9.3% (n = 42) met diagnostic criteria for PCOS; 411 were included as controls. Mean age was 48.0 and body mass index was 27.3 for women with PCOS. The majority of participants were white (72%). There was no difference between PCOS and control women for levels of follicle-stimulating hormone, testosterone, progesterone, or estradiol. Multivariate logistic regression demonstrated that PCOS was not associated with increased odds of hot flash incidence. Smoking was the only variable associated with experiencing hot flashes (odds ratio 2.0, 95% confidence interval 1.05-3.98). A history of PCOS was not associated with increased hot flash symptoms during the midlife period. Additional research should continue to investigate the health and quality of life associated with a history of PCOS in the aging population.

  7. An investigation of life circumstances associated with the experience of hot flashes in Campeche, Mexico.

    PubMed

    Huicochea-Gómez, Laura; Sievert, Lynnette Leidy; Cahuich-Campos, Diana; Brown, Daniel E

    2017-01-01

    The purpose of this study was to better understand the experience of calores (hot flashes) in the state of Campeche, Mexico, and characteristics of women's lives. This study was carried out to understand the sociocultural context of women's lives before conducting a larger semistructured survey in the same communities. Eighty-five women from rural and urban settings participated in open-ended interviews about the menopausal transition, with particular attention to hot flashes. Univariate and logistic regression analyses identified potential determinants of hot flashes. Qualitative responses were analyzed for central themes from the 40 women who experienced "calores" associated with menopause at the time of interview. The word "calores" was used to describe a variety of sensations and experiences related to the hot climate, infections, going in and out of air-conditioning, emotional stress, and physical exertion, as well as the symptom associated with menopause. In quantitative analyses, the likelihood of experiencing hot flashes varied by menopause status and rural/urban residence. In qualitative analyses, themes that characterized the lives of women with hot flashes were as follows: the search for, and the availability of, biomedical care; presence or absence of networks of social support; marital status and quality of the relationship; and occupational stress. Hot flash questionnaires can elicit different symptom frequencies depending on the language used and the sociocultural context of women's lives. Qualitative findings suggest that the themes most likely to influence the perception and experience of hot flashes in Campeche are biomedicine, social support, marriage, and stress.

  8. Nocturnal Hot Flashes: Relationship to Objective Awakenings and Sleep Stage Transitions

    PubMed Central

    Bianchi, Matt T.; Kim, Semmie; Galvan, Thania; White, David P.; Joffe, Hadine

    2016-01-01

    Study Objectives: While women report sleep interruption secondary to nighttime hot flashes, the sleep disrupting impact of nocturnal hot flashes (HF) is not well characterized. We utilized a model of induced HF to investigate the relationship of nighttime HF to sleep architecture and sleep-stage transitions. Methods: Twenty-eight healthy, premenopausal volunteers received the depot gonadotropin-releasing hormone agonist (GnRHa) leuprolide to rapidly induce menopause, manifesting with HF. Sleep disruption was measured on 2 polysomnograms conducted before and after 4–5 weeks on leuprolide, when HF had developed. Results: 165 HF episodes were recorded objectively during 48 sleep studies (mean 3.4 HF/night). After standardizing to sleep-stage time distribution, the majority of HF were recorded during wake (51.0%) and stage N1 (18.8%). Sixty-six percent of HF occurred within 5 minutes of an awakening, with 80% occurring just before or during the awakening. Objective HF were not associated with sleep disruption as measured by increased transitions to wake or N1, but self-reported nocturnal HF correlated with an increase from pre- to post-leuprolide in the rate of transitions to wake (p = 0.01), and to N1 (p = 0.008). Conclusions: By isolating the effect of HF on sleep in women without the confound of age-related sleep changes associated with natural menopause, this experimental model shows that HF arise most commonly during N1 and wake, typically preceding or occurring simultaneously with wake episodes. Perception of HF, but not objective HF, is linked to increased sleep-stage transitions, suggesting that sleep disruption increases awareness of and memory for nighttime HF events. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT01116401. Citation: Bianchi MT, Kim S, Galvan T, White DP, Joffe H. Nocturnal hot flashes: relationship to objective awakenings and sleep stage transitions. J Clin Sleep Med 2016;12(7):1003–1009. PMID:26951410

  9. A Novel Animal Model to Study Hot Flashes: No Effect of GnRH

    PubMed Central

    Albertson, Asher J.; Skinner, Donal C.

    2009-01-01

    Menopausal hot flushes compromise the quality of life for the majority of women. The physiological mechanisms underlying hot flushes remain poorly understood and the absence of an animal model to investigate hot flushes hinders investigations in this field. We have developed the sheep as a model to study peripheral skin temperature changes. Subjecting sheep to fever-inducing treatments with lipopolysaccharide, a significant (P<0.01) change in ear skin temperature was observed. As a strong correlation between luteinizing hormone pulses and hot flushes has previously been reported, we then determined whether intravenous gonadotropin-releasing hormone (GnRH), at doses sufficient to elevate CSF GnRH concentrations, could modulate ear skin temperature. No effect was observed, suggesting that GnRH per se dose not play a role in the etiology of hot flashes. PMID:19512948

  10. Diurnal rhythm and concordance between objective and subjective hot flashes: The Hilo Women’s Health Study

    PubMed Central

    Sievert, Lynnette L.; Reza, Angela; Mills, Phoebe; Morrison, Lynn; Rahberg, Nichole; Goodloe, Amber; Sutherland, Michael; Brown, Daniel E.

    2010-01-01

    Objective To test for a diurnal pattern in hot flashes in a multi-ethnic population living in a hot, humid environment. To examine rates of concordance between objective and subjective measures of hot flashes using ambulatory and laboratory measures. Methods Study participants aged 45–55 were recruited from the general population of Hilo, Hawaii. Women wore a Biolog hot flash monitor, kept a diary for 24-hours, and also participated in 3-hour laboratory measures (n=199). Diurnal patterns were assessed using polynomial regression. For each woman, objectively recorded hot flashes that matched subjective experience were treated as true positive readings. Subjective hot flashes were considered the standard for computing false positive and false negative readings. True positive, false positive, and false negative readings were compared across ethnic groups by chi-square analyses. Results Frequencies of sternal, nuchal and subjective hot flashes peaked at 15:00 ± 1 hour with no difference by ethnicity. Laboratory results supported the pattern seen in ambulatory monitoring. Sternal and nuchal monitoring showed the same frequency of true positive measures, but non-sternal electrodes picked up more false positive readings. Laboratory monitoring showed very low frequencies of false negatives. There were no ethnic differences in the frequency of true positive or false positive measures. Women of European descent were more likely to report hot flashes that were not objectively demonstrated (false negative measures). Conclusions The diurnal pattern and peak in hot flash occurrence in the hot humid environment of Hilo was similar to results from more temperate environments. Lack of variation in sternal vs. non-sternal measures, and in true positive measures across ethnicities suggests no appreciable effect of population variation in sweating patterns. PMID:20220538

  11. CSC-3436 switched tamoxifen-induced autophagy to apoptosis through the inhibition of AMPK/mTOR pathway.

    PubMed

    Wu, Sheng-Tang; Sun, Guang-Huan; Cha, Tai-Lung; Kao, Chien-Chang; Chang, Sun-Yran; Kuo, Sheng-Chu; Way, Tzong-Der

    2016-08-15

    Triple-negative breast cancer (TNBC) lacks specific therapeutic target and limits to chemotherapy and is essential to develop novel therapeutic regimens. Increasing studies indicated that tamoxifen, a selective estrogen receptor modulators (SERMs), has anti-tumor therapeutic effect in estrogen receptor α (ERα)-negative tumor. Here, we determined whether autophagy was activated by tamoxifen in TNBC cells. Moreover, CSC-3436 displayed strong and selective growth inhibition on cancer cells. Next, we investigated the anti-proliferation effect of combination of CSC-3436 plus tamoxifen on cell death in TNBC cells. Our study found that tamoxifen induces autophagy in TNBC cells. Endoplasmic reticulum stress and AMPK/mTOR contributed tamoxifen-induced autophagy. Interestingly, in combination treatment with CSC-3436 enhanced the anti-proliferative effect of tamoxifen. We found that CSC-3436 switched tamoxifen-induced autophagy to apoptosis via cleavage of ATG-5. Moreover, AMPK/mTOR pathway may involve in CSC-3436 switched tamoxifen-induced autophagy to apoptosis. The combination of tamoxifen and CSC-3436 produced stronger tumor growth inhibition compared with CSC-3436 or tamoxifen alone treatments in vivo. These data indicated that CSC-3436 combined with tamoxifen may be a potential approach for treatment TNBC.

  12. A comparative study on the effect of "black cohosh" and "evening primrose oil" on menopausal hot flashes.

    PubMed

    Mehrpooya, Maryam; Rabiee, Soghra; Larki-Harchegani, Amir; Fallahian, Amir-Mohammad; Moradi, Abbas; Ataei, Sara; Javad, Masoumeh Taravati

    2018-01-01

    Hot flashes are considered to be a common experience for menopausal women and they can compromise the quality of life. The objective of this study is to assess the efficacy of Cimicifuga racemosa in comparison with evening primrose oil (EPO) in postmenopausal women with menopause-related symptoms. This study was performed on 80 postmenopausal women with hot flashes. The participants were randomly divided into two groups by blocked randomization. The participants of one group received black cohosh and the other group received EPO for 8 weeks. The severity and number of hot flashes and quality of life were measured by four-point scale, and the Menopause-Specific Quality of Life (MENQOL) questionnaire at pre-intervention, 1 st , 4 th , and 8 th weeks after treatment. Data were analyzed in SPSS Version 16 using independent t -test, Chi-square, and Fisher's exact test. Average severity of hot flashes in both groups and number of hot flashes in black cohosh group in 8 th week were significantly lower than 1 st week ( P < 0.001), but number of hot flashes in primrose oil group in 8 th week showed no significant differences ( P = 0.32). The number of hot flashes and quality of life score in black cohosh arm compared to EPO showed a significant decrease in the 8 th week ( P < 0.05). All MENQOL scores were significantly improved in two groups ( P < 0.05), but the percentage of improvement in black cohosh arm was significantly superior to EPO group. Both herbs were effective in reduction of severity of hot flashes and improvement of the quality of life, but it seems that black cohosh is more effective than primrose oil because it was able to reduce the number of hot flashes too.

  13. Red clover for treatment of hot flashes and menopausal symptoms: A systematic review and meta-analysis.

    PubMed

    Ghazanfarpour, M; Sadeghi, R; Roudsari, R Latifnejad; Khorsand, I; Khadivzadeh, T; Muoio, B

    2016-01-01

    This study evaluated the efficacy of red clover to relieve hot flashes and menopausal symptoms in peri/postmenopausal women. Electronic databases (MEDLINE, Scopus and the Cochrane Library) were searched. The mean frequency of hot flashes in red clover groups was lower compared with that in the control groups (close to statistical significance). Difference in means (MD) of hot flashes frequency was - 1.99 (- 4.12-0.139; p = 0.067; heterogeneity P > 0.01; I(2) = 94.93%; Random effect model). Subjective (vaginal dryness) and objective (maturation value) symptoms of vaginal atrophy showed a significant improvement with 80-mg dose of red clover. Red clover showed less therapeutic effect on psychology status, sexual problems and sleeping disorders. Red clover consumption may decrease frequency of hot flashes, especially in women with severe hot flashes (≥ 5 per day). Red clover may reduce other menopausal symptoms. Further trials are needed to confirm the current systematic review findings.

  14. Hypnotherapy to Reduce Hot Flashes: Examination of Response Expectancies as a Mediator of Outcomes

    PubMed Central

    Sliwinski, Jim R.; Elkins, Gary R.

    2017-01-01

    The mechanism of action responsible for hypnotherapy’s effect in reducing hot flashes is not yet known. The purpose of this study was to examine the role of response expectancies as a potential mediator. Hypnotizability was also tested as an effect moderator. Data were collected from a sample of 172 postmenopausal women, who had been randomized to receive either a 5-week hypnosis intervention or structured attention counseling. Measures of response expectancies were analyzed to determine if the relationship between group assignment and hot flashes frequency was mediated by expectancies for treatment efficacy. A series of simple mediation and conditional process analyses did not support mediation of the relationship between treatment condition and hot flash frequency through response expectancy. The effect of hypnotherapy in reducing hot flashes does not appear to be due to placebo effects as determined by response expectancies. Implications for clinical practice and future research are discussed. PMID:28528570

  15. Hypnosis for hot flashes among postmenopausal women study: A study protocol of an ongoing randomized clinical trial

    PubMed Central

    2011-01-01

    Background Hot flashes are a highly prevalent problem associated with menopause and breast cancer treatments. The recent findings from the Women's Health Initiative have important implications for the significance of a non-hormonal, mind-body intervention for hot flashes in breast cancer survivors. Women who take hormone therapy long-term may have a 1.2 to 2.0 fold increased risk of developing breast cancer. In addition, it is now known that hormone therapy with estrogen and progestin is associated with increased risk of cardiovascular disease and stroke. Currently there are limited options to hormone replacement therapy as non-hormonal pharmacological agents are associated with only modest activity and many adverse side effects. Because of this there is a need for more alternative, non-hormonal therapies. Hypnosis is a mind-body intervention that has been shown to reduce self-reported hot flashes by up to 68% among breast cancer survivors, however, the use of hypnosis for hot flashes among post-menopausal women has not been adequately explored and the efficacy of hypnosis in reducing physiologically measured hot flashes has not yet been determined. Methods/design A sample of 180 post-menopausal women will be randomly assigned to either a 5-session Hypnosis Intervention or 5-session structured-attention control with 12 week follow-up. The present study will compare hypnosis to a structured-attention control in reducing hot flashes (perceived and physiologically monitored) in post-menopausal women in a randomized clinical trial. Outcomes will be hot flashes (self-report daily diaries; physiological monitoring; Hot Flash Related Daily Interference Scale), anxiety (State-Trait Anxiety Inventory; Hospital Anxiety and Depression Scale (HADS); anxiety visual analog scale (VAS rating); depression (Center for Epidemiologic Studies Depression Scale), sexual functioning (Sexual Activity Questionnaire), sleep quality (Pittsburgh Sleep Quality Index) and cortisol. Discussion

  16. Risk factors for hot flashes among women undergoing the menopausal transition: baseline results from the Midlife Women's Health Study

    PubMed Central

    Gallicchio, Lisa; Miller, Susan R.; Kiefer, Judith; Greene, Teresa; Zacur, Howard A.; Flaws, Jodi A.

    2015-01-01

    Objective The aim of this study was to examine the associations between demographic characteristics, health behaviors, hormone concentrations, and the experiencing of any, current, more severe, and more frequent midlife hot flashes. Methods Baseline data were analyzed from 732 women aged 45 to 54 years enrolled in the Midlife Women's Health Study. A clinic visit was conducted to collect blood samples for hormone assays and to measure ovarian volume using transvaginal ultrasound. A self-administered questionnaire ascertained information on demographic factors, health habits, and hot flashes history. Multivariable logistic regression was conducted to examine the associations between potential risk factors and the hot flashes outcomes. Results Approximately 45% of participants reported experiencing midlife hot flashes. In the covariate-adjusted models, older age, peri-menopausal status, current and former cigarette smoking, and depressive symptoms were significantly associated with increased odds of all of the hot flashes outcomes. In addition, history of oral contraceptive use was associated with increased odds of any hot flashes. In contrast, higher current alcohol intake was significantly associated with decreased odds of any, current, and more severe hot flashes. Higher estradiol and progesterone concentrations were significantly associated with decreased odds of all hot flashes outcomes. Conclusions Although the temporalities of such associations are not known due to the cross-sectional nature of the data, these observed relationships can help to identify women at risk for hot flashes. PMID:25783472

  17. Tamoxifen protects male mice nigrostriatal dopamine against methamphetamine-induced toxicity.

    PubMed

    Bourque, Mélanie; Liu, Bin; Dluzen, Dean E; Di Paolo, Thérèse

    2007-11-01

    The selective estrogen receptor modulator tamoxifen and estradiol were shown to protect nigrostriatal dopamine concentration loss by methamphetamine in female mice whereas male mice were protected only by tamoxifen. The present study examined the protective properties of tamoxifen in male mice on several nigrostriatal dopaminergic markers and body temperature. Intact male mice were administered 12.5 or 50 microg tamoxifen 24 h before methamphetamine treatment. Basal body temperatures of male mice remained unchanged by the tamoxifen treatment. Methamphetamine reduced striatal dopamine and its metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid concentrations, striatal and substantia nigra dopamine and vesicular monoamine transporter specific binding as well substantia nigra dopamine and vesicular monoamine transporter mRNA levels and increased striatal preproenkephalin mRNA levels. These methamphetamine effects were not altered by 12.5 microg tamoxifen except for increased striatal dopamine metabolites and turnover. Tamoxifen at 50 microg reduced the methamphetamine effect on striatal dopamine concentration, dopamine transporter specific binding and prevented the increase in preproenkephalin mRNA levels; in the substantia nigra tamoxifen prevented the decrease of dopamine transporter mRNA levels. The present results show a tamoxifen dose-dependent prevention of loss of various dopaminergic markers against methamphetamine-induced toxicity in male mice. Since this is the only known hormonal protection of male mice against methamphetamine toxicity, these findings provide important new information on specific parameters of nigrostriatal dopaminergic function preserved by tamoxifen.

  18. Gabapentin for hot flashes in 420 women with breast cancer: a randomised double-blind placebo-controlled trial

    PubMed Central

    Pandya, K J; Morrow, G R; Roscoe, J A; Hickok, J T; Zhao, H; Pajon, E; Sweeney, T J; Banerjee, T K; Flynn, P J

    2005-01-01

    Summary Background Most women receiving systemic therapy for breast cancer experience hot flashes. We undertook a randomised, double-blind, placebo-controlled, multi-institutional trial to assess the efficacy of gabapentin in controlling hot flashes in women with breast cancer. Methods 420 women with breast cancer who were having two or more hot flashes per day were randomly assigned placebo, gabapentin 300 mg/day, or gabapentin 900 mg/day by mouth in three divided doses for 8 weeks. Each patient kept a 1-week, self-report diary on the frequency, severity, and duration of hot flashes before the start of the study and during weeks 4 and 8 of treatment. Analyses were by intention to treat. Findings Evaluable data were available on 371 participants at 4 weeks (119 placebo, 123 gabapentin 300 mg, and 129 gabapentin 900 mg) and 347 at 8 weeks (113 placebo, 114 gabapentin 300 mg, and 120 gabapentin 900 mg). The percentage decreases in hot-flash severity score between baseline and weeks 4 and 8, respectively were: 21% (95% CI 12 to 30) and 15% (1 to 29) in the placebo group; 33% (23 to 43) and 31% (16 to 46) in the group assigned gabapentin 300 mg; and 49% (42 to 56) and 46% (34 to 58) in the group assigned gabapentin 900 mg. The differences between the groups were significant (p=0.0001 at 4 weeks and p=0.007 at 8 weeks by ANCOVA for overall treatment effect, adjusted for baseline values); only the higher dose of gabapentin was associated with significant decreases in hot-flash frequency and severity. Interpretation Gabapentin is effective in the control of hot flashes at a dose of 900 mg/day, but not at a dose of 300 mg/day. This drug should be considered for treatment of hot flashes in women with breast cancer. PMID:16139656

  19. Beneficial role of tamoxifen in experimentally induced cardiac hypertrophy.

    PubMed

    Patel, Bhoomika M; Desai, Vishal J

    2014-04-01

    Protein kinase C (PKC) activation is associated with cardiac hypertrophy (CH), fibrosis, inflammation and cardiac dysfunction. Tamoxifen is a PKC inhibitor. Despite these, reports on effect of tamoxifen on cardiac hypertrophy are not available. Hence, we have investigated effect of tamoxifen (2mg/kg/day, po) on CH. In isoproterenol (ISO) induced CH, ISO (5mg/kg/day, ip) was administered for 10 days in Wistar rats. For partial abdominal aortic constriction (PAAC), abdominal aorta was ligated by 4-0 silk thread around 7.0mm diameter blunt needle. Then the needle was removed to leave the aorta partially constricted for 30 days. Tamoxifen was given for 10 days and 30 days, respectively, in ISO and PAAC models and at end of each studies, animals were sacrificed and biochemical and cardiac parameters were evaluated. ISO and PAAC produced significant dyslipidemia, hypertension, bradycardia, oxidative stress and increase in serum lactate dehydrogenase and creatine kinase-MB, C-reactive protein. Treatment with tamoxifen significantly controlled dyslipidemia, hypertension, bradycardia, oxidative stress and reduced serum cardiac markers. ISO control and PAAC control rats exhibited significantly increased cardiac and left ventricular (LV) hypertrophic index, LV thickness, cardiomyocyte diameter. Treatment with tamoxifen significantly reduced these hypertrophic indices. There was a significant increase in LV collagen level, decrease in Na(+)K(+)ATPase activity, and reduction in the rate of pressure development and decay. Tamoxifen significantly reduced LV collagen, increased Na(+)K(+)ATPase activity and improved hemodynamic function. This was further supported by histopathological studies, in which tamoxifen showed marked decrease in fibrosis and increase in extracellular spaces in the treated animals. Our data suggest that tamoxifen produces beneficial effects on cardiac hypertrophy and hence may be considered as a preventive measure for cardiac hypertrophy. Copyright © 2014

  20. Interaction of Tamoxifen and noise induced damage to the cochlea

    PubMed Central

    Pillai, Jagan A; Siegel, Jonathan H

    2011-01-01

    Tamoxifen has been used extensively in the treatment of breast cancer and other neoplasms. In addition to its well-known action on estrogen receptors it is also known to acutely block chloride channels that participate in cell volume regulation. Tamoxifen’s role in preventing cochlear outer hair cell (OHC) swelling in vitro suggested that OHC swelling noted following noise exposure could potentially be a therapeutic target for Tamoxifen in its role as a chloride channel blocker to help prevent noise induced hearing loss. To investigate this possiblity, the effects of exposure to Tamoxifen on physiologic measures of cochlear function in the presence and absence of subsequent noise exposure were studied. Male Mongolian gerbils (2–4 months old) were randomly assigned to different groups. Tamoxifen at ~10 mg/kg was administered to one of the groups. Five hours later they were exposed to a one-third octave band of noise centered at 8 kHz in a sound isolation chamber for 30 minutes at 108dB SPL. Compound action potential (CAP) thresholds and distortion product otoacoustic emission (DPOAE) levels were measured 30–35 days following noise exposure. Tamoxifen administration did not produce any changes in CAP thresholds and DPOAE levels when administered by itself in the absence of noise. Tamoxifen causes a significant increase in CAP thresholds from 8–15 kHz following noise exposure compared to CAP thresholds in animals exposed to noise alone. No significant differences were seen in the DPOAE levels the f2 = 8–15 kHz frequency range where maximum noise-induced increases in CAP thresholds were seen. Contrary to our original expectation, it is concluded that Tamoxifen potentiates the degree of damage to the cochlea resulting from noise exposure. PMID:21907781

  1. Phenomenology of the sound-induced flash illusion.

    PubMed

    Abadi, Richard V; Murphy, Jonathan S

    2014-07-01

    Past studies, using pairings of auditory tones and visual flashes, which were static and coincident in space but variable in time, demonstrated errors in judging the temporal patterning of the visual flashes-the sound-induced flash illusion. These errors took one of the two forms: under-reporting (sound-induced fusion) or over-reporting (sound-induced fission) of the flash numbers. Our study had three objectives: to examine the robustness of both illusions and to consider the effects of stimulus set and response bias. To this end, we used an extended range of fixed spatial location flash-tone pairings, examined stimuli that were variable in space and time and measured confidence in judging flash numbers. Our results indicated that the sound-induced flash illusion is a robust percept, a finding underpinned by the confidence measures. Sound-induced fusion was found to be more robust than sound-induced fission and a most likely outcome when high numbers of flashes were incorporated within an incongruent flash-tone pairing. Conversely, sound-induced fission was the most likely outcome for the flash-tone pairing which contained two flashes. Fission was also shown to be strongly driven by stimuli confounds such as categorical boundary conditions (e.g. flash-tone pairings with ≤2 flashes) and compressed response options. These findings suggest whilst both fission and fusion are associated with 'auditory driving', the differences in the occurrence and strength of the two illusions not only reflect the separate neuronal mechanisms underlying audio and visual signal processing, but also the test conditions that have been used to investigate the sound-induced flash illusion.

  2. Hot Flashes Among Prostate Cancer Patients Undergoing Androgen Deprivation Therapy: Psychosocial and Quality of Life Issues

    DTIC Science & Technology

    2005-12-01

    hot flashes on sleep, fatigue, and quality of life , and compare the accuracy of alternative means of assessing hot flashes. The overarching goal is to...diverse applications. Results will have implications for the education of oncologists with respect to quality of life issues in prostate cancer, set

  3. Hot Flashes Among Prostate Cancer Patients Undergoing Androgen Deprivation Therapy: Psychosocial and Quality of Life Issues

    DTIC Science & Technology

    2005-01-01

    of hot flashes on sleep, fatigue, and quality of life , and compare the accuracy of alternative means of assessing hot flashes. The overarching goal is...diverse applications. Results will have implications for the education of oncologists with respect to quality of life issues in prostate cancer, set

  4. Gene expression profiling reveals underlying molecular mechanisms of the early stages of tamoxifen-induced rat hepatocarcinogenesis

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Pogribny, Igor P.; Bagnyukova, Tetyana V.; Tryndyak, Volodymyr P.

    2007-11-15

    Tamoxifen is a widely used anti-estrogenic drug for chemotherapy and, more recently, for the chemoprevention of breast cancer. Despite the indisputable benefits of tamoxifen in preventing the occurrence and re-occurrence of breast cancer, the use of tamoxifen has been shown to induce non-alcoholic steatohepatitis, which is a life-threatening fatty liver disease with a risk of progression to cirrhosis and hepatocellular carcinoma. In recent years, the high-throughput microarray technology for large-scale analysis of gene expression has become a powerful tool for increasing the understanding of the molecular mechanisms of carcinogenesis and for identifying new biomarkers with diagnostic and predictive values. Inmore » the present study, we used the high-throughput microarray technology to determine the gene expression profiles in the liver during early stages of tamoxifen-induced rat hepatocarcinogenesis. Female Fisher 344 rats were fed a 420 ppm tamoxifen containing diet for 12 or 24 weeks, and gene expression profiles were determined in liver of control and tamoxifen-exposed rats. The results indicate that early stages of tamoxifen-induced liver carcinogenesis are characterized by alterations in several major cellular pathways, specifically those involved in the tamoxifen metabolism, lipid metabolism, cell cycle signaling, and apoptosis/cell proliferation control. One of the most prominent changes during early stages of tamoxifen-induced hepatocarcinogenesis is dysregulation of signaling pathways in cell cycle progression from the G{sub 1} to S phase, evidenced by the progressive and sustained increase in expression of the Pdgfc, Calb3, Ets1, and Ccnd1 genes accompanied by the elevated level of the PI3K, p-PI3K, Akt1/2, Akt3, and cyclin B, D1, and D3 proteins. The early appearance of these alterations suggests their importance in the mechanism of neoplastic cell transformation induced by tamoxifen.« less

  5. A Comprehensive Method To Quantify Adaptations by Male and Female Mice With Hot Flashes Induced by the Neurokinin B Receptor Agonist Senktide.

    PubMed

    Krull, Ashley A; Larsen, Sarah A; Clifton, Donald K; Neal-Perry, Genevieve; Steiner, Robert A

    2017-10-01

    Vasomotor symptoms (VMS; or hot flashes) plague millions of reproductive-aged men and women who have natural or iatrogenic loss of sex steroid production. Many affected individuals are left without treatment options because of contraindications to hormone replacement therapy and the lack of equally effective nonhormonal alternatives. Moreover, development of safer, more effective therapies has been stymied by the lack of an animal model that recapitulates the hot-flash phenomenon and enables direct testing of hypotheses regarding the pathophysiology underlying hot flashes. To address these problems, we developed a murine model for hot flashes and a comprehensive method for measuring autonomic and behavioral thermoregulation in mice. We designed and constructed an instrument called a thermocline that produces a thermal gradient along which mice behaviorally adapt to a thermal challenge to their core body temperature set point while their thermal preference over time is tracked and recorded. We tested and validated this murine model for VMS by administration of a TRPV1 agonist and a neurokinin B receptor agonist, capsaicin and senktide, respectively, to unrestrained mice and observed their autonomic and behavioral responses. Following both treatments, the mice exhibited a VMS-like response characterized by a drop in core body temperature and cold-seeking behavior on the thermocline. Senktide also caused a rise in tail skin temperature and increased Fos expression in the median preoptic area, a hypothalamic temperature control center. This dynamic model may be used to fully explore the cellular and molecular bases for VMS and to develop and test new therapeutic options. Copyright © 2017 Endocrine Society.

  6. Tamoxifen induces a pluripotency signature in breast cancer cells and human tumors.

    PubMed

    Notas, George; Pelekanou, Vassiliki; Kampa, Marilena; Alexakis, Konstantinos; Sfakianakis, Stelios; Laliotis, Aggelos; Askoxilakis, John; Tsentelierou, Eleftheria; Tzardi, Maria; Tsapis, Andreas; Castanas, Elias

    2015-11-01

    Tamoxifen is the treatment of choice in estrogen receptor alpha breast cancer patients that are eligible for adjuvant endocrine therapy. However, ∼50% of ERα-positive tumors exhibit intrinsic or rapidly acquire resistance to endocrine treatment. Unfortunately, prediction of de novo resistance to endocrine therapy and/or assessment of relapse likelihood remain difficult. While several mechanisms regulating the acquisition and the maintenance of endocrine resistance have been reported, there are several aspects of this phenomenon that need to be further elucidated. Altered metabolic fate of tamoxifen within patients and emergence of tamoxifen-resistant clones, driven by evolution of the disease phenotype during treatment, appear as the most compelling hypotheses so far. In addition, tamoxifen was reported to induce pluripotency in breast cancer cell lines, in vitro. In this context, we have performed a whole transcriptome analysis of an ERα-positive (T47D) and a triple-negative breast cancer cell line (MDA-MB-231), exposed to tamoxifen for a short time frame (hours), in order to identify how early pluripotency-related effects of tamoxifen may occur. Our ultimate goal was to identify whether the transcriptional actions of tamoxifen related to induction of pluripotency are mediated through specific ER-dependent or independent mechanisms. We report that even as early as 3 hours after the exposure of breast cancer cells to tamoxifen, a subset of ERα-dependent genes associated with developmental processes and pluripotency are induced and this is accompanied by specific phenotypic changes (expression of pluripotency-related proteins). Furthermore we report an association between the increased expression of pluripotency-related genes in ERα-positive breast cancer tissues samples and disease relapse after tamoxifen therapy. Finally we describe that in a small group of ERα-positive breast cancer patients, with disease relapse after surgery and tamoxifen treatment, ALDH

  7. CROSS CULTURAL ANALYSIS OF DETERMINANTS OF HOT FLASHES AND NIGHT SWEATS: LATIN-AMERICAN IMMIGRANTS TO MADRID AND THEIR SPANISH NEIGHBORS

    PubMed Central

    Pérez-Alcalá, Irene; Sievert, Lynnette Leidy; Obermeyer, Carla Makhlouf; Reher, David Sven

    2013-01-01

    Objective This study applies a biocultural perspective to better understand the determinants of hot flashes and night sweats within immigrant and local populations in Madrid, Spain. Methods A combined sample of 575 women from Madrid, aged 45 to 55, was drawn from two studies. The Spanish sample (n=274) participated in the Decisions at Menopause Study (DAMES) in 2000–2002. The Latin-American sample (n=301) was drawn from immigrants to Madrid in 2010–2011. Chi square analyses and logistic regression models were carried out among the combined controlling by origin of provenance. Results Forty four percent of the women reported hot flashes, 36% reported night sweats and 26% both symptoms. Compared to Spanish women, Latin-American women were less likely to report hot flashes (OR 0.7, 95% CI 0.4–0.9) after controlling for demographic variables and menopausal status. The same was not found for night sweats and for both symptoms combined. Determinants of hot flashes differed from determinants of night sweats. Conclusions Because determinants differed, hot flashes and night sweats should be queried and analyzed separately. Latin-American women were less likely to report hot flashes, but not night sweats or both symptoms combined. More research is needed to clarify the differences in reported hot flashes as the lesser report among immigrants could have been a cultural rather than a biological phenomenon. PMID:23571525

  8. Hot Flashes and Night Sweats (PDQ®)—Health Professional Version

    Cancer.gov

    Hot flashes and night sweats can be cancer or treatment related and occur commonly in both women and men. Get information on hormonal and nonhormonal agents, cognitive and behavioral methods, and integrative medicine treatment options in this clinician summary.

  9. Hot flashes, fatigue, treatment exposures and work productivity in breast cancer survivors.

    PubMed

    Lavigne, Jill E; Griggs, Jennifer J; Tu, Xin M; Lerner, Debra J

    2008-12-01

    While fatigue has been associated with work limitations the combined influence of specific diagnosis and treatment exposures based on medical records on work limitations in breast cancer survivors is currently unknown. Since symptom burden and perceived health can interfere with work, the present study investigated the relationship among these variables and work outcomes. Medical chart abstraction, demographic measures, SF 36, the Work Limitations Questionnaire (WLQ) and measures of symptom burden, including hot flushes were obtained in 83 breast cancer survivors a mean of three years post treatment. OLS and poisson regression were used to determine the relationship of these factors to work productivity and work absences. Breast cancer survivors reported a mean reduction in productivity of 3.1% below the healthy worker norm. This amounts to a loss of 2.48 hours of work over two weeks of full time employment. Stages 1 and 2 were related to work limitations. After controlling for stage, fatigue and hot flashes were each associated with work performance losses of 1.6% (p = 0.05) and 2.2% (p < 0.001), respectively. Protective factors included marriage and greater personal earned income. Fatigue and hot flashes are important factors related to work productivity in breast cancer survivors even at three years post treatment. IMPLICATIONS FOR SURVIVORS: Therapy for hot flashes should be given serious consideration in breast cancer survivors who are experiencing work limitations.

  10. Hot flashes severity, complementary and alternative medicine use, and self-rated health in women with breast cancer.

    PubMed

    Chandwani, Kavita D; Heckler, Charles E; Mohile, Supriya G; Mustian, Karen M; Janelsins, Michelle; Peppone, Luke J; Bushunow, Peter; Flynn, Patrick J; Morrow, Gary R

    2014-01-01

    Hot flashes (HF) are a common distressing symptom in women with breast cancer (BC). Current pharmacologic options are moderately effective and are associated with bothersome side effects. Complementary and alternative medicine is commonly used by cancer patients. However, information on the association of hot flashes severity with such use and self-rated health is lacking. To examine the hot flashes severity in women with breast cancer and its association with complementary and alternative medicine use and self-rated health (SRH). Longitudinal multicenter study to assess information needs of cancer outpatients. Patients with a diagnosis of breast cancer who were scheduled to undergo chemotherapy and/or radiotherapy. Hot flashes severity (0 = not present and 10 = as bad as you can imagine), use of complementary and alternative medicine (yes/no), and self-rating of health (SRH) status post-treatment and six-months thereafter (1-5, higher score = better SRH). The majority of women with HF (mean age = 54.4 years) were Caucasian and married, with higher education, and 93% had received surgical treatment for BC. At the end of treatment, 79% women reported experiencing HF [mean severity = 5.87, standard deviation (SD) = 2.9]; significantly more severe HF were reported by younger women with poor SRH, poor performance status, and those reporting doing spiritual practices. At follow-up, 73% had HF (mean severity = 4.86, SD = 3.0), and more severe HF were reported by younger women with poor self-rated health who had undergone chemotherapy plus radiotherapy, used vitamins, and did not exercise. A high percentage of women experienced hot flashes at the end of treatment and at six-month follow-up. A significant association of hot flashes severity with spiritual practice, increased vitamin use, and reduced exercise emphasize the need for future studies to confirm the results. This can facilitate safe use of complementary and alternative medicine and favorable outcomes while

  11. Randomised controlled trial comparing hypnotherapy versus gabapentin for the treatment of hot flashes in breast cancer survivors: a pilot study

    PubMed Central

    MacLaughlan David, Shannon; Salzillo, Sandra; Bowe, Patrick; Scuncio, Sandra; Malit, Bridget; Raker, Christina; Gass, Jennifer S; Granai, C O; Dizon, Don S

    2013-01-01

    Objectives To compare the efficacy of hypnotherapy versus gabapentin for the treatment of hot flashes in breast cancer survivors, and to evaluate the feasibility of conducting a clinical trial comparing a drug with a complementary or alternative method (CAM). Design Prospective randomised trial. Setting Breast health centre of a tertiary care centre. Participants 15 women with a personal history of breast cancer or an increased risk of breast cancer who reported at least one daily hot flash. Interventions Gabapentin 900 mg daily in three divided doses (control) compared with standardised hypnotherapy. Participation lasted 8 weeks. Outcome measures The primary endpoints were the number of daily hot flashes and hot flash severity score (HFSS). The secondary endpoint was the Hot Flash Related Daily Interference Scale (HFRDIS). Results 27 women were randomised and 15 (56%) were considered evaluable for the primary endpoint (n=8 gabapentin, n=7 hypnotherapy). The median number of daily hot flashes at enrolment was 4.5 in the gabapentin arm and 5 in the hypnotherapy arm. HFSS scores were 7.5 in the gabapentin arm and 10 in the hypnotherapy arm. After 8 weeks, the median number of daily hot flashes was reduced by 33.3% in the gabapentin arm and by 80% in the hypnotherapy arm. The median HFSS was reduced by 33.3% in the gabapentin arm and by 85% in the hypnotherapy arm. HFRDIS scores improved by 51.6% in the gabapentin group and by 55.2% in the hypnotherapy group. There were no statistically significant differences between groups. Conclusions Hypnotherapy and gabapentin demonstrate efficacy in improving hot flashes. A definitive trial evaluating traditional interventions against CAM methods is feasible, but not without challenges. Further studies aimed at defining evidence-based recommendations for CAM are necessary. Trial registration clinicaltrials.gov (NCT00711529). PMID:24022390

  12. Flash Mixing on the White-Dwarf Cooling Curve: Understanding Hot Horizontal Branch Anomalies in NGC 2808

    NASA Technical Reports Server (NTRS)

    Brown, Thomas M.; Sweigart, Allen V.; Lanz, Thierry; Landsman, Wayne B.; Hubeny, Ivan; Fisher, Richard R. (Technical Monitor)

    2001-01-01

    We present an ultraviolet color-magnitude diagram (CMD) spanning the hot horizontal branch (HB), blue straggler, and white dwarf populations of the globular cluster NGC 2808. These data, obtained with the Space Telescope Imaging Spectrograph (STIS), demonstrate that NGC 2808 harbors a significant population of hot subluminous HB stars, an anomaly only previously reported for the globular cluster omega Cen. Our theoretical modeling indicates that the location of these subluminous stars in the CMD, as well as the high temperature gap along the HB of NGC 2808, can be explained if these stars underwent a late helium-core flash while descending the white dwarf cooling curve. We show that the convective zone produced by such a late helium flash will penetrate into the hydrogen envelope, thereby mixing hydrogen into the hot helium-burning interior, where it is rapidly consumed. This phenomenon is analogous to the "born again" scenario for producing hydrogen-deficient stars following a late helium-shell flash. The flash mixing of the envelope greatly enhances the envelope helium and carbon abundances that, in turn, leads to a discontinuous increase in the HB effective temperatures. We argue that the hot HB gap is associated with this theoretically predicted dichotomy in the HB properties. Moreover, the changes in the emergent spectral energy distribution caused by these abundance changes are primarily responsible for explaining the hot subluminous HB stars. Although further evidence is needed to confirm that a late helium-core flash can account for the subluminous HB stars and the hot HB gap, we demonstrate that an understanding of these stars requires the use of appropriate theoretical models for their evolution, atmospheres, and spectra.

  13. Is Homepathy Effective for Hot Flashes and other Estrogen-Withdrawal Symptoms in Breast Cancer Survivors? A Preliminary Randomized Controlled Trial

    DTIC Science & Technology

    2000-04-01

    AD__________ Award Number: DAMD17-99-1-9438 TITLE: Is Homeopathy Effective for Hot Flashes and Other Estrogen-Withdrawal Symptoms in Breast Cancer...Mar 00) 4. TITLE AND SUBTITLE 5. FUNDING NUMBERS Is Homeopathy Effective for Hot Flashes and Other Estrogen- DAMD17-99-1-9438 Withdrawal Symptoms in...there is evidence that homeopathy is an effective treatment to improve the quality of life in breast cancer survivors who are experiencing hot flashes

  14. The effect of Valerian on the severity and frequency of hot flashes: A triple-blind randomized clinical trial.

    PubMed

    Jenabi, Ensiyeh; Shobeiri, Fatemeh; Hazavehei, Seyyed Mohammad Mahdi; Roshanaei, Ghodratollah

    2018-03-01

    Valerian is one of the most widely used herbal supplements and a phytoestrogenic herb. The aim of this study was to determine the effect of Valerian on the severity and frequency of hot flashes. This triple-blind, randomized, controlled clinical trial was conducted during a three-month period in Hamadan, Iran, in 60 postmenopausal women aged 45-55 years. Participants were randomly assigned to one of two groups- either placebo or Valerian. An oral Valerian 530 mg capsule was given twice per day for two months. An oral placebo 530 mg capsule (starch) was similarly administered. The severity and frequency of hot flashes were determined by the Kupperman index, before the intervention, one month after, and two months after initiation of the intervention. The severity of hot flashes in the Valerian group was significantly lower than that in the placebo group at one (p = .048) and two months (p = .020) after initiation of the intervention. Compared with the placebo group, the mean frequency of hot flashes was significantly reduced two months after initiating the use of Valerian (p = .033). Health-care providers should consider Valerian to be effective for menopausal women with hot flashes.

  15. Nitric oxide synthase inhibition attenuates cutaneous vasodilation during the post-menopausal hot flash

    PubMed Central

    Hubing, Kimberly A.; Wingo, Jonathan E.; Brothers, R. Matthew; Coso, Juan Del; Low, David A.; Crandall, Craig G.

    2010-01-01

    Objective The purpose of this study was to test the hypothesis that local inhibition of nitric oxide and prostaglandin synthesis attenuates cutaneous vasodilator responses during post-menopausal hot flashes. Methods Four microdialysis membranes were inserted into forearm skin (dorsal surface) of 8 post-menopausal women (mean ± SD, 51±7 y). Ringers solution (control), 10mM Ketorolac (Keto) to inhibit prostaglandin synthesis, 10mM NG-L-arginine methyl ester (L-NAME) to inhibit nitric oxide synthase, and a combination of 10mM Keto + 10mM L-NAME were each infused at the separate sites. Skin blood flow at each site was indexed using laser-Doppler flowmetry. Cutaneous vascular conductance (CVC) was calculated as laser-Doppler flux/mean arterial blood pressure and was expressed as a percentage of the maximal calculated CVC (CVCmax) obtained following infusion of 50mM sodium nitropruside at all sites at the end of the study. Data from 13 hot flashes were analyzed. Results At the control site, the mean ± SD peak increase in CVC was 15.5±6% CVCmax units. This value was not different relative to the peak increase in CVC at the Keto site (13.0±5 % CVCmax units, P = 0.09). However, the peak increase in CVC during the flash was attenuated at the L-NAME and L-NAME + Keto sites (7.4±4 % CVCmax units and 8.7±7 % CVCmax units, respectively) relative to both the control and the Keto sites (P<0.05 for both comparisons). There were no significant differences in the peak increases in sweat rate between any of the sites (P = 0.24). Conclusions These data demonstrate that cutaneous vasodilation during a hot flash has a nitric oxide component. Increases in CVC despite the inhibition of prostaglandin synthesis suggest prostaglandins do not contribute to cutaneous vasodilation during a hot flash. PMID:20505548

  16. Antiarrhythmic effect of tamoxifen on the vulnerability induced by hyperthyroidism to heart ischemia/reperfusion damage.

    PubMed

    Pavón, Natalia; Hernández-Esquivel, Luz; Buelna-Chontal, Mabel; Chávez, Edmundo

    2014-09-01

    Hyperthyroidism, known to have deleterious effects on heart function, and is associated with an enhanced metabolic state, implying an increased production of reactive oxygen species. Tamoxifen is a selective antagonist of estrogen receptors. These receptors make the hyperthyroid heart more susceptible to ischemia/reperfusion. Tamoxifen is also well-known as an antioxidant. The aim of the present study was to explore the possible protective effect of tamoxifen on heart function in hyperthyroid rats. Rats were injected daily with 3,5,3'-triiodothyronine at 2mg/kg body weight during 5 days to induce hyperthyroidism. One group was treated with 10mg/kg tamoxifen and another was not. The protective effect of the drug on heart rhythm was analyzed after 5 min of coronary occlusion followed by 5 min reperfusion. In hyperthyroid rats not treated with tamoxifen, ECG tracings showed post-reperfusion arrhythmias, and heart mitochondria isolated from the ventricular free wall lost the ability to accumulate and retain matrix Ca(2+) and to form a high electric gradient. Both of these adverse effects were avoided with tamoxifen treatment. Hyperthyroidism-induced oxidative stress caused inhibition of cis-aconitase and disruption of mitochondrial DNA, effects which were also avoided by tamoxifen treatment. The current results support the idea that tamoxifen inhibits the hypersensitivity of hyperthyroid rat myocardium to reperfusion damage, probably because its antioxidant activity inhibits the mitochondrial permeability transition. Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. In vitro metabolic interactions between black cohosh (Cimicifuga racemosa) and tamoxifen via inhibition of cytochromes P450 2D6 and 3A4

    PubMed Central

    Li, Jinghu; Gödecke, Tanja; Chen, Shao-Nong; Imai, Ayano; Lankin, David; Farnsworth, Norman R.; Pauli, Guido F.; van Breemen, Richard B.; Nikolić, Dejan

    2012-01-01

    Women who experience hot flashes as a side effect of tamoxifen therapy often try botanical remedies such as black cohosh to alleviate these symptoms. Since pharmacological activity of tamoxifen is dependent on the metabolic conversion into active metabolites by the action of cytochromes P450 2D6 and 3A4, the objective of this study was to evaluate whether black cohosh extracts can inhibit formation of active tamoxifen metabolites and possibly reduce its clinical efficacy.At 50 µg/ml, a 75% ethanolic extract of black cohosh inhibited formation of 4-hydroxy-tamoxifen by 66.3%, N-desmethyl tamoxifen by 74.6% and α-hydroxy tamoxifen by 80.3%. In addition, using midazolam and dextromethorphan as probe substrates, this extract inhibited CYP3A4 and CYP2D6 with IC50 values of 16.5 and 50.1 µg/ml, respectively.Eight triterpene glycosides were identified as competitive CYP3A4 inhibitors with IC50 values ranging from 2.3–5.1 µM, while the alkaloids protopine and allocryptopine were identified as competitive CYP2D6 inhibitors with Ki values of 78 and 122 nM, respectively.The results of this study suggests that co-administration of black cohosh with tamoxifen might interfere with the clinical efficacy of this drug. However, additional clinical studies are needed to determine the clinical significance of these in vitro results. PMID:21827327

  18. Sleep disturbance in men receiving androgen deprivation therapy for prostate cancer: The role of hot flashes and nocturia.

    PubMed

    Gonzalez, Brian D; Small, Brent J; Cases, Mallory G; Williams, Noelle L; Fishman, Mayer N; Jacobsen, Paul B; Jim, Heather S L

    2018-02-01

    Patients with prostate cancer receiving androgen deprivation therapy (ADT) are at risk of sleep disturbance; however, to the authors' knowledge, the mechanisms by which ADT may affect sleep are not well understood. The current study compared objective and subjective sleep disturbance in ADT recipients and controls and examined whether sleep disturbance in ADT recipients is attributable to the influence of ADT on hot flashes and nocturia. Patients with prostate cancer were assessed before or within 1 month after the initiation of ADT as well as 6 months and 12 months later (78 patients). Patients with prostate cancer were treated with prostatectomy only (99 patients) and men with no history of cancer (108 men) were assessed at similar intervals. Participants self-reported their sleep disturbance (Insomnia Severity Index) and interference from hot flashes (Hot Flash Related Daily Interference Scale). One hundred participants also wore actigraphs for 3 days at the 6-month assessment to measure objective sleep disturbance and reported their nocturia frequency. ADT recipients reported worse sleep disturbance, higher rates of clinically significant sleep disturbance, and greater hot flash interference than controls (Ps≤.03). In cross-sectional analyses among those with actigraphy data, ADT recipients had greater objective sleep disturbance and more episodes of nocturia (Ps<.01). Cross-sectional mediation analyses demonstrated that the association between ADT and objectively and subjectively measured sleep disturbance was partly attributable to nocturia and hot flashes (Ps<.05). The results of the current study suggest that the association between ADT and sleep may be partly explained by nocturia and hot flash interference. Future studies should examine behavioral and pharmacologic interventions to address these symptoms among ADT recipients. Cancer 2018;124:499-506. © 2017 American Cancer Society. © 2017 American Cancer Society.

  19. Hot Flashes among Prostate Cancer Patients Undergoing Androgen Deprivation Therapy: Psychosocial and Quality of Life Issues

    DTIC Science & Technology

    2006-12-01

    SCL magnitude indicative of hot flashes in menopausal women is valid for PCS (Carpenter, 2005b). Due to a lack of validation studies, we aimed to...objective assessment of hot flashes has been based entirely on studies of menopausal women and women with breast cancer, and ours is the first study to...presence of chest hair proved to be an obstacle to ease of use. Removal of chest hair was not an option, as this also removes skin which, in turn

  20. Joint Effects of Smoking and Gene Variants Involved in Sex Steroid Metabolism on Hot Flashes in Late Reproductive-Age Women

    PubMed Central

    Freeman, Ellen W.; Sammel, Mary D.; Queen, Kaila; Lin, Hui; Rebbeck, Timothy R.

    2012-01-01

    Background: Although smoking has a known association with hot flashes, the factors distinguishing smokers at greatest risk for menopausal symptoms have not been well delineated. Recent evidence supports a relationship between menopausal symptoms and variants in several genes encoding enzymes that metabolize substrates such as sex steriods, xenobiotics, and catechols. It is currently not known whether the impact of smoking on hot flashes is modified by the presence of such variants. Objective: The objective of the study was to investigate the relationship between smoking and hot flash occurrence as a function of genetic variation in sex steroid-metabolizing enzymes. Methods: A cross-sectional analysis of data from the Penn Ovarian Aging study, an ongoing population-based cohort of late reproductive-aged women, was performed. Smoking behavior was characterized. Single-nucleotide polymorphisms in five genes were investigated: COMT Val158Met (rs4680), CYP1A2*1F (rs762551), CYP1B1*4 (Asn452Ser, rs1800440), CYP1B1*3 (Leu432Val, rs1056836), and CYP3A4*1B (rs2740574). Results: Compared with nonsmokers, European-American COMT Val158Met double-variant carriers who smoked had increased odds of hot flashes [adjusted odds ratio (AOR) 6.15, 95% confidence interval (CI) 1.32–28.78)]; European-American COMT Val158Met double-variant carriers who smoked heavily had more frequent moderate or severe hot flashes than nonsmokers (AOR 13.7, 95% CI 1.2–154.9). European-American CYP 1B1*3 double-variant carriers who smoked described more frequent moderate or severe hot flashes than nonsmoking (AOR 20.6, 95% CI 1.64–257.93) and never-smoking (AOR 20.59, 95% CI 1.39–304.68) carriers, respectively. African-American single-variant CYP 1A2 carriers who smoked were more likely to report hot flashes than the nonsmoking carriers (AOR 6.16, 95% CI 1.11–33.91). Conclusion: This is the first report demonstrating the effects of smoking within the strata of gene variants involved in sex

  1. Joint effects of smoking and gene variants involved in sex steroid metabolism on hot flashes in late reproductive-age women.

    PubMed

    Butts, Samantha F; Freeman, Ellen W; Sammel, Mary D; Queen, Kaila; Lin, Hui; Rebbeck, Timothy R

    2012-06-01

    Although smoking has a known association with hot flashes, the factors distinguishing smokers at greatest risk for menopausal symptoms have not been well delineated. Recent evidence supports a relationship between menopausal symptoms and variants in several genes encoding enzymes that metabolize substrates such as sex steriods, xenobiotics, and catechols. It is currently not known whether the impact of smoking on hot flashes is modified by the presence of such variants. The objective of the study was to investigate the relationship between smoking and hot flash occurrence as a function of genetic variation in sex steroid-metabolizing enzymes. A cross-sectional analysis of data from the Penn Ovarian Aging study, an ongoing population-based cohort of late reproductive-aged women, was performed. Smoking behavior was characterized. Single-nucleotide polymorphisms in five genes were investigated: COMT Val158Met (rs4680), CYP1A2*1F (rs762551), CYP1B1*4 (Asn452Ser, rs1800440), CYP1B1*3 (Leu432Val, rs1056836), and CYP3A4*1B (rs2740574). Compared with nonsmokers, European-American COMT Val158Met double-variant carriers who smoked had increased odds of hot flashes [adjusted odds ratio (AOR) 6.15, 95% confidence interval (CI) 1.32-28.78)]; European-American COMT Val158Met double-variant carriers who smoked heavily had more frequent moderate or severe hot flashes than nonsmokers (AOR 13.7, 95% CI 1.2-154.9). European-American CYP 1B1*3 double-variant carriers who smoked described more frequent moderate or severe hot flashes than nonsmoking (AOR 20.6, 95% CI 1.64-257.93) and never-smoking (AOR 20.59, 95% CI 1.39-304.68) carriers, respectively. African-American single-variant CYP 1A2 carriers who smoked were more likely to report hot flashes than the nonsmoking carriers (AOR 6.16, 95% CI 1.11-33.91). This is the first report demonstrating the effects of smoking within the strata of gene variants involved in sex steroid metabolism on hot flashes in late reproductive-age women

  2. Tamoxifen induces apoptotic neutrophil efferocytosis in horses.

    PubMed

    Olave, C; Morales, N; Uberti, B; Henriquez, C; Sarmiento, J; Ortloff, A; Folch, H; Moran, G

    2018-03-01

    Macrophages and neutrophils are important cellular components in the process of acute inflammation and its subsequent resolution, and evidence increasingly suggests that they play important functions during the resolution of chronic, adaptive inflammatory processes. Exacerbated neutrophil activity can be harmful to surrounding tissues; this is important in a range of diseases, including allergic asthma and chronic obstructive pulmonary disease in humans, and equine asthma (also known as recurrent airway obstruction (RAO). Tamoxifen (TX) is a non-steroidal estrogen receptor modulator with effects on cell growth and survival. Previous studies showed that TX treatment in horses with induced acute pulmonary inflammation promoted early apoptosis of blood and BALF neutrophils, reduction of BALF neutrophils, and improvement in animals' clinical status. The aim of this study was to describe if TX induces in vitro efferocytosis of neutrophils by alveolar macrophages. Efferocytosis assay, myeloperoxidase (MPO) detection and translocation phosphatidylserine (PS) were performed on neutrophils isolated from peripheral blood samples from five healthy horses. In in vitro samples from heathy horses, TX treatment increases the phenomenon of efferocytosis of peripheral neutrophils by alveolar macrophages. Similar increases in supernatant MPO concentration and PS translocation were observed in TX-treated neutrophils, compared to control cells. In conclusion, these results confirm that tamoxifen has a direct effect on equine peripheral blood neutrophils, through stimulation of the engulfment of apoptotic neutrophils by alveolar macrophages.

  3. Hot-Electron-Induced Device Degradation during Gate-Induced Drain Leakage Stress

    NASA Astrophysics Data System (ADS)

    Kim, Kwang-Soo; Han, Chang-Hoon; Lee, Jun-Ki; Kim, Dong-Soo; Kim, Hyong-Joon; Shin, Joong-Shik; Lee, Hea-Beoum; Choi, Byoung-Deog

    2012-11-01

    We studied the interface state generation and electron trapping by hot electrons under gate-induced drain leakage (GIDL) stress in p-type metal oxide semiconductor field-effect transistors (P-MOSFETs), which are used as the high-voltage core circuit of flash memory devices. When negative voltage was applied to a drain in the off-state, a GIDL current was generated, but when high voltage was applied to the drain, electrons had a high energy. The hot electrons produced the interface state and electron trapping. As a result, the threshold voltage shifted and the off-state leakage current (trap-assisted drain junction leakage current) increased. On the other hand, electron trapping mitigated the energy band bending near the drain and thus suppressed the GIDL current generation.

  4. Fatigue, insomnia and hot flashes after definitive radiochemotherapy and image-guided adaptive brachytherapy for locally advanced cervical cancer: An analysis from the EMBRACE study.

    PubMed

    Smet, Stéphanie; Pötter, Richard; Haie-Meder, Christine; Lindegaard, Jacob C; Schulz-Juergenliemk, Ina; Mahantshetty, Umesh; Segedin, Barbara; Bruheim, Kjersti; Hoskin, Peter; Rai, Bhavana; Huang, Fleur; Cooper, Rachel; van Limbergen, Erik; Tanderup, Kari; Kirchheiner, Kathrin

    2018-04-04

    To evaluate the pattern of manifestation of fatigue, insomnia and hot flashes within the prospective, observational, multi-center EMBRACE study. Morbidity was prospectively assessed according to CTCAE v.3 and patient-reported outcome with EORTC QLQ-C30/CX24 at baseline and regular follow-up. Analyses of crude incidence, prevalence rates and actuarial estimates were performed. A total of 1176 patients were analyzed with a median follow-up of 27 months. At baseline, CTCAE G1/G2 prevalence rates for fatigue were 29%/6.2%, for insomnia 18%/3.1% and for hot flashes 7.9%/1.6% with respective 3-year prevalence rates of 29%/6.8%, 17%/4.4% and 19%/5.9%. Similar patterns of manifestation were seen in patient-reported EORTC outcomes. The 3-year actuarial estimates for G ≥ 3 CTCAE fatigue, insomnia and hot flashes were 5.5%, 4.7% and 1.9%. Younger age was associated with significantly higher risk for fatigue, insomnia and hot flashes. Fatigue, insomnia and hot flashes occurred mainly in the mild to moderate range. Fatigue and insomnia were already present before treatment and showed minor fluctuations or recovery during follow-up, whereas hot flashes showed a considerable increase after treatment. More research is needed to evaluate contributing risk factors in order to define intervention strategies. Copyright © 2018 Elsevier B.V. All rights reserved.

  5. The efficacy of nonestrogenic therapy to hot flashes in cancer patients under hormone manipulation therapy: a systematic review and meta-analysis.

    PubMed

    Yamaguchi, N; Okajima, Y; Fujii, T; Natori, A; Kobayashi, D

    2013-10-01

    The incidence of hot flashes under hormone manipulation therapy is so high that this symptom caused by sex hormone blocking agents has been bothering patients and has a negative impact on their quality of life. Venlafaxine and gabapentin are most promising novel nonestrogenic agents to control the symptom. We seek to quatitatively summarize the efficacy of these novel agents. We conducted a meta-analysis of randomized controlled studies on the efficacy of venlafaxine/gabapentin to hot flashes in cancer patient under hormone deprivation therapies. A search for Medline, Embase, Cochrane Central Register of Controlled Trials, Ichushi, and Google Scholar yielded 733 citations, which were independently assessed by two authors. We estimated overall effect sizes and its 95 % confidence intervals (CI) for the efficacy of these agents compared with the controls with standardized mean difference. A total of 5 studies involving 588 cancer patients with hot flashes finally fulfilled the predefined inclusion criteria. Overall effect size of the efficacy of venlafaxine/gabapentin was -0.630 (95 % CI [-0.801, -0.459]). Venlafaxine/gabapentin significantly improved hot flashes in cancer patients under hormone manipulation therapies.

  6. Validity, cut-points, and minimally important differences for two hot flash-related daily interference scales.

    PubMed

    Carpenter, Janet S; Bakoyannis, Giorgos; Otte, Julie L; Chen, Chen X; Rand, Kevin L; Woods, Nancy; Newton, Katherine; Joffe, Hadine; Manson, JoAnn E; Freeman, Ellen W; Guthrie, Katherine A

    2017-08-01

    To conduct psychometric analyses to condense the Hot Flash-Related Daily Interference Scale (HFRDIS) into a shorter form termed the Hot Flash Interference (HFI) scale; evaluate cut-points for both scales; and establish minimally important differences (MIDs) for both scales. We analyzed baseline and postrandomization patient-reported data pooled across three randomized trials aimed at reducing vasomotor symptoms (VMS) in 899 midlife women. Trials were conducted across five MsFLASH clinical sites between July 2009 and October 2012. We eliminated HFRDIS items based on experts' content validity ratings and confirmatory factor analysis, and evaluated cut-points and established MIDs by mapping HFRDIS and HFI to other measures. The three-item HFI (interference with sleep, mood, and concentration) demonstrated strong internal consistency (alphas of 0.830 and 0.856), showed good fit to the unidimensional "hot flash interference factor," and strong convergent validity with HFRDIS scores, diary VMS, and menopausal quality of life. For both scales, cut-points of mild (0-3.9), moderate (4-6.9), and severe (7-10) interference were associated with increasing diary VMS ratings, sleep, and anxiety. The average MID was 1.66 for the HFRDIS and 2.34 for the HFI. The HFI is a brief assessment of VMS interference and will be useful in busy clinics to standardize VMS assessment or in research studies where response burden may be an issue. The scale cut-points and MIDs should prove useful in targeting those most in need of treatment, monitoring treatment response, and interpreting existing and future research findings.

  7. Opposite effects of tamoxifen on metabolic syndrome-induced bladder and prostate alterations: a role for GPR30/GPER?

    PubMed

    Comeglio, P; Morelli, A; Cellai, I; Vignozzi, L; Sarchielli, E; Filippi, S; Maneschi, E; Corcetto, F; Corno, C; Gacci, M; Vannelli, G B; Maggi, M

    2014-01-01

    BPH and LUTS have been associated to obesity, hypogonadism, and metabolic syndrome (MetS). MetS-induced prostate and bladder alterations, including inflammation and tissue remodeling, have been related to a low-testosterone and high-estrogen milieu. In addition to ERs, GPR30/GPER is able to mediate several estrogenic non-genomic actions. Supplementing a subgroup of MetS rabbits with tamoxifen, we analyzed the in vivo effects on MetS-induced prostate and bladder alterations. The effects of selective ER/GPER ligands and GPER silencing on prostate inflammation were also studied in vitro using hBPH cells. ERα, ERβ, and PR expression was upregulated in MetS bladder, where tamoxifen decreased ERα and PR expression, further stimulating ERβ. In addition, tamoxifen-dosing decreased MetS-induced overexpression of inflammatory and tissue remodeling genes. In prostate, sex steroid receptors, pro-inflammatory and pro-fibrotic genes were upregulated in MetS. However, tamoxifen did not affect them and even increased COX-2. In hBPH cells, 17β-estradiol increased IL-8 secretion, an effect blunted by co-treatment with GPER antagonist G15 but not by ER antagonist ICI 182,780, which further increased it. GPER agonist G1 dose-dependently (IC50  = 1.6 nM) induced IL-8 secretion. In vitro analysis demonstrated that GPER silencing reverted these stimulatory effects. GPER can be considered the main mediator of estrogen action in prostate, whereas in bladder the mechanism appears to rely on ERα, as indicated by in vivo experiments with tamoxifen dosing. Limiting the effects of the MetS-induced estrogen action via GPER could offer new perspectives in the management of BPH/LUTS, whereas tamoxifen dosing showed potential benefits in bladder. © 2013 Wiley Periodicals, Inc.

  8. Effects of estradiol and venlafaxine on insomnia symptoms and sleep quality in women with hot flashes.

    PubMed

    Ensrud, Kristine E; Guthrie, Katherine A; Hohensee, Chancellor; Caan, Bette; Carpenter, Janet S; Freeman, Ellen W; LaCroix, Andrea Z; Landis, Carol A; Manson, JoAnn; Newton, Katherine M; Otte, Julie; Reed, Susan D; Shifren, Jan L; Sternfeld, Barbara; Woods, Nancy F; Joffe, Hadine

    2015-01-01

    Determine effects of low-dose estradiol and low-dose venlafaxine on self-reported sleep measures in menopausal women with hot flashes. 3-arm double-blind randomized trial. Participants assigned in a 2:2:3 ratio to 17β estradiol 0.5 mg/day (n = 97), venlafaxine XR 75 mg/day (n = 96), or placebo (n = 146) for 8 weeks. Academic research centers. 339 community-dwelling perimenopausal and postmenopausal women with ≥2 bothersome hot flashes per day. Insomnia symptoms (Insomnia Severity Index [ISI]) and sleep quality (Pittsburgh Sleep Quality Index [PSQI]) at baseline, week 4 and 8; 325 women (96%) provided ISI data and 312 women (92%) provided PSQI data at baseline and follow-up. At baseline, mean (SD) hot flash frequency was 8.1/day (5.3), mean ISI was 11.1 (6.0), and mean PSQI was 7.5 (3.4). Mean (95% CI) change from baseline in ISI at week 8 was -4.1 points (-5.3 to -3.0) with estradiol, -5.0 points (-6.1 to -3.9) with venlafaxine, and -3.0 points (-3.8 to -2.3) with placebo (P overall treatment effect vs. placebo 0.09 for estradiol and 0.007 for venlafaxine). Mean (95% CI) change from baseline in PSQI at week 8 was -2.2 points (-2.8 to -1.6) with estradiol, -2.3 points (-2.9 to -1.6) with venlafaxine, and -1.2 points (-1.7 to -0.8) with placebo (P overall treatment effect vs. placebo 0.04 for estradiol and 0.06 for venlafaxine). Among perimenopausal and postmenopausal women with hot flashes, both low dose oral estradiol and low-dose venlafaxine compared with placebo modestly reduced insomnia symptoms and improved subjective sleep quality. NCT01418209 at www.clinicaltrials.gov. © 2014 Associated Professional Sleep Societies, LLC.

  9. Mechanisms of the hepatoprotective effects of tamoxifen against drug-induced and chemical-induced acute liver injuries

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Yoshikawa, Yukitaka; Miyashita, Taishi; Higuchi, Satonori

    Although estrogen receptor (ER)α agonists, such as estradiol and ethinylestradiol (EE2), cause cholestasis in mice, they also reduce the degree of liver injury caused by hepatotoxicants as well as ischemia–reperfusion. The functional mechanisms of ERα have yet to be elucidated in drug-induced or chemical-induced liver injury. The present study investigated the effects of an ERα agonist, selective ER modulators (SERMs) and an ER antagonist on drug-induced and chemical-induced liver injuries caused by acetaminophen, bromobenzene, diclofenac, and thioacetamide (TA). We observed hepatoprotective effects of EE2, tamoxifen (TAM) and raloxifene pretreatment in female mice that were exposed to a variety of hepatotoxicmore » compounds. In contrast, the ER antagonist did not show any hepatoprotective effects. DNA microarray analyses suggested that monocyte to macrophage differentiation-associated 2 (Mmd2) protein, which has an unknown function, is commonly increased by TAM and RAL pretreatment, but not by pretreatment with the ER antagonist. In ERα-knockout mice, the hepatoprotective effects of TAM and the increased expression of Mmd2 mRNA were not observed in TA-induced liver injury. To investigate the function of Mmd2, the expression level of Mmd2 mRNA was significantly knocked down to approximately 30% in mice by injection of siRNA for Mmd2 (siMmd2). Mmd2 knockdown resulted in a reduction of the protective effects of TAM on TA-induced liver injury in mice. This is the first report of the involvement of ERα in drug-induced or chemical-induced liver injury. Upregulation of Mmd2 protein in the liver was suggested as the mechanism of the hepatoprotective effects of EE2 and SERMs. -- Highlights: ► Liver injury induced by drugs or chemicals was investigated in mice. ► Liver injury was suppressed by pretreatment with tamoxifen in female mice. ► Mmd2, whose function was unknown, could be a candidate gene for liver protection. ► Tamoxifen up-regulated Mmd2 m

  10. Col2-Cre and tamoxifen-inducible Col2-CreER target different cell populations in the knee joint

    PubMed Central

    Nagao, Masashi; Cheong, Chan Wook; Olsen, Bjorn

    2015-01-01

    Objective Collagen type 2 (Col2)-Cre or tamoxifen-inducible Col2-CreER transgenic mouse lines have been used for studies to explore the cellular and molecular pathogenesis of osteoarthritis (OA). The purpose of this study is to investigate whether the targeted cells are the same or different in the two mouse lines. Methods We crossed tamoxifen inducible Col2-CreER and Col2-Cre mice with Rosa tdTomato reporter mice and analyzed the labeling patterns at different time points. Results In the Col2-CreER mice, 90.8 [95% confidence interval (CI) (88.3, 93.2)] and 82.8 (77.4, 88.3) % of the articular surface cells are Tomato positive when tamoxifen was administered at 2 and 2.5 weeks of age and strong activity was observed even 4.5 months after injection. However, 46.0 (32.8, 59.1) and 22.2 (11.7, 32.6) % of the surface cells were Tomato positive when tamoxifen was administered at 3 and 4 weeks of age, respectively. Little to no Tomato activity in the articular surface cells was observed when tamoxifen was administered at 8 weeks of age. At any stage of tamoxifen injection, the Tomato activity was detected in growth plate and epiphyseal bone in addition to articular chondrocytes, but little in endothelium and not in the synovium and ligament. In contrast, the targeted tissues in the Col2-Cre mouse line were articular cartilage, growth plate, meniscus, endosteum, ligament, bone and synovium. Conclusions This study demonstrates that the pattern of targeted cells in the inducible Col2-CreER mice are partially overlapping with but different from that of targeted cells in Col2-Cre mice and the pattern varies dependent on when tamoxifen is administered. PMID:26256767

  11. Efficacy of Crocus sativus (saffron) in treatment of major depressive disorder associated with post-menopausal hot flashes: a double-blind, randomized, placebo-controlled trial.

    PubMed

    Kashani, Ladan; Esalatmanesh, Sophia; Eftekhari, Farzaneh; Salimi, Samrand; Foroughifar, Tahereh; Etesam, Farnaz; Safiaghdam, Hamideh; Moazen-Zadeh, Ehsan; Akhondzadeh, Shahin

    2018-03-01

    Due to concerns regarding the side effects of hormone therapy, many studies have focused on the development of non-hormonal agents for treatment of hot flashes. The aim of this study was to evaluate the efficacy and safety of saffron (stigma of Crocus sativus) in treatment of major depressive disorder associated with post-menopausal hot flashes. Sixty women with post-menopausal hot flashes participated in this study. The patients randomly received either saffron (30 mg/day, 15 mg twice per day) or placebo for 6 weeks. The patients were assessed using the Hot Flash-Related Daily Interference Scale (HFRDIS), Hamilton Depression Rating Scale (HDRS) and the adverse event checklist at baseline and also at the second, fourth, and sixth weeks of the study. Fifty-six patients completed the trial. Baseline characteristics of the participants did not differ significantly between the two groups. General linear model repeated measures demonstrated significant effect for time × treatment interaction on the HFRDIS score [F (3, 162) = 10.41, p = 0.0001] and HDRS score [F (3, 162) = 5.48, p = 0.001]. Frequency of adverse events was not significantly different between the two groups. Results from this study revealed that saffron is a safe and effective treatment in improving hot flashes and depressive symptoms in post-menopausal healthy women. On the other hand, saffron, with fewer side effects, may provide a non-hormonal and alternative herbal medicine option in treatment of women with hot flashes.

  12. Light-Induced Toxic Effects of Tamoxifen: A Chemotherapeutic and Chemopreventive Agent.

    PubMed

    Wang, Lei; Wang, Shuguang; Yin, Jun-Jie; Fu, Peter P; Yu, Hongtao

    2009-01-01

    Tamoxifen is a powerful drug used to treat breast cancer patients, and more than 500,000 women in the U. S. are being treated with this drug. In our study, tamoxifen is found to be photomutagenic in Salmonella typhimurium TA102 at concentrations as low as 0.08 muM and reaches maximum photomutagenicity at 0.4 muM under a light dose equivalent to 20 min sunlight. These concentrations are comparable to the plasma tamoxifen concentration of 0.4 to 3 muM for patients undergoing tamoxifen therapy. The toxicity seems to be the result of DNA damage and/or lipid peroxidation caused by light irradiation of tamoxifen. The DNA damage caused by irradiation of PhiX174 DNA in the presence of tamoxifen appears to be formation of DNA-tamoxifen covalent adducts, not single strand/double strand cleavages, and there is no oxygen involvement. This is confirmed by EPR experiments that carbon-centerd radicals are formed by light irradiation of tamoxifen and there is no singlet oxygen formation. Although superoxide radical is formed, it is not involved in DNA damage.

  13. Size and oxidative susceptibility of low-density lipoprotein particles in breast cancer patients with tamoxifen-induced fatty liver.

    PubMed

    Wakatsuki, Akihiko; Ogawa, Yasuhiro; Saibara, Toshiji; Okatani, Yuji; Fukaya, Takao

    2002-08-01

    The purpose of the present study was to investigate the effects of tamoxifen on the size and oxidative susceptibility of low-density lipoprotein (LDL) particles in breast cancer patients with tamoxifen-induced fatty liver. We investigated the following breast cancer patients: 13 receiving no tamoxifen (group A), 13 receiving tamoxifen 40 mg daily but without fatty liver (group B), and 13 receiving tamoxifen 40 mg daily with fatty liver (group C). Plasma lipids and diameter of LDL particles were measured. Susceptibility of LDL to oxidation was analyzed by incubation with CuSO(4) while monitoring conjugated diene formation and assaying thiobarbituric acid reactive substances (TBARS). Plasma total and LDL cholesterol concentrations in groups B and C were significantly lower than those in group A. In group C, concentrations of plasma triglyceride (TG) and TBARS were significantly greater, but LDL particle diameter and lag time for LDL oxidation were significantly smaller than those in groups A and B. Plasma TG concentrations correlated negatively with computed tomography ratio of liver to spleen (r = -0.76; P < 0.001). LDL particle diameter correlated negatively with plasma TG (r = -0.62; P < 0.001) and TBARS (r = -0.44; P < 0.01), but positively with LDL lag time (r = 0.47; P < 0.01). Tamoxifen-induced fatty liver in breast cancer patients may be atherogenic, via increased TG and consequent small, easily oxidized LDL particles.

  14. Lithium and Tamoxifen Modulate Behavior and Protein Kinase C Activity in the Animal Model of Mania Induced by Ouabain

    PubMed Central

    Dal-Pont, Gustavo C; Resende, Wilson R; Varela, Roger B; Peterle, Bruna R; Gava, Fernanda F; Mina, Francielle G; Cararo, José H; Carvalho, André F; Quevedo, João

    2017-01-01

    Abstract Background The intracerebroventricular injection of ouabain, a specific inhibitor of the Na+/K+-adenosine-triphosphatase (Na+/K+-ATPase) enzyme, induces hyperactivity in rats in a putative animal model of mania. Several evidences have suggested that the protein kinase C signaling pathway is involved in bipolar disorder. In addition, it is known that protein kinase C inhibitors, such as lithium and tamoxifen, are effective in treating acute mania. Methods In the present study, we investigated the effects of lithium and tamoxifen on the protein kinase C signaling pathway in the frontal cortex and hippocampus of rats submitted to the animal model of mania induced by ouabain. We showed that ouabain induced hyperlocomotion in the rats. Results Ouabain increased the protein kinase C activity and the protein kinase C and MARCKS phosphorylation in frontal cortex and hippocampus of rats. Lithium and tamoxifen reversed the behavioral and protein kinase C pathway changes induced by ouabain. These findings indicate that the Na+/K+-ATPase inhibition can lead to protein kinase C alteration. Conclusions The present study showed that lithium and tamoxifen modulate changes in the behavior and protein kinase C signalling pathway alterations induced by ouabain, underlining the need for more studies of protein kinase C as a possible target for treatment of bipolar disorder. PMID:29020306

  15. Role of RBP2-Induced ER and IGF1R-ErbB Signaling in Tamoxifen Resistance in Breast Cancer.

    PubMed

    Choi, Hee-Joo; Joo, Hyeong-Seok; Won, Hee-Young; Min, Kyueng-Whan; Kim, Hyung-Yong; Son, Taekwon; Oh, Young-Ha; Lee, Jeong-Yeon; Kong, Gu

    2018-04-01

    Despite the benefit of endocrine therapy, acquired resistance during or after treatment still remains a major challenge in estrogen receptor (ER)-positive breast cancer. We investigated the potential role of histone demethylase retinoblastoma-binding protein 2 (RBP2) in endocrine therapy resistance of breast cancer. Survival of breast cancer patients according to RBP2 expression was analyzed in three different breast cancer cohorts including METABRIC (n = 1980) and KM plotter (n = 1764). RBP2-mediated tamoxifen resistance was confirmed by invitro sulforhodamine B (SRB) colorimetric, colony-forming assays, and invivo xenograft models (n = 8 per group). RNA-seq analysis and receptor tyrosine kinase assay were performed to identify the tamoxifen resistance mechanism by RBP2. All statistical tests were two-sided. RBP2 was associated with poor prognosis to tamoxifen therapy in ER-positive breast cancer (P = .04 in HYU cohort, P = .02 in KM plotter, P = .007 in METABRIC, log-rank test). Furthermore, RBP2 expression was elevated in patients with tamoxifen-resistant breast cancer (P = .04, chi-square test). Knockdown of RBP2 conferred tamoxifen sensitivity, whereas overexpression of RBP2 induced tamoxifen resistance invitro and invivo (MCF7 xenograft: tamoxifen-treated control, mean [SD] tumor volume = 70.8 [27.9] mm3, vs tamoxifen-treated RBP2, mean [SD] tumor volume = 387.9 [85.1] mm3, P < .001). Mechanistically, RBP2 cooperated with ER co-activators and corepressors and regulated several tamoxifen resistance-associated genes, including NRIP1, CCND1, and IGFBP4 and IGFBP5. Furthermore, epigenetic silencing of IGFBP4/5 by RBP2-ER-NRIP1-HDAC1 complex led to insulin-like growth factor-1 receptor (IGF1R) activation. RBP2 also increased IGF1R-ErbB crosstalk and subsequent PI3K-AKT activation via demethylase activity-independent ErbB protein stabilization. Combinational treatment with tamoxifen and PI3K inhibitor could overcome RBP2-mediated tamoxifen

  16. Crystalline maculopathy: a rare complication of tamoxifen therapy.

    PubMed

    Srikantia, Nirmala; Mukesh, S; Krishnaswamy, Malavika

    2010-01-01

    Tamoxifen is a selective estrogen receptor modulator widely used in the treatment of hormone-responsive breast cancer. Tamoxifen-induced ocular complications are very rare. A post-menopausal woman, diagnosed and treated case of carcinoma of left breast, on follow-up presented with history of gradual diminution of vision in both eyes of 3 months duration. Patient was on tamoxifen therapy 20 mg daily for the last 2 years. Fundus examination showed crystalline maculopathy. Fluorescein angiography, ocular coherence tomography confirmed the diagnosis. Tamoxifen therapy was discontinued. Although ocular toxicity is rare, careful evaluation of patients with visual symptoms on tamoxifen therapy is required.

  17. Establishment of a tamoxifen-inducible Cre-driver mouse strain for widespread and temporal genetic modification in adult mice.

    PubMed

    Ichise, Hirotake; Hori, Akiko; Shiozawa, Seiji; Kondo, Saki; Kanegae, Yumi; Saito, Izumu; Ichise, Taeko; Yoshida, Nobuaki

    2016-07-29

    Temporal genetic modification of mice using the ligand-inducible Cre/loxP system is an important technique that allows the bypass of embryonic lethal phenotypes and access to adult phenotypes. In this study, we generated a tamoxifen-inducible Cre-driver mouse strain for the purpose of widespread and temporal Cre recombination. The new line, named CM32, expresses the GFPneo-fusion gene in a wide variety of tissues before FLP recombination and tamoxifen-inducible Cre after FLP recombination. Using FLP-recombined CM32 mice (CM32Δ mice) and Cre reporter mouse lines, we evaluated the efficiency of Cre recombination with and without tamoxifen administration to adult mice, and found tamoxifen-dependent induction of Cre recombination in a variety of adult tissues. In addition, we demonstrated that conditional activation of an oncogene could be achieved in adults using CM32Δ mice. CM32Δ;T26 mice, which harbored a Cre recombination-driven, SV40 large T antigen-expressing transgene, were viable and fertile. No overt phenotype was found in the mice up to 3 months after birth. Although they displayed pineoblastomas (pinealoblastomas) and/or thymic enlargement due to background Cre recombination by 6 months after birth, they developed epidermal hyperplasia when administered tamoxifen. Collectively, our results suggest that the CM32Δ transgenic mouse line can be applied to the assessment of adult phenotypes in mice with loxP-flanked transgenes.

  18. Prevalence and predictors of night sweats, day sweats, and hot flashes in older primary care patients: an OKPRN study.

    PubMed

    Mold, James W; Roberts, Michelle; Aboshady, Hesham M

    2004-01-01

    We wanted to estimate the prevalence of night sweats, day sweats, and hot flashes in older primary care patients and identify associated factors. We undertook a cross-sectional study of patients older than 64 years recruited from the practices of 23 family physicians. Variables included sociodemographic information, health habits, chronic medical problems, symptoms, quality of life, and the degree to which patients were bothered by night sweats, daytime sweating, and hot flashes. Among the 795 patients, 10% reported being bothered by night sweats, 9% by day sweats, and 8% by hot flashes. Eighteen percent reported at least 1 of these symptoms. The 3 symptoms were strongly correlated. Factors associated with night sweats in the multivariate models were age (odds ratio [OR] 0.94/y; 95% confidence interval [CI], 0.89-0.98), fever (OR 12.60; 95% CI, 6.58-24.14), muscle cramps (OR 2.84; 95% CI, 1.53-5.24), numbness of hands and feet (OR 3.34; 95% CI, 1.92-5.81), impaired vision (OR 2.45; 95% CI, 1.41-4.27), and hearing loss (OR 1.84; 95% CI, 1.03-3.27). Day sweats were associated with fever (OR 4.10; 95% CI, 2.14-7.87), restless legs (OR 3.22; 95% CI, 1.76-5.89), lightheadedness (OR 2.24; 95% CI, 1.30-3.88), and diabetes (OR 2.19; 95% CI, 1.22-3.92). Hot flashes were associated with nonwhite race (OR 3.10; 95% CI, 1.60-5.98), fever (OR 3.98; 95% CI, 1.97-8.04), bone pain (OR 2.31; CI 95%: 1.30-4.08), impaired vision (OR 2.12; 95% CI, 1.19-3.79), and nervous spells (OR 1.87; 95% CI, 1.01-3.46). All 3 symptoms were associated with reduced quality of life. Many older patients are bothered by night sweats, day sweats, and hot flashes. Though these symptoms are similar and related, they have somewhat different associations with other variables. Clinical evaluation should include questions about febrile illnesses, sensory deficits, anxiety, depression, pain, muscle cramps, and restless legs syndrome.

  19. Efficacy of a non-hormonal treatment, BRN-01, on menopausal hot flashes: a multicenter, randomized, double-blind, placebo-controlled trial.

    PubMed

    Colau, Jean-Claude; Vincent, Stéphane; Marijnen, Philippe; Allaert, François-André

    2012-09-01

    Homeopathic medicines have a place among the non-hormonal therapies for the treatment of hot flashes during the menopause. The objective of this study was to evaluate the efficacy of the non-hormonal treatment BRN-01 in reducing hot flashes in menopausal women. This was a multicenter, randomized, double-blind, placebo-controlled study carried out between June 2010 and July 2011. The study was conducted in 35 active centers in France (gynecologists in private practice). One hundred and eight menopausal women, ≥ 50 years of age, were enrolled in the study. The eligibility criteria included menopause for <24 months and ≥ 5 hot flashes per day with a significant negative effect on the women's professional and/or personal life. Treatment was either BRN-01 tablets, a registered homeopathic medicine containing Actaea racemosa (4 centesimal dilutions [4CH]), Arnica montana (4CH), Glonoinum (4CH), Lachesis mutus (5CH), and Sanguinaria canadensis (4CH), or identical placebo tablets, prepared by Laboratoires Boiron according to European Pharmacopoeia standards. Oral treatment (2 to 4 tablets per day) was started on day 3 after study enrollment and was continued for 12 weeks. The main outcome measure was the hot flash score (HFS) compared before, during, and after treatment. Secondary outcome criteria were the quality of life (QoL) [measured using the Hot Flash Related Daily Interference Scale (HFRDIS)], severity of symptoms (measured using the Menopause Rating Scale), evolution of the mean dosage, and compliance. All adverse events (AEs) were recorded. One hundred and one women were included in the final analysis (intent-to-treat population: BRN-01, n = 50; placebo, n = 51). The global HFS over the 12 weeks, assessed as the area under the curve (AUC) adjusted for baseline values, was significantly lower in the BRN-01 group than in the placebo group (mean ± SD 88.2 ± 6.5 versus 107.2 ± 6.4; p = 0.0411). BRN-01 was well tolerated; the frequency of

  20. Presence of young children at home may moderate development of hot flashes during the menopausal transition.

    PubMed

    Lorenz, Tierney K; McGregor, Bonnie A; Vitzthum, Virginia J

    2015-04-01

    This work aims to determine the role of child care in hot flashes. Broad differences in vasomotor symptom experience are observed among perimenopausal women across cultures. Women in cultures where contact with young children is common report significantly fewer and less severe hot flashes than women in cultures where older women spend less time around children. Could these differences be related to the presence of young children? We surveyed 117 healthy women undergoing prophylactic bilateral oophorectomy (removal of both ovaries to reduce the risk of gynecologic cancers). Participants provided demographic information, including pre-surgical operation menopause status and number of children (younger than 13 y, 13-17 y, and 18 y or older) living at home. They were surveyed for menopausal symptoms 2 weeks before surgical operation and at 2 months, 6 months, and 1 year after surgical operation. Women who were premenopausal at the time of surgical operation experienced a significant increase in vasomotor symptoms. Within this group, participants with young children at home reported significantly fewer vasomotor symptoms across time than did women who did not live with young children. Women who were already menopausal at the time of surgical operation who had young children at home reported more vasomotor symptoms before surgical operation than did those without young children; however, this effect did not remain significant across follow-ups. These findings suggest that interactions with young children may mitigate hot flashes in women undergoing surgical menopause. These findings may be used to counsel women who are considering prophylactic oophorectomy about the likelihood of menopausal symptoms.

  1. An open, randomised, multicentre, phase 3 trial comparing the efficacy of two tamoxifen schedules in preventing gynaecomastia induced by bicalutamide monotherapy in prostate cancer patients.

    PubMed

    Bedognetti, Davide; Rubagotti, Alessandra; Conti, Giario; Francesca, Francesco; De Cobelli, Ottavio; Canclini, Luca; Gallucci, Michele; Aragona, Francesco; Di Tonno, Pasquale; Cortellini, Pietro; Martorana, Giuseppe; Lapini, Alberto; Boccardo, Francesco

    2010-02-01

    Bicalutamide monotherapy is a valuable option for prostate cancer (PCa) patients who wish to avoid the consequences of androgen deprivation; however, this treatment induces gynaecomastia and mastalgia in most patients. Tamoxifen is safe and effective in preventing breast events induced by bicalutamide monotherapy without affecting antitumor activity, but possible interference between bicalutamide and tamoxifen remains a matter of concern. To reduce the exposure to tamoxifen, we considered the putative advantages of weekly administration. To compare the efficacy of two different schedules of tamoxifen in preventing breast events. Toxicity, prostate-specific antigen behaviour, and sexual-functioning scores were also evaluated. This was a noninferiority trial. From December 2003 to February 2006, 80 patients with localised/locally advanced or biochemically recurrent PCa who were also candidates for bicalutamide single therapy were randomised to receive two different schedules of tamoxifen: daily (n=41) and weekly (n=39). Median follow-up was 24.2 mo. Daily bicalutamide (150 mg) plus daily tamoxifen 20mg continuously (daily group) or the same but with tamoxifen at 20mg weekly after the first 8 wk of daily treatment (weekly group). Three patients in the weekly group and one in the daily group were discontinued for adverse events. For gynaecomastia, we used ultrasonography. For mastalgia and sexual functioning, we used questionnaires. Gynaecomastia developed in 31.7% of patients in the daily group and in 74.4% of patients in the weekly group (p<0.0001), and it was more severe in patients who switched to weekly tamoxifen (p=0.001). Mastalgia occurred in 12.2% and 46.1% of patients, respectively (p=0.001). There were no major differences among treatment schedules relative to sexual functioning scores and incidence and severity of adverse events. No differences between groups in PSA behaviour and disease progression have been detected so far. This study demonstrated that

  2. Tamoxifen treatment in hamsters induces protection during taeniosis by Taenia solium.

    PubMed

    Escobedo, Galileo; Palacios-Arreola, M Isabel; Olivos, Alfonso; López-Griego, Lorena; Morales-Montor, Jorge

    2013-01-01

    Human neurocysticercosis by Taenia solium is considered an emergent severe brain disorder in developing and developed countries. Discovery of new antiparasitic drugs has been recently aimed to restrain differentiation and establishment of the T. solium adult tapeworm, for being considered a central node in the disease propagation to both pigs and humans. Tamoxifen is an antiestrogenic drug with cysticidal action on Taenia crassiceps, a close relative of T. solium. Thus, we evaluated the effect of tamoxifen on the in vitro evagination and the in vivo establishment of T. solium. In vitro, tamoxifen inhibited evagination of T. solium cysticerci in a dose-time dependent manner. In vivo, administration of tamoxifen to hamsters decreased the intestinal establishment of the parasite by 70%, while recovered tapeworms showed an 80% reduction in length, appearing as scolices without strobilar development. Since tamoxifen did not show any significant effect on the proliferation of antigen-specific immune cells, intestinal inflammation, and expression of Th1/Th2 cytokines in spleen and duodenum, this drug could exert its antiparasite actions by having direct detrimental effects upon the adult tapeworm. These results demonstrate that tamoxifen exhibits a strong cysticidal and antitaeniasic effect on T. solium that should be further explored in humans and livestock.

  3. Arachidonic acid-containing phosphatidylcholine characterized by consolidated plasma and liver lipidomics as an early onset marker for tamoxifen-induced hepatic phospholipidosis.

    PubMed

    Saito, Kosuke; Goda, Keisuke; Kobayashi, Akio; Yamada, Naohito; Maekawa, Kyoko; Saito, Yoshiro; Sugai, Shoichiro

    2017-08-01

    Lipid profiling has emerged as an effective approach to not only screen disease and drug toxicity biomarkers but also understand their underlying mechanisms of action. Tamoxifen, a widely used antiestrogenic agent for adjuvant therapy against estrogen-positive breast cancer, possesses side effects such as hepatic steatosis and phospholipidosis (PLD). In the present study, we administered tamoxifen to Sprague-Dawley rats and used lipidomics to reveal tamoxifen-induced alteration of the hepatic lipid profile and its association with the plasma lipid profile. Treatment with tamoxifen for 28 days caused hepatic PLD in rats. We compared the plasma and liver lipid profiles in treated vs. untreated rats using a multivariate analysis to determine differences between the two groups. In total, 25 plasma and 45 liver lipids were identified and altered in the tamoxifen-treated group. Of these lipids, arachidonic acid (AA)-containing phosphatidylcholines (PCs), such as PC (17:0/20:4) and PC (18:1/20:4), were commonly reduced in both plasma and liver. Conversely, tamoxifen increased other phosphoglycerolipids in the liver, such as phosphatidylethanolamine (18:1/18:1) and phosphatidylinositol (18:0/18:2). We also examined alteration of AA-containing PCs and some phosphoglycerolipids in the pre-PLD stage and found that these lipid alterations were initiated before pathological alteration in the liver. In addition, changes in plasma and liver levels of AA-containing PCs were linearly associated. Moreover, levels of free AA and mRNA levels of AA-synthesizing enzymes, such as fatty acid desaturase 1 and 2, were decreased by tamoxifen treatment. Therefore, our study demonstrated that AA-containing PCs might have potential utility as novel and predictive biomarkers for tamoxifen-induced PLD. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

  4. Alternatives to hormone therapy for hot flashes: many choices but science is lacking.

    PubMed

    Richardson, Marcie K

    2013-09-01

    A 51-year-old postmenopausal third-grade teacher requests help for her hot flashes. She finds them especially troubling as she stands in front of her class and starts sweating. Although one student offers her tissues, others make fun of her--disrupting the class. Her sleep is interrupted several times a night. She refuses to use any form of estrogen because her mother died of breast cancer at the age of 60 years. Perhaps alternative therapies can help her.

  5. Effects of flaxseed and Hypericum perforatum on hot flash, vaginal atrophy and estrogen-dependent cancers in menopausal women: a systematic review and meta-analysis.

    PubMed

    Ghazanfarpour, Masumeh; Sadeghi, Ramin; Latifnejad Roudsari, Robab; Khadivzadeh, Talat; Khorsand, Imaneh; Afiat, Maliheh; Esmaeilizadeh, Mahdi

    2016-01-01

    In this study, we aimed at evaluation of the efficacy of Hypericum perforatum and flaxseed on hot flash, vaginal atrophy and estrogen-dependent cancers in menopausal women. We searched MEDLINE, Scopus, and the Cochrane Central Register of Controlled Trials (RCT) to explore trials that assessed the effectiveness of H. perforatum and flaxseed on hot flash, vaginal atrophy and estrogen-dependent cancers. In this regard, the following terms were used "menopause AND H. perforatum OR flaxseed OR Linum usitatissimum. Only randomized controlled trials were included in the study. Nine RCTs were included in this systematic review. Based on the literature, flaxseed showed beneficial effect on hot flash frequency and intensity, which was not statistically significant. According to two trials, flaxseed showed estrogenic effects; however, no conclusion regarding cancer promoting or protecting effects can be made. The evidence of the efficacy of the flaxseed on alleviating vaginal atrophy was also limited due to inconsistent findings in this regard. One trial declared that Vitex agnus-castus and H. perforatum showed comparable decrease in the frequency of hot flashes. The results of our systematic review suggest beneficial effect on vasomotor symptom with both of flaxseed and H. perforatum. Consistent conclusion regarding estrogen-dependent cancers and maturation value is limited due to small number of trials related to flaxseed. Further trials are still needed to confirm the results of our systematic review.

  6. Is anxiety associated with hot flashes in women with breast cancer?

    PubMed

    Guimond, Anne-Josée; Massicotte, Elsa; Savard, Marie-Hélène; Charron-Drolet, Jade; Ruel, Sophie; Ivers, Hans; Savard, Josée

    2015-08-01

    Women with breast cancer are at higher risk for experiencing hot flashes (HFs), which is attributable, in large part, to systemic cancer treatments and their effects on estrogen levels. However, other factors, such as anxiety, could also play a role. This study aimed to assess the cross-sectional and temporal relationships between anxiety and HFs among women treated for breast cancer and to clarify the direction of these relationships. Fifty-six women recently treated for breast cancer were assessed prospectively using a 14-day Hot Flashes and Anxiety Diary (HFAD). Anxiety and HFs were also assessed using the Hospital Anxiety and Depression Scale-anxiety subscale and the Menopause-Specific Quality of Life Questionnaire-vasomotor subscale. In addition, HFs were objectively recorded for a continuous 24-hour period using home-based sternal skin conductance. No cross-sectional relationship was found between anxiety and subjectively assessed HFs, or between anxiety and the frequency and intensity of objectively assessed HFs. However, a greater anxiety level on the HFAD was significantly associated with a shorter time to reach the HF peak, as assessed with sternal skin conductance (partial Spearman correlation coefficient rsp = -0.44). Moreover, greater anxiety predicted more severe self-reported HFs on the following night, both assessed with the HFAD (rsp = 0.13). Conversely, self-reported diurnal and nocturnal HFs on the HFAD did not predict next-day anxiety level. This study reveals a significant relationship between anxiety and faster-developing objectively measured HFs. Furthermore, anxiety has been found to significantly predict subsequent increases in self-reported HFs, suggesting that strategies that target anxiety could potentially have a beneficial effect on HFs in women with breast cancer.

  7. A hot hole-programmed and low-temperature-formed SONOS flash memory

    PubMed Central

    2013-01-01

    In this study, a high-performance TixZrySizO flash memory is demonstrated using a sol–gel spin-coating method and formed under a low annealing temperature. The high-efficiency charge storage layer is formed by depositing a well-mixed solution of titanium tetrachloride, silicon tetrachloride, and zirconium tetrachloride, followed by 60 s of annealing at 600°C. The flash memory exhibits a noteworthy hot hole trapping characteristic and excellent electrical properties regarding memory window, program/erase speeds, and charge retention. At only 6-V operation, the program/erase speeds can be as fast as 120:5.2 μs with a 2-V shift, and the memory window can be up to 8 V. The retention times are extrapolated to 106 s with only 5% (at 85°C) and 10% (at 125°C) charge loss. The barrier height of the TixZrySizO film is demonstrated to be 1.15 eV for hole trapping, through the extraction of the Poole-Frenkel current. The excellent performance of the memory is attributed to high trapping sites of the low-temperature-annealed, high-κ sol–gel film. PMID:23899050

  8. Effects of flaxseed and Hypericum perforatum on hot flash, vaginal atrophy and estrogen-dependent cancers in menopausal women: a systematic review and meta-analysis

    PubMed Central

    Ghazanfarpour, Masumeh; Sadeghi, Ramin; Latifnejad Roudsari, Robab; Khadivzadeh, Talat; khorsand, Imaneh; Afiat, Maliheh; Esmaeilizadeh, Mahdi

    2016-01-01

    Objective: In this study, we aimed at evaluation of the efficacy of Hypericum perforatum and flaxseed on hot flash, vaginal atrophy and estrogen-dependent cancers in menopausal women Materials and Methods: We searched MEDLINE, Scopus, and the Cochrane Central Register of Controlled Trials (RCT) to explore trials that assessed the effectiveness of H. perforatum and flaxseed on hot flash, vaginal atrophy and estrogen-dependent cancers. In this regard, the following terms were used “menopause AND H. perforatum OR flaxseed OR Linum usitatissimum. Only randomized controlled trials were included in the study. Results: Nine RCTs were included in this systematic review. Based on the literature, flaxseed showed beneficial effect on hot flash frequency and intensity, which was not statistically significant. According to two trials, flaxseed showed estrogenic effects; however, no conclusion regarding cancer promoting or protecting effects can be made. The evidence of the efficacy of the flaxseed on alleviating vaginal atrophy was also limited due to inconsistent findings in this regard. One trial declared that Vitex agnus-castus and H. perforatum showed comparable decrease in the frequency of hot flashes. Conclusion: The results of our systematic review suggest beneficial effect on vasomotor symptom with both of flaxseed and H. perforatum. Consistent conclusion regarding estrogen-dependent cancers and maturation value is limited due to small number of trials related to flaxseed. Further trials are still needed to confirm the results of our systematic review. PMID:27462550

  9. Steroid receptor coactivators, HER-2 and HER-3 expression is stimulated by tamoxifen treatment in DMBA-induced breast cancer.

    PubMed

    Moi, Line L Haugan; Flågeng, Marianne Hauglid; Gjerde, Jennifer; Madsen, Andre; Røst, Therese Halvorsen; Gudbrandsen, Oddrun Anita; Lien, Ernst A; Mellgren, Gunnar

    2012-06-15

    Steroid receptor coactivators (SRCs) may modulate estrogen receptor (ER) activity and the response to endocrine treatment in breast cancer, in part through interaction with growth factor receptor signaling pathways. In the present study the effects of tamoxifen treatment on the expression of SRCs and human epidermal growth factor receptors (HERs) were examined in an animal model of ER positive breast cancer. Sprague-Dawley rats with DMBA-induced breast cancer were randomized to 14 days of oral tamoxifen 40 mg/kg bodyweight/day or vehicle only (controls). Tumors were measured throughout the study period. Blood samples and tumor tissue were collected at sacrifice and tamoxifen and its main metabolites were quantified using LC-MS/MS. The gene expression in tumor of SRC-1, SRC-2/transcription intermediary factor-2 (TIF-2), SRC-3/amplified in breast cancer 1 (AIB1), ER, HER-1, -2, -3 and HER-4, as well as the transcription factor Ets-2, was measured by real-time RT-PCR. Protein levels were further assessed by Western blotting. Tamoxifen and its main metabolites were detected at high concentrations in serum and accumulated in tumor tissue in up to tenfolds the concentration in serum. Mean tumor volume/rat decreased in the tamoxifen treated group, but continued to increase in controls. The mRNA expression levels of SRC-1 (P = 0.035), SRC-2/TIF-2 (P = 0.002), HER-2 (P = 0.035) and HER-3 (P = 0.006) were significantly higher in tamoxifen treated tumors compared to controls, and the results were confirmed at the protein level using Western blotting. SRC-3/AIB1 protein was also higher in tamoxifen treated tumors. SRC-1 and SRC-2/TIF-2 mRNA levels were positively correlated with each other and with HER-2 (P ≤ 0.001), and the HER-2 mRNA expression correlated with the levels of the other three HER family members (P < 0.05). Furthermore, SRC-3/AIB1 and HER-4 were positively correlated with each other and Ets-2 (P < 0.001). The expression of SRCs

  10. Steroid receptor coactivators, HER-2 and HER-3 expression is stimulated by tamoxifen treatment in DMBA-induced breast cancer

    PubMed Central

    2012-01-01

    Background Steroid receptor coactivators (SRCs) may modulate estrogen receptor (ER) activity and the response to endocrine treatment in breast cancer, in part through interaction with growth factor receptor signaling pathways. In the present study the effects of tamoxifen treatment on the expression of SRCs and human epidermal growth factor receptors (HERs) were examined in an animal model of ER positive breast cancer. Methods Sprague-Dawley rats with DMBA-induced breast cancer were randomized to 14 days of oral tamoxifen 40 mg/kg bodyweight/day or vehicle only (controls). Tumors were measured throughout the study period. Blood samples and tumor tissue were collected at sacrifice and tamoxifen and its main metabolites were quantified using LC-MS/MS. The gene expression in tumor of SRC-1, SRC-2/transcription intermediary factor-2 (TIF-2), SRC-3/amplified in breast cancer 1 (AIB1), ER, HER-1, -2, -3 and HER-4, as well as the transcription factor Ets-2, was measured by real-time RT-PCR. Protein levels were further assessed by Western blotting. Results Tamoxifen and its main metabolites were detected at high concentrations in serum and accumulated in tumor tissue in up to tenfolds the concentration in serum. Mean tumor volume/rat decreased in the tamoxifen treated group, but continued to increase in controls. The mRNA expression levels of SRC-1 (P = 0.035), SRC-2/TIF-2 (P = 0.002), HER-2 (P = 0.035) and HER-3 (P = 0.006) were significantly higher in tamoxifen treated tumors compared to controls, and the results were confirmed at the protein level using Western blotting. SRC-3/AIB1 protein was also higher in tamoxifen treated tumors. SRC-1 and SRC-2/TIF-2 mRNA levels were positively correlated with each other and with HER-2 (P ≤ 0.001), and the HER-2 mRNA expression correlated with the levels of the other three HER family members (P < 0.05). Furthermore, SRC-3/AIB1 and HER-4 were positively correlated with each other and Ets-2 (P < 0

  11. Cancer treatment: dealing with hot flashes and night sweats

    MedlinePlus

    ... women with certain types of breast cancer. Opioids. Strong pain relievers given to some people with cancer. Tamoxifen. A drug used to treat breast cancer in both women and men. It is also used to prevent cancer in ...

  12. Parietal disruption alters audiovisual binding in the sound-induced flash illusion.

    PubMed

    Kamke, Marc R; Vieth, Harrison E; Cottrell, David; Mattingley, Jason B

    2012-09-01

    Selective attention and multisensory integration are fundamental to perception, but little is known about whether, or under what circumstances, these processes interact to shape conscious awareness. Here, we used transcranial magnetic stimulation (TMS) to investigate the causal role of attention-related brain networks in multisensory integration between visual and auditory stimuli in the sound-induced flash illusion. The flash illusion is a widely studied multisensory phenomenon in which a single flash of light is falsely perceived as multiple flashes in the presence of irrelevant sounds. We investigated the hypothesis that extrastriate regions involved in selective attention, specifically within the right parietal cortex, exert an influence on the multisensory integrative processes that cause the flash illusion. We found that disruption of the right angular gyrus, but not of the adjacent supramarginal gyrus or of a sensory control site, enhanced participants' veridical perception of the multisensory events, thereby reducing their susceptibility to the illusion. Our findings suggest that the same parietal networks that normally act to enhance perception of attended events also play a role in the binding of auditory and visual stimuli in the sound-induced flash illusion. Copyright © 2012 Elsevier Inc. All rights reserved.

  13. Restoration of Tamoxifen Sensitivity in Estrogen Receptor–Negative Breast Cancer Cells: Tamoxifen-Bound Reactivated ER Recruits Distinctive Corepressor Complexes

    PubMed Central

    Sharma, Dipali; Saxena, Neeraj K.; Davidson, Nancy E.; Vertino, Paula M.

    2010-01-01

    Breast tumors expressing estrogen receptor-α (ER) respond well to therapeutic strategies using selective ER modulators, such as tamoxifen. However, ~ 30% of invasive breast cancers are hormone independent because they lack ER expression due to hypermethylation of ER promoter. Treatment of ER-negative breast cancer cells with demethylating agents [5-aza-2′-deoxycytidine (5-aza-dC)] and histone deacetylase (HDAC) inhibitors (trichostatin A) leads to expression of ER mRNA and functional protein. Here, we examined whether epigenetically reactivated ER is a target for tamoxifen therapy. Following treatment with trichostatin A and 5-aza-dC, the formerly unresponsive ER-negative MDA-MB-231 breast cancer cells became responsive to tamoxifen. Tamoxifen-mediated inhibition of cell growth in these cells is mediated at least in part by the tamoxifen-bound ER. Tamoxifen-bound reactivated ER induces transcriptional repression at estrogen-responsive genes by ordered recruitment of multiple distinct chromatin-modifying complexes. Using chromatin immunoprecipitation, we show recruitment of two different corepressor complexes to ER-responsive promoters in a mutually exclusive and sequential manner: the nuclear receptor corepressor-HDAC3 complex followed by nucleosome remodeling and histone deacetylation complex. The mechanistic insight provided by this study might help in designing therapeutic strategies directed toward epigenetic mechanisms in the prevention or treatment of breast cancer. PMID:16778215

  14. Tamoxifen dosing for Cre-mediated recombination in experimental bronchopulmonary dysplasia.

    PubMed

    Ruiz-Camp, Jordi; Rodríguez-Castillo, José Alberto; Herold, Susanne; Mayer, Konstantin; Vadász, István; Tallquist, Michelle D; Seeger, Werner; Ahlbrecht, Katrin; Morty, Rory E

    2017-02-01

    Bronchopulmonary dysplasia (BPD) is the most common complication of preterm birth characterized by blunted post-natal lung development. BPD can be modelled in mice by exposure of newborn mouse pups to elevated oxygen levels. Little is known about the mechanisms of perturbed lung development associated with BPD. The advent of transgenic mice, where genetic rearrangements can be induced in particular cell-types at particular time-points during organogenesis, have great potential to explore the pathogenic mechanisms at play during arrested lung development. Many inducible, conditional transgenic technologies available rely on the application of the estrogen-receptor modulator, tamoxifen. While tamoxifen is well-tolerated and has been widely employed in adult mice, or in healthy developing mice; tamoxifen is not well-tolerated in combination with hyperoxia, in the most widely-used mouse model of BPD. To address this, we set out to establish a safe and effective tamoxifen dosing regimen that can be used in newborn mouse pups subjected to injurious stimuli, such as exposure to elevated levels of environmental oxygen. Our data reveal that a single intraperitoneal dose of tamoxifen of 0.2 mg applied to newborn mouse pups in 10 μl Miglyol vehicle was adequate to successfully drive Cre recombinase-mediated genome rearrangements by the fifth day of life, in a murine model of BPD. The number of recombined cells was comparable to that observed in regular tamoxifen administration protocols. These findings will be useful to investigators where tamoxifen dosing is problematic in the background of injurious stimuli and mouse models of human and veterinary disease.

  15. Influence of tangeretin on tamoxifen's therapeutic benefit in mammary cancer.

    PubMed

    Bracke, M E; Depypere, H T; Boterberg, T; Van Marck, V L; Vennekens, K M; Vanluchene, E; Nuytinck, M; Serreyn, R; Mareel, M M

    1999-02-17

    Tamoxifen and the citrus flavonoid tangeretin exhibit similar inhibitory effects on the growth and invasive properties of human mammary cancer cells in vitro; furthermore, the two agents have displayed additive effects in vitro. In this study, we examined whether tangeretin would enhance tamoxifen's therapeutic benefit in vivo. Female nude mice (n = 80) were inoculated subcutaneously with human MCF-7/6 mammary adenocarcinoma cells. Groups of 20 mice were treated orally by adding the following substances to their drinking water: tamoxifen (3 x 10(-5) M), tangeretin (1 x 10(-4) M), tamoxifen plus tangeretin (3 x 10(-5) M plus 1 x 10(-4) M), or solvent. Oral treatment of mice with tamoxifen resulted in a statistically significant inhibition of tumor growth compared with solvent treatment (two-sided P = .001). Treatment with tangeretin did not inhibit tumor growth, and addition of this compound to drinking water with tamoxifen completely neutralized tamoxifen's inhibitory effect. The median survival time of tumor-bearing mice treated with tamoxifen plus tangeretin was reduced in comparison with that of mice treated with tamoxifen alone (14 versus 56 weeks; two-sided P = .002). Tangeretin (1 x 10(-6) M or higher) inhibited the cytolytic effect of murine natural killer cells on MCF-7/6 cells in vitro, which may explain why tamoxifen-induced inhibition of tumor growth in mice is abolished when tangeretin is present in drinking water. We describe an in vivo model to study potential interference of dietary compounds, such as flavonoids, with tamoxifen, which could lead to reduced efficacy of adjuvant therapy. In our study, the tumor growth-inhibiting effect of oral tamoxifen was reversed upon addition of tangeretin to the diet. Our data argue against excessive consumption of tangeretin-added products and supplements by patients with mammary cancer during tamoxifen treatment.

  16. Regulation of tamoxifen sensitivity by a PAK1–EBP1 signalling pathway in breast cancer

    PubMed Central

    Ghosh, A; Awasthi, S; Peterson, J R; Hamburger, A W

    2013-01-01

    Background: EBP1, an ErbB3-binding protein, sensitises breast cancer cells to tamoxifen in part by decreasing ErbB2 protein levels. The p21-regulated serine/threonine kinase PAK1, implicated in tamoxifen resistance, phosphorylates EBP1 in vitro and in vivo at T261. Phosphorylation of EBP1 at this site induces tamoxifen resistance. We thus postulated that inhibition of PAK1 activity, by restoring EBP1 function, could ameliorate the hormone refractory phenotype of ErbB2-overexpressing breast cancer cells. Methods: Effects of EBP1 on ErbB2 levels were measured by western blotting. Effects of EBP1 and IPA-3 on tamoxifen sensitivity were measured using a tetrazolium based cell viability assay. Results: Transient transfection studies indicated that an EBP1 T261E mutant, which mimics EPB1 phosphorylated by PAK1, increased ErbB2 protein levels. An EBP1 T261A mutant, unable to be phosphorylated by PAK1, ameliorated PAK1-induced tamoxifen resistance, suggesting that phosphorylation of EBP1 by PAK1 contributes to tamoxifen resistance. We then tested if pharmacological inhibition of PAK1 activity might render hormone resistant cells, which endogenously overexpress PAK1, tamoxifen sensitive. IPA-3, a specific small MW PAK1 inhibitor, sensitised cells to tamoxifen only when EBP1 was ectopically expressed. IPA had no effect on tamoxifen resistance in T47D cells in which EBP1 protein had been ablated by shRNA. The IPA-induced increase in tamoxifen sensitivity was accompanied by a decrease in ErbB2 levels only in EBP1-overexpressing cells. Conclusion: These studies suggest that phosphorylation of EBP1 may be one mechanism of PAK1-induced hormone resistance and that PAK1 inhibitors may be useful in cells in which EBP1 is overexpressed. PMID:23361053

  17. Tamoxifen for the management of breast events induced by non-steroidal antiandrogens in patients with prostate cancer: a systematic review

    PubMed Central

    2012-01-01

    Background Tamoxifen has emerged as a potential management option for gynecomastia and breast pain due to non-steroidal antiandrogens, and it is considered an alternative to surgery or radiotherapy. The objective of this systematic review was to assess the benefits and harms of tamoxifen, in comparison to other treatment options, for either the prophylaxis or treatment of breast events induced by non-steroidal antiandrogens in prostate cancer patients. Methods We searched CENTRAL, MEDLINE, EMBASE, reference lists, the abstracts of three major conferences and three trial registers to identify ongoing randomized controlled trials (RCTs). Two authors independently screened the articles identified, assessed the trial quality and extracted data. The protocol was prospectively registered (CRD42011001320; http://www.crd.york.ac.uk/PROSPERO). Results Four studies were identified. Tamoxifen significantly reduced the risk of suffering from gynecomastia (risk ratio 9RR0 0.10, 95% CI 0.05 to 0.22) or breast pain (RR 0.06, 95% CI 0.02 to 0.17) at six months compared to untreated controls. Tamoxifen also showed a significant benefit for the prevention of gynecomastia (RR 0.22, 95% CI 0.08 to 0.58) and breast pain (RR 0.25, 95% CI 0.10 to 0.64) when compared to anastrozole after a median of 12 months. One study showed a significant benefit of tamoxifen for the prevention of gynecomastia (RR 0.24, 95% CI 0.09 to 0.65) and breast pain (RR 0.20, 95% CI 0.06 to 0.65) when compared with radiotherapy at six months. Radiotherapy increased the risk of suffering from nipple erythema and skin irritation, but there were no significant differences for any other adverse events (all P > 0.05). Conclusions The currently available evidence suggests good efficacy of tamoxifen for the prevention and treatment of breast events induced by non-steroidal antiandrogens. The impact of tamoxifen therapy on long-term adverse events, disease progression and survival remains unclear. Further large, well

  18. Tamoxifen accelerates the repair of demyelinated lesions in the central nervous system

    PubMed Central

    Gonzalez, Ginez A.; Hofer, Matthias P.; Syed, Yasir A.; Amaral, Ana I.; Rundle, Jon; Rahman, Saifur; Zhao, Chao; Kotter, Mark R. N.

    2016-01-01

    Enhancing central nervous system (CNS) myelin regeneration is recognized as an important strategy to ameliorate the devastating consequences of demyelinating diseases such as multiple sclerosis. Previous findings have indicated that myelin proteins, which accumulate following demyelination, inhibit remyelination by blocking the differentiation of rat oligodendrocyte progenitor cells (OPCs) via modulation of PKCα. We therefore screened drugs for their potential to overcome this differentiation block. From our screening, tamoxifen emerges as a potent inducer of OPC differentiation in vitro. We show that the effects of tamoxifen rely on modulation of the estrogen receptors ERα, ERβ, and GPR30. Furthermore, we demonstrate that administration of tamoxifen to demyelinated rats in vivo accelerates remyelination. Tamoxifen is a well-established drug and is thus a promising candidate for a drug to regenerate myelin, as it will not require extensive safety testing. In addition, Tamoxifen plays an important role in biomedical research as an activator of inducible genetic models. Our results highlight the importance of appropriate controls when using such models. PMID:27554391

  19. Is Homeopathy Effective for Hot Flashes and Other Estrogen-Withdrawal Symptoms in Breast Cancer Survivors? A Preliminary Randomized Controlled Trial

    DTIC Science & Technology

    2003-04-01

    homeopathy may be effective in improving hot flashes and quality of life in breast cancer survivors with symptoms of estrogen withdrawal. Methods- A...scores improved significantly in both homeopathy groups compared to placebo. Results of this study suggest that a larger study should be done.

  20. Study of experimental endometriosis using fluorescence of eosin-tamoxifen association

    NASA Astrophysics Data System (ADS)

    Brogniez, A.; Mordon, Serge R.; Devoisselle, Jean-Marie; Querleu, Denis; Brunetaud, Jean Marc

    1993-08-01

    The main problem of endometriosis is the detection of microscopic and atypical lesions. The successful destruction of these endometriotic sites depends on their detection. This study aimed to develop a spectrofluorometric method to increase the sensitivity of detection of endometriosis. A surgical-induced endometriosis was performed in ten rabbits. Five weeks later, the fluorescence of these endometriotic lesions was studied after injection of tamoxifen and local application of eosin. This fluorescence was compared with that of healthy broad ligament and that obtained without tamoxifen and without eosin. A spectral analysis showed a specific fluorescence of eosin-tamoxifen association, more intense than autofluorescence and selectively observed within endometriosis.

  1. Temporal Binding Window of the Sound-Induced Flash Illusion in Amblyopia.

    PubMed

    Narinesingh, Cindy; Goltz, Herbert C; Wong, Agnes M F

    2017-03-01

    Amblyopia is a neurodevelopmental visual disorder caused by abnormal visual experience in childhood. In addition to known visual deficits, there is evidence for changes in audiovisual integration in amblyopia using explicit tasks. We examined audiovisual integration in amblyopia using an implicit task that is more relevant in a real-world context. A total of 11 participants with amblyopia and 16 controls were tested binocularly and monocularly on the sound-induced flash illusion, in which flashes and beeps are presented concurrently and the perceived number of flashes is influenced by the number of beeps. The task used 1 to 2 rapid peripheral flashes presented with 0 to 2 beeps, at 5 stimulus onset asynchronies, that is, beep (-200 milliseconds, -100 milliseconds) or flash leading (100 milliseconds, 200 milliseconds) or simultaneous (0 milliseconds). Participants reported the number of perceived flashes. Susceptibility was indicated by a "2 flashes" response to "fission" (1 flash, 2 beeps) or "1 flash" to "fusion" (2 flashes, 1 beep). For fission with the beep leading during binocular viewing, controls showed an expected decrease in illusion strength as stimulus onset asynchronies increased, whereas the illusion strength remained constant in participants with amblyopia, indicating a wider temporal binding window in amblyopia (P = 0.007). For fusion, participants with amblyopia showed reduced illusion strength during amblyopic eye viewing (P = 0.044) with the flash leading. Amblyopia is associated with the widening of the temporal binding window, specifically for fission when viewing binocularly with the beep leading. This suggests a developmental adaptation to delayed amblyopic eye visual processing to optimize audiovisual integration.

  2. Is Homeopathy Effective for Hot Flashes and Other Estrogen-Withdrawl Symptoms in Breast Cancer Survivors? A Preliminary Randomized Controlled Trial

    DTIC Science & Technology

    2001-09-01

    symptoms for more than 100 years. To carry out a pilot study to determine whether there is evidence that homeopathy is an effective treatment to improve the...one month, with at least 3 hot flashes per day. Subjects have been randomized to one of three treatment arms: classical homeopathy , a combination

  3. Refined protocols of tamoxifen injection for inducible DNA recombination in mouse astroglia.

    PubMed

    Jahn, Hannah M; Kasakow, Carmen V; Helfer, Andreas; Michely, Julian; Verkhratsky, Alexei; Maurer, Hans H; Scheller, Anja; Kirchhoff, Frank

    2018-04-12

    Inducible DNA recombination of floxed alleles in vivo by liver metabolites of tamoxifen (TAM) is an important tool to study gene functions. Here, we describe protocols for optimal DNA recombination in astrocytes, based on the GLAST-Cre ERT2 /loxP system. In addition, we demonstrate that quantification of genomic recombination allows to determine the proportion of cell types in various brain regions. We analyzed the presence and clearance of TAM and its metabolites (N-desmethyl-tamoxifen, 4-hydroxytamoxifen and endoxifen) in brain and serum of mice by liquid chromatographic-high resolution-tandem mass spectrometry (LC-HR-MS/MS) and assessed optimal injection protocols by quantitative RT-PCR of several floxed target genes (p2ry1, gria1, gabbr1 and Rosa26-tdTomato locus). Maximal recombination could be achieved in cortex and cerebellum by single daily injections for five and three consecutive days, respectively. Furthermore, quantifying the loss of floxed alleles predicted the percentage of GLAST-positive cells (astroglia) per brain region. We found that astrocytes contributed 20 to 30% of the total cell number in cortex, hippocampus, brainstem and optic nerve, while in the cerebellum Bergmann glia, velate astrocytes and white matter astrocytes accounted only for 8% of all cells.

  4. ANXIETY REDUCTION AMONG BREAST-CANCER SURVIVORS RECEIVING HYPNOTIC RELAXATION THERAPY FOR HOT FLASHES

    PubMed Central

    Johnson, Alisa J.; Marcus, Joel; Hickman, Kimberly; Barton, Debra; Elkins, Gary

    2017-01-01

    Anxiety is common among breast-cancer survivors. This analysis examined the effect of a hypnotic relaxation therapy, developed to reduce hot flashes, on anxiety levels of female breast-cancer survivors. Anxiety was assessed using a numeric analog scale and the Hospital Anxiety and Depression Scale-Anxiety subscale. Significant reductions in anxiety were found from pre- to postintervention for each weekly session and were predictive of overall reductions in anxiety from baseline to after the last intervention. In this analysis, hypnotizability did not significantly predict for anxiety reductions measured before and after each session or from baseline to exit. These data provide initial support for the use of hypnotic relaxation therapy to reduce anxiety among breast-cancer survivors. PMID:27585723

  5. Anxiety Reduction Among Breast-Cancer Survivors Receiving Hypnotic Relaxation Therapy for Hot Flashes.

    PubMed

    Johnson, Alisa J; Marcus, Joel; Hickman, Kimberly; Barton, Debra; Elkins, Gary

    2016-01-01

    Anxiety is common among breast-cancer survivors. This analysis examined the effect of a hypnotic relaxation therapy, developed to reduce hot flashes, on anxiety levels of female breast-cancer survivors. Anxiety was assessed using a numeric analog scale and the Hospital Anxiety and Depression Scale-Anxiety subscale. Significant reductions in anxiety were found from pre- to postintervention for each weekly session and were predictive of overall reductions in anxiety from baseline to after the last intervention. In this analysis, hypnotizability did not significantly predict for anxiety reductions measured before and after each session or from baseline to exit. These data provide initial support for the use of hypnotic relaxation therapy to reduce anxiety among breast-cancer survivors.

  6. The Relationship between Hot Flashes and Testosterone Recovery after 12 Months of Androgen Suppression for Men with Localised Prostate Cancer in the ASCENDE-RT Trial.

    PubMed

    Dosani, M; Morris, W J; Tyldesley, S; Pickles, T

    2017-10-01

    This study describes the proportion of men who experienced hot flashes (flashes), and the testosterone level at onset, peak frequency and cessation of flashes after 12 months of androgen deprivation therapy (ADT) in men undergoing curative-intent external beam radiation therapy (± brachytherapy boost). We also aimed to characterise testosterone recovery in this population. This was a pre-specified secondary analysis of the ASCENDE-RT clinical trial. Three hundred and ninety-eight men were randomised. All received 12 months of ADT. The presence and frequency of flashes were patient reported. Cessation of flashes was defined as the first date a patient reported resolution of this symptom. Testosterone recovery was defined as any single serum testosterone above the threshold of 5, 7.5 or 10 nmol/l. The median age and follow-up were 68 years and 6.1 years. Flashes were reported in 93% of men. Flashes began and reached peak frequency at a median time of 4.0 months from the first luteinizing hormone-releasing hormone injection when testosterone levels had fallen to castrate. The median time to cessation of flashes was 7.6 months after the cessation of ADT (last injection + 3 months), when the median testosterone had risen to 5.7 nmol/l. A resolution of flashes was reported in 99% of patients. Baseline testosterone was available in 338 patients (85%). The median baseline testosterone was 13.2 nmol/l. The median (95% confidence interval) time of testosterone recovery to thresholds of 5 nmol/l, 7.5 nmol/l and 10 nmol/l were 9 (9-10) months, 13 (10-15) months and 18 (17-19) months from the cessation of ADT. At the time of censor, 96, 94 and 91% of patients had recovered testosterone to thresholds of 5, 7.5 and 10 nmol/l. Flashes occur at castrate levels of testosterone, with cessation of hot flashes antedating full recovery of testosterone in most patients. Rates of testosterone recovery after 12 months of ADT exceed 90%, although it can be delayed. Copyright © 2017 The

  7. Switching to letrozole or exemestane improves hot flushes, mood and quality of life in tamoxifen intolerant women

    PubMed Central

    Thomas, R; Williams, M; Marshall, C; Walker, L

    2008-01-01

    We report an open-label, prospective, crossover study involving 184 post-menopausal women experiencing hot flushes on adjuvant tamoxifen (T). Six weeks after switching to an AI, the primary end point, hot flush score, improved by 47.3% (P<0.001) compared to those reported on T. The mean mood rating scale (MRS) score improved by 9.7% (P=0.01). The total mean combined FACT (b+es) score improved from 134.2 (95% CI ±2.96) to 143.5 (95% CI ±2.96 <0.001), and the endocrine subscale improved by 9.8% from 51.73 (95% CI ±1.38) to 57.34 (CI ±1.38, P<0.001). At 6 weeks, significantly more women chose to remain on an AI: 133 (72%), vs 40 (22%) (P<0.001) preferring T. At 3 months, 107 (58%) preferred to remain on an AI, 55(30%) on T, and 22 (12%) withdrew. The overall arthralgia rate at 3 months was 47% on AI and 30% on T (P=0.001). In all 182 (99%) women reported appreciating the opportunity to experience both drugs. These data suggest that if patients suffering significant adverse effects on T are given the opportunity to try an AI, this empowers them to prioritise relative side-effects, improving wellbeing in a significant proportion. These data also highlight the need for hospital follow-up in this intolerant cohort. PMID:18392053

  8. Differential effects of tamoxifen and anastrozole on optic cup size in breast cancer survivors

    PubMed Central

    Toomey, Maureen D.; Falardeau, Julie; Samples, John R.; Vetto, John T.

    2007-01-01

    Introduction The main purpose of this study was to determine whether the optic cups of tamoxifen users and anastrozole users differ in size, with the cups of the tamoxifen users being smaller. Methods Optic nerve head (ONH) topography was measured using a commercially available, confocal scanning laser ophthalmoscope for three populations of amenorrheic women ages 40–69 years: subjects using (1) tamoxifen (20 mg/day) or (2) anastrozole (1 mg/day) for ≤ 2 years as adjuvant therapy after successful primary treatment for breast cancer, and (3) control subjects with no breast cancer histories and not using any hormonal medication. All subjects had excellent visual acuity and healthy eyes, based on conventional photographic assessment. Results The cup volumes of the tamoxifen users were shown to be significantly smaller than the cup volumes of the anastrozole users, which were indistinguishable from normal. Because the cup volumes of the tamoxifen users decreased markedly with age at about 50 years and because anastrozole is indicated only for post-menopausal women, comparisons were reassessed for subjects older than 50 years. For these subjects, the cup volumes of the tamoxifen users averaged less than half of the volumes for each of the other two subject groups, and significant between-group differences existed in both the lateral (cup area) and axial (cup depth) directions. In contrast, any between-group differences at the ONH margin were small and not significant. Conclusions The results of this study suggest that the ONH be assessed biomorphometrically for tamoxifen users reporting visual change that cannot be attributed to non-tamoxifen causes. The ability of modern intraocular imaging techniques to reveal anatomic change on the order of tens of microns may be useful for assessing tamoxifen-induced effects occurring simultaneously elsewhere in the brain, particularly since the presence of small cups is consistent with the possibility of tamoxifen-induced

  9. Induction of UO-44 gene expression by tamoxifen in the rat uterus and ovary.

    PubMed

    Huynh, H; Ng, C Y; Lim, K B; Ong, C K; Ong, C S; Tran, E; Tuyen Nguyen, T T; Chan, T W

    2001-07-01

    A complementary DNA, uterine-ovarian-specific gene 44 (UO-44), has been isolated from tamoxifen-induced rat uterine complementary DNA library using differential display techniques. UO-44 transcripts are found to be abundant in the uterus and ovary. UO-44 gene expression in the uterus is strictly regulated by estrogens, tamoxifen, and GH, whereas the pure antiestrogen ICI 182780 is inhibitory. Treatment of ovariectomized rats and hypophysectomized rats with tamoxifen and GH, respectively, resulted in up-regulation of UO-44 expression in a dose-dependent manner. In situ hybridization revealed that UO-44 gene expression was restricted to the luminal and glandular epithelial cells of the uterus and to granulosa cells of medium-size ovarian follicles. Transfection studies showed that UO-44 was a membrane-associated protein. Because estrogens, tamoxifen, and GH are stimulators of uterine luminal epithelial cell growth in vivo, UO-44 protein may serve as a mediator of the effect of these compounds in inducing epithelial proliferation and differentiation in these tissues.

  10. Flash (Ultra-Rapid) Spark-Plasma Sintering of Silicon Carbide

    PubMed Central

    Olevsky, Eugene A.; Rolfing, Stephen M.; Maximenko, Andrey L.

    2016-01-01

    A new ultra-rapid process of flash spark plasma sintering is developed. The idea of flash spark plasma sintering (or flash hot pressing - FHP) stems from the conducted theoretical analysis of the role of thermal runaway phenomena for material processing by flash sintering. The major purpose of the present study is to theoretically analyze the thermal runaway nature of flash sintering and to experimentally address the challenge of uncontrollable thermal conditions by the stabilization of the flash sintering process through the application of the external pressure. The effectiveness of the developed FHP technique is demonstrated by the few seconds–long consolidation of SiC powder in an industrial spark plasma sintering device. Specially designed sacrificial dies heat the pre-compacted SiC powder specimens to a critical temperature before applying any voltage to the powder volume and allowing the electrode-punches of the SPS device setup to contact the specimens and pass electric current through them under elevated temperatures. The experimental results demonstrate that flash sintering phenomena can be realized using conventional SPS devices. The usage of hybrid heating SPS devices is pointed out as the mainstream direction for the future studies and utilization of the new flash hot pressing (ultra-rapid spark plasma sintering) technique. PMID:27624641

  11. Flash (Ultra-Rapid) Spark-Plasma Sintering of Silicon Carbide

    DOE PAGES

    Olevsky, Eugene A.; Rolfing, Stephen M.; Maximenko, Andrey L.

    2016-09-14

    A new ultra-rapid process of flash spark plasma sintering is developed. The idea of flash spark plasma sintering (or flash hot pressing - FHP) stems from the conducted theoretical analysis of the role of thermal runaway phenomena for material processing by flash sintering. The major purpose of the present study is to theoretically analyze the thermal runaway nature of flash sintering and to experimentally address the challenge of uncontrollable thermal conditions by the stabilization of the flash sintering process through the application of the external pressure. The effectiveness of the developed FHP technique is demonstrated by the few seconds–long consolidationmore » of SiC powder in an industrial spark plasma sintering device. Specially designed sacrificial dies heat the pre-compacted SiC powder specimens to a critical temperature before applying any voltage to the powder volume and allowing the electrode-punches of the SPS device setup to contact the specimens and pass electric current through them under elevated temperatures. The experimental results demonstrate that flash sintering phenomena can be realized using conventional SPS devices. The usage of hybrid heating SPS devices is pointed out as the mainstream direction for the future studies and utilization of the new flash hot pressing (ultra-rapid spark plasma sintering) technique.« less

  12. Tamoxifen affects glucose and lipid metabolism parameters, causes browning of subcutaneous adipose tissue and transient body composition changes in C57BL/6NTac mice

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Hesselbarth, Nico; Pettinelli, Chiara; Gericke, Martin

    Tamoxifen is a selective estrogen receptor (ER) modulator which is widely used to generate inducible conditional transgenic mouse models. Activation of ER signaling plays an important role in the regulation of adipose tissue (AT) metabolism. We therefore tested the hypothesis that tamoxifen administration causes changes in AT biology in vivo. 12 weeks old male C57BL/6NTac mice were treated with either tamoxifen (n = 18) or vehicle (n = 18) for 5 consecutive days. Tamoxifen treatment effects on body composition, energy homeostasis, parameters of AT biology, glucose and lipid metabolism were investigated up to an age of 18 weeks. We found that tamoxifen treatment causes: I)more » significantly increased HbA{sub 1c}, triglyceride and free fatty acid serum concentrations (p < 0.01), II) browning of subcutaneous AT and increased UCP-1 expression, III) increased AT proliferation marker Ki67 mRNA expression, IV) changes in adipocyte size distribution, and V) transient body composition changes. Tamoxifen may induce changes in body composition, whole body glucose and lipid metabolism and has significant effects on AT biology, which need to be considered when using Tamoxifen as a tool to induce conditional transgenic mouse models. Our data further suggest that tamoxifen-treated wildtype mice should be characterized in parallel to experimental transgenic models to control for tamoxifen administration effects. - Highlights: • Tamoxifen treatment causes significantly increased HbA{sub 1c}, triglyceride and free fatty acid serum concentrations. • Tamoxifen induces browning of subcutaneous AT and increased UCP-1 expression. • Tamoxifen changes adipocyte size distribution, and transient body composition.« less

  13. Do Japanese American Women Really Have Fewer Hot Flashes than European Americans? The Hilo Women's Health Study

    PubMed Central

    Brown, Daniel E.; Sievert, Lynnette Leidy; Morrison, Lynn A.; Reza, Angela M.; Mills, Phoebe S.

    2009-01-01

    Objective Many studies have found a significantly lower frequency of reported hot flashes (HFs) in Japanese and Japanese American (JA) populations, leading to speculation about possible dietary, genetic, or cultural differences. These studies have relied upon subjective reports of HFs. Accordingly, the purpose of this study was to compare both reported and objective HFs measured by sternal and nuchal skin conductance among JA and European American (EA) women. Design Two surveys of hot flash frequencies were carried out among women of either EA or JA ethnicity, aged 45-55, living in Hilo, Hawaii, and not using exogenous hormones. The first was a postal questionnaire (N=325), the second was carried out during a clinical study of hot flashes (N=134). Women in the second group underwent 24-hour ambulatory and 3-hour laboratory monitoring for objective HFs measured through skin conductance at sternal and nuchal sites. Subjective HFs were recorded on the monitor, or in a diary. Results JAs were significantly less likely to report having had HFs in the previous two weeks compared with EAs (postal sample: JAs: 30.9%, EAs: 43.9%, χ2=6.9, p < .01; monitored sample: JAs: 26.1%, EAs: 46.6%, χ2=5.3, p < 0.05). JAs were also significantly less likely to report experiencing other symptoms (15 out of 30 in the postal sample; 6 of 30 in the monitored sample) than EAs. However, JAs did not significantly differ in likelihood of reporting subjective HFs during the 24-hour ambulatory period (JAs: 51.1%, EAs: 55.8%, χ2=0.3, ns), nor in percentage of individuals displaying one or more objective HFs as measured by the skin conductance monitor (JAs: 77.8%, EAs: 72.1%, χ2=0.5, ns). JAs also did not have a significantly fewer number of objective HFs (t=0.2, ns) nor of subjective HFs (t = 0.8, ns) during the monitoring period, and these results were unchanged when analyses controlled for menopausal status and BMI. Conclusions The common finding of fewer reported HFs in people of Japanese

  14. Direct and Systemic Administration of a CNS-Permeant Tamoxifen Analog Reduces Amphetamine-Induced Dopamine Release and Reinforcing Effects.

    PubMed

    Carpenter, Colleen; Zestos, Alexander G; Altshuler, Rachel; Sorenson, Roderick J; Guptaroy, Bipasha; Showalter, Hollis D; Kennedy, Robert T; Jutkiewicz, Emily; Gnegy, Margaret E

    2017-09-01

    Amphetamines (AMPHs) are globally abused. With no effective treatment for AMPH addiction to date, there is urgent need for the identification of druggable targets that mediate the reinforcing action of this stimulant class. AMPH-stimulated dopamine efflux is modulated by protein kinase C (PKC) activation. Inhibition of PKC reduces AMPH-stimulated dopamine efflux and locomotor activity. The only known CNS-permeant PKC inhibitor is the selective estrogen receptor modulator tamoxifen. In this study, we demonstrate that a tamoxifen analog, 6c, which more potently inhibits PKC than tamoxifen but lacks affinity for the estrogen receptor, reduces AMPH-stimulated increases in extracellular dopamine and reinforcement-related behavior. In rat striatal synaptosomes, 6c was almost fivefold more potent at inhibiting AMPH-stimulated dopamine efflux than [ 3 H]dopamine uptake through the dopamine transporter (DAT). The compound did not compete with [ 3 H]WIN 35,428 binding or affect surface DAT levels. Using microdialysis, direct accumbal administration of 1 μM 6c reduced dopamine overflow in freely moving rats. Using LC-MS, we demonstrate that 6c is CNS-permeant. Systemic treatment of rats with 6 mg/kg 6c either simultaneously or 18 h prior to systemic AMPH administration reduced both AMPH-stimulated dopamine overflow and AMPH-induced locomotor effects. Finally, 18 h pretreatment of rats with 6 mg/kg 6c s.c. reduces AMPH-self administration but not food self-administration. These results demonstrate the utility of tamoxifen analogs in reducing AMPH effects on dopamine and reinforcement-related behaviors and suggest a new avenue of development for therapeutics to reduce AMPH abuse.

  15. Deterministic filtering of breakdown flashing at telecom wavelengths

    NASA Astrophysics Data System (ADS)

    Marini, Loris; Camphausen, Robin; Eggleton, Benjamin J.; Palomba, Stefano

    2017-11-01

    Breakdown flashes are undesired photo-emissions from the active area of single-photon avalanche photo-diodes. They arise from radiative recombinations of hot carriers generated during an avalanche and can induce crosstalk, compromise the measurement of optical quantum states, and hinder the security of quantum communications. Although the spectrum of this emission extends over hundreds of nanometers, active quenching may lead to a smaller uncertainty in the time of emission, thus enabling deterministic filtering. Our results pave the way to broadband interference mitigation in time-correlated single-photon applications.

  16. Tamoxifen Provides Structural and Functional Rescue in Murine Models of Photoreceptor Degeneration

    PubMed Central

    Wang, Xu; Ma, Wenxin; Gonzalez, Shaimar R.; Kretschmer, Friedrich; Badea, Tudor C.

    2017-01-01

    Photoreceptor degeneration is a cause of irreversible vision loss in incurable blinding retinal diseases including retinitis pigmentosa (RP) and atrophic age-related macular degeneration. We found in two separate mouse models of photoreceptor degeneration that tamoxifen, a selective estrogen receptor modulator and a drug previously linked with retinal toxicity, paradoxically provided potent neuroprotective effects. In a light-induced degeneration model, tamoxifen prevented onset of photoreceptor apoptosis and atrophy and maintained near-normal levels of electroretinographic responses. Rescue effects were correlated with decreased microglial activation and inflammatory cytokine production in the retina in vivo and a reduction of microglia-mediated toxicity to photoreceptors in vitro, indicating a microglia-mediated mechanism of rescue. Tamoxifen also rescued degeneration in a genetic (Pde6brd10) model of RP, significantly improving retinal structure, electrophysiological responses, and visual behavior. These prominent neuroprotective effects warrant the consideration of tamoxifen as a drug suitable for being repurposed to treat photoreceptor degenerative disease. SIGNIFICANCE STATEMENT Photoreceptor degeneration is a cause of irreversible blindness in a number of retinal diseases such as retinitis pigmentosa (RP) and atrophic age-related macular degeneration. Tamoxifen, a selective estrogen receptor modulator approved for the treatment of breast cancer and previously linked to a low incidence of retinal toxicity, was unexpectedly found to exert marked protective effects against photoreceptor degeneration. Structural and functional protective effects were found for an acute model of light-induced photoreceptor injury and for a genetic model for RP. The mechanism of protection involved the modulation of microglial activation and the production of inflammatory cytokines, highlighting the role of inflammatory mechanisms in photoreceptor degeneration. Tamoxifen may be

  17. Differential effect of EGFR inhibitors on tamoxifen-resistant breast cancer cells.

    PubMed

    Kim, Sangmin; Lee, Jeongmin; Oh, Soo Jin; Nam, Seok Jin; Lee, Jeong Eon

    2015-09-01

    Although tamoxifen is the most common and effective therapy for treatment of estrogen receptor-α (ER-α) breast cancer patients, resistance of endocrine therapy occurs, either de novo or acquired during therapy. Here, we investigated the clinical value of epidermal growth factor receptor (EGFR) in tamoxifen-resistant (TamR) patients and the differential effect of EGFR inhibitors, neratinib and gefitinib, on TamR breast cancer cell model. The morphology of TamR MCF7 cells showed mesenchymal phenotypes and did not induce cell death by tamoxifen treatment compared with tamoxifen‑sensitive (TamS) MCF7 cells. In addition, mesenchymal marker proteins, including N-cadherin (N-cad), fibronectin (FN), and Slug, significantly increased in TamR cells. In contrast, ER-α and E-cadherin (E-cad) were greatly decreased. We also found that the levels of EGFR and HER2 expression were increased in TamR cells. Furthermore, we observed that EGFR expression was directly involved with poor prognosis of tamoxifen-treated breast cancer patients using the GSE1378 date set. Thus, we treated TamR and TamS cells with EGFR inhibitors, neratinib and gefitinib, respectively. Interestingly, neratinib induced apoptotic cell death of TamR but not gefitinib. Cleaved PARP-1 expression was also increased by neratinib treatment in TamR cells. Therefore, we suggest that neratinib may be a potential therapeutic drug for treating TamR breast cancer.

  18. The use of Chinese herbal products and its influence on tamoxifen induced endometrial cancer risk among female breast cancer patients: a population-based study.

    PubMed

    Tsai, Yueh-Ting; Lai, Jung-Nien; Wu, Chien-Tung

    2014-09-11

    The increased practice of traditional Chinese medicine (TCM) worldwide has raised concerns regarding herb-drug interactions. The purpose of our study was to analyze the use of Chinese herbal products (CHPs) and to estimate the influence of the use of CHP on tamoxifen induced endometrial cancer risk among female breast cancer patients in Taiwan. All patients newly diagnosed with invasive breast cancer receiving tamoxifen treatment from January 1, 1998 to December 31, 2008 were selected from the National Health Insurance Research Database. The usage, frequency of service, and CHPs prescribed among the 20,466 tamoxifen-treated female breast cancer patients were analyzed. The logistic regression method was employed to estimate the odds ratios (ORs) for utilization of CHPs. Cox proportional hazard regression was performed to calculate the hazard ratios (HRs) for subsequent endometrial cancer for CHP non-users and CHP users among female breast cancer patients who had undergone tamoxifen treatment. More than half of the subjects had ever used a CHP. Jia-Wei-Xiao-Yao-San (Augmented Rambling Powder) and Shu-Jing-Huo-Xue-Tang (Channel-Coursing Blood-Quickening Decoction) were the two most commonly used CHPs. The HR for the development of endometrial cancer among CHP users was 0.50-fold (95% CI=0.38-0.64) compared to that of CHP non-users. More than half of the study subjects had ever used a CHP. Jia-Wei-Xiao-Yao-San was the most commonly used CHP. Among female breast cancer patients who had undergone tamoxifen therapy, CHP consumption decreased the risk of subsequent endometrial cancer. Exploring potential Chinese herb-tamoxifen interactions and integrating both healthcare approaches are beneficial to the overall health outcomes of tamoxifen-treated female breast cancer patients. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  19. Berberine enhances the anti‑tumor activity of tamoxifen in drug‑sensitive MCF‑7 and drug‑resistant MCF‑7/TAM cells.

    PubMed

    Wen, Chunjie; Wu, Lanxiang; Fu, Lijuan; Zhang, Xue; Zhou, Honghao

    2016-09-01

    Berberine, an isoquinoline alkaloid, has been previously demonstrated to possess anti‑breast cancer properties. Tamoxifen is widely used in the prevention and treatment of estrogen receptor-positive breast cancer. Thus, the aim of the present study was to assess whether berberine enhanced the anticancer effect of tamoxifen, and the underlying mechanism involved in this combined effect in tamoxifen-sensitive (MCF-7) and tamoxifen-resistant (MCF-7/TAM) cells using MTS, flow cytometry and western blot assays. The results indicated that berberine demonstrated dose‑ and time‑dependent anti‑proliferative activity in MCF‑7 and MCF‑7/TAM cells. Furthermore, the combination of berberine and tamoxifen induced cell growth inhibition more effectively than tamoxifen alone. The present study also demonstrated that combinational treatment is more effective in inducing G1 phase arrest and activating apoptosis compared tamoxifen alone, which may be due to upregulation of P21 expression and downregulation of the B‑cell CLL/lymphoma 2(Bcl‑2)/Bcl‑2 associated X protein ratio. The results of the present study suggested that berberine may potentially be useful as an adjuvant agent in cancer chemotherapy to enhance the effect of tamoxifen, which will be useful for anti‑tumor therapy and further research.

  20. Tamoxifen as the First Targeted Long Term Adjuvant Therapy for Breast Cancer

    PubMed Central

    Jordan, V. Craig

    2014-01-01

    Tamoxifen is an unlikely pioneering medicine in medical oncology. Nevertheless, the medicine has continued to surprise us, perform and save lives for the past 40 years. Unlike any other medicine in oncology, it is used to treat all stages of breast cancer, ductal carcinoma in situ, male breast cancer, pioneered the use of chemoprevention by reducing the incidence of breast cancer in women at high risk and induces ovulation in subfertile women! The impact of tamoxifen is ubiquitous. However, the power to save lives from this unlikely success story came from the first laboratory studies which defined that “longer was going to be better” when tamoxifen was being considered as an adjuvant therapy (Jordan 1978 Use of the DMBA-induced rat mammary carcinoma system for the evaluation of tamoxifen as a potential adjuvant therapy Reviews in Endocrine Related Cancer. October Supplement: 49–55.). This is that success story, with a focus on the interdependent components of: excellence in drug discovery, investment in self-selecting young investigators, a conversation with Nature, a conversation between the laboratory and the clinic, and the creation of the Oxford Overview Analysis. Each of these factors was essential to propel the progress of tamoxifen to evolve as an essential part of the fabric of society. “Science is adventure, discovery, new horizons, insight into our world, a means of predicting the future and enormous power to help others”(Hoagland 1990).- Mahlon Hoagland, MD. Director, Worcester Foundation for Experimental Biology (1970–85) PMID:24659478

  1. Glucose impairs tamoxifen responsiveness modulating connective tissue growth factor in breast cancer cells.

    PubMed

    Ambrosio, Maria Rosaria; D'Esposito, Vittoria; Costa, Valerio; Liguoro, Domenico; Collina, Francesca; Cantile, Monica; Prevete, Nella; Passaro, Carmela; Mosca, Giusy; De Laurentiis, Michelino; Di Bonito, Maurizio; Botti, Gerardo; Franco, Renato; Beguinot, Francesco; Ciccodicola, Alfredo; Formisano, Pietro

    2017-12-12

    Type 2 diabetes and obesity are negative prognostic factors in patients with breast cancer (BC). We found that sensitivity to tamoxifen was reduced by 2-fold by 25 mM glucose (High Glucose; HG) compared to 5.5 mM glucose (Low Glucose; LG) in MCF7 BC cells. Shifting from HG to LG ameliorated MCF7 cell responsiveness to tamoxifen. RNA-Sequencing of MCF7 BC cells revealed that cell cycle-related genes were mainly affected by glucose. Connective Tissue Growth Factor (CTGF) was identified as a glucose-induced modulator of cell sensitivity to tamoxifen. Co-culturing MCF7 cells with human adipocytes exposed to HG, enhanced CTGF mRNA levels and reduced tamoxifen responsiveness of BC cells. Inhibition of adipocyte-released IL8 reverted these effects. Interestingly, CTGF immuno-detection in bioptic specimens from women with estrogen receptor positive (ER + ) BC correlated with hormone therapy resistance, distant metastases, reduced overall and disease-free survival. Thus, glucose affects tamoxifen responsiveness directly modulating CTGF in BC cells, and indirectly promoting IL8 release by adipocytes.

  2. Increased Expression of CCN2 in the Red Flashing Light-Induced Myopia in Guinea Pigs

    PubMed Central

    Wang, Hong; Zhuang, Kang; Gao, Lei; Zhang, Linna; Yang, Hongling

    2013-01-01

    Visual environment plays an important role in the occurrence of myopia. We previously showed that the different flashing lights could result in distinct effects on the ocular growth and development of myopia. CCN2 has been reported to regulate various cellular functions and biological processes. However, whether CCN2 signaling was involved in the red flashing light-induced myopia still remains unknown. In the present study, we investigated the effects of the red flashing lights exposure on the refraction and axial length of the eyes in vivo and then evaluated their effects on the expression of CCN2 and TGF-β in sclera tissues. Our data showed that the eyes exposed to the red flashing light became more myopic with a significant increase of the axial length and decrease of the refraction. Both CCN2 and TGF-β, as well as p38 MAPK and PI3K, were highly expressed in the sclera tissues exposed to the red flashing light. Both CCN2 and TGF-β were found to have the same gene expression profile in vivo. In conclusion, our findings found that CCN2 signaling pathway plays an important role in the red flashing light-induced myopia in vivo. Moreover, our study establishes a useful animal model for experimental myopia research. PMID:23936844

  3. Tamoxifen dose and serum concentrations of tamoxifen and six of its metabolites in routine clinical outpatient care.

    PubMed

    Jager, N G L; Rosing, H; Schellens, J H M; Linn, S C; Beijnen, J H

    2014-02-01

    A sensitive and selective HPLC-MS/MS assay was used to analyze steady-state serum concentrations of tamoxifen, N-desmethyltamoxifen (E)-endoxifen, (Z)-endoxifen, N-desmethyl-4'-hydroxytamoxifen, 4-hydroxytamoxifen, and 4'-hydroxytamoxifen to support therapeutic drug monitoring (TDM) in patients treated with tamoxifen according to standard of care. When the (Z)-endoxifen serum concentration was below the predefined therapeutic threshold concentration of 5.9 ng/mL, the clinician was advised to increase the tamoxifen dose and to collect another serum sample. Paired serum samples from patients at one dose level at different time points during the tamoxifen treatment were used to assess the intra-patient variability. A total of 251 serum samples were analyzed, obtained from 205 patients. Of these patients, 197 used 20 mg tamoxifen per day and 8 patients used 10 mg/day. There was wide variability in tamoxifen and metabolite concentrations within the dosing groups. The threshold concentration for (Z)-endoxifen was reached in one patient (12 %) in the 10 mg group, in 153 patients (78 %) in the 20 mg group, and in 26 (96 %) of the patients who received a dose increase to 30 or 40 mg/day. Dose increase from 20 to 30 or 40 mg per day resulted in a significant increase in the mean serum concentrations of all analytes (p < 0.001). The mean intra-patient variability was between 10 and 20 % for all analytes. These results support the suitability of TDM for optimizing the tamoxifen treatment. It is shown that tamoxifen dose is related to (Z)-endoxifen exposure and increasing this dose leads to a higher serum concentration of tamoxifen and its metabolites. The low intra-patient variability suggests that only one serum sample is needed for TDM, making this a relatively noninvasive way to optimize the patient's treatment.

  4. Inhibition of herpes simplex virus type 1 entry by chloride channel inhibitors tamoxifen and NPPB

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Zheng, Kai; College of Life Science and Technology, Jinan University, Guangzhou; Chen, Maoyun

    2014-04-18

    Highlights: • We analyze the anti-HSV potential of chloride channel inhibitors. • Tamoxifen and NPPB show anti-HSV-1 and anti-ACV-resistant HSV-1 activities. • HSV-1 infection induces intracellular chloride concentration increasing. • Tamoxifen and NPPB inhibit HSV-1 early infection. • Tamoxifen and NPPB prevent the fusion process of HSV-1. - Abstract: Herpes simplex virus type 1 (HSV-1) infection is very common worldwide and can cause significant health problems from periodic skin and corneal lesions to encephalitis. Appearance of drug-resistant viruses in clinical therapy has made exploring novel antiviral agents emergent. Here we show that chloride channel inhibitors, including tamoxifen and 5-nitro-2-(3-phenyl-propylamino) benzoicmore » acid (NPPB), exhibited extensive antiviral activities toward HSV-1 and ACV-resistant HSV viruses. HSV-1 infection induced chloride ion influx while treatment with inhibitors reduced the increase of intracellular chloride ion concentration. Pretreatment or treatment of inhibitors at different time points during HSV-1 infection all suppressed viral RNA synthesis, protein expression and virus production. More detailed studies demonstrated that tamoxifen and NPPB acted as potent inhibitors of HSV-1 early entry step by preventing viral binding, penetration and nuclear translocation. Specifically the compounds appeared to affect viral fusion process by inhibiting virus binding to lipid rafts and interrupting calcium homeostasis. Taken together, the observation that tamoxifen and NPPB can block viral entry suggests a stronger potential for these compounds as well as other ion channel inhibitors in antiviral therapy against HSV-1, especially the compound tamoxifen is an immediately actionable drug that can be reused for treatment of HSV-1 infections.« less

  5. Identification of a putative protein profile associated with tamoxifen therapy resistance in breast cancer.

    PubMed

    Umar, Arzu; Kang, Hyuk; Timmermans, Annemieke M; Look, Maxime P; Meijer-van Gelder, Marion E; den Bakker, Michael A; Jaitly, Navdeep; Martens, John W M; Luider, Theo M; Foekens, John A; Pasa-Tolić, Ljiljana

    2009-06-01

    Tamoxifen resistance is a major cause of death in patients with recurrent breast cancer. Current clinical factors can correctly predict therapy response in only half of the treated patients. Identification of proteins that are associated with tamoxifen resistance is a first step toward better response prediction and tailored treatment of patients. In the present study we intended to identify putative protein biomarkers indicative of tamoxifen therapy resistance in breast cancer using nano-LC coupled with FTICR MS. Comparative proteome analysis was performed on approximately 5,500 pooled tumor cells (corresponding to approximately 550 ng of protein lysate/analysis) obtained through laser capture microdissection (LCM) from two independently processed data sets (n = 24 and n = 27) containing both tamoxifen therapy-sensitive and therapy-resistant tumors. Peptides and proteins were identified by matching mass and elution time of newly acquired LC-MS features to information in previously generated accurate mass and time tag reference databases. A total of 17,263 unique peptides were identified that corresponded to 2,556 non-redundant proteins identified with > or = 2 peptides. 1,713 overlapping proteins between the two data sets were used for further analysis. Comparative proteome analysis revealed 100 putatively differentially abundant proteins between tamoxifen-sensitive and tamoxifen-resistant tumors. The presence and relative abundance for 47 differentially abundant proteins were verified by targeted nano-LC-MS/MS in a selection of unpooled, non-microdissected discovery set tumor tissue extracts. ENPP1, EIF3E, and GNB4 were significantly associated with progression-free survival upon tamoxifen treatment for recurrent disease. Differential abundance of our top discriminating protein, extracellular matrix metalloproteinase inducer, was validated by tissue microarray in an independent patient cohort (n = 156). Extracellular matrix metalloproteinase inducer levels were

  6. Overexpression of the erythropoietin receptor in RAMA 37 breast cancer cells alters cell growth and sensitivity to tamoxifen.

    PubMed

    Ilkovičová, Lenka; Trošt, Nina; Szentpéteriová, Erika; Solár, Peter; Komel, Radovan; Debeljak, Nataša

    2017-08-01

    Erythropoietin (EPO) is the main regulator of erythropoiesis, and its receptor (EPOR) is expressed in various tissues, including tumors. Expression of EPOR in breast cancer tissue has been shown to correlate with expression of the estrogen receptor (ER). However, EPOR promotes proliferation in an EPO-independent manner. In patients with breast cancer, EPOR is associated with impaired tamoxifen response in ER-positive tumors, but not in ER-negative tumors. Furthermore, a positive correlation between EPOR/ER status and increased local cancer recurrence has been demonstrated, and EPOR expression is associated with G-protein coupled ER (GPER). Herein, we assessed the effects of EPOR on cell physiology and tamoxifen response in the absence of EPO stimulation using two cell lines that differ only in their EPOR expression status: RAMA 37 cells (low EPOR expression) and RAMA 37-28 cells (high EPOR expression). Alterations in cell growth, morphology, response to tamoxifen cytotoxicity, and EPOR-activated signal transduction were observed. RAMA 37 cells showed higher proliferation capacity without tamoxifen treatment, while RAMA 37-28 cells were more resistant to tamoxifen and proliferated more rapidly in the presence of tamoxifen. EPOR overexpression induced cell-morphology changes upon tamoxifen treatment, which resulted in the production of cell protrusions and subsequent cell death. Short-term treatment with tamoxifen (6 h) prompted RAMA 37 cells to acquired longer protrusions than RAMA 37-28 cells, which indicated a pre-apoptotic stage. Furthermore, prolonged treatment with tamoxifen (72 h) caused a greater reduction in RAMA 37 cell numbers, which indicated a higher rate of cell death. RAMA 37-28 cells showed prolonged activation of AKT signaling. We propose sustained AKT phosphorylation in EPOR-overexpressing cells as a mechanism that can lead to EPOR-induced tamoxifen resistance.

  7. Rainstorms able to induce flash floods in a Mediterranean-climate region (Calabria, southern Italy)

    NASA Astrophysics Data System (ADS)

    Terranova, O. G.; Gariano, S. L.

    2014-03-01

    Heavy rainstorms often induce flash flooding, one of the natural disasters most responsible for damage to man-made infrastructure and loss of lives, adversely affecting also the opportunities for socio-economic development of Mediterranean Countries. The frequently dramatic damage of flash floods are often detected with sufficient accuracy by post-event surveys, but rainfall causing them are still only roughly characterized. With the aim of improving the understanding of the temporal structure and spatial distribution of heavy rainstorms in the Mediterranean context, a statistical analysis was carried out in Calabria (southern Italy) concerning rainstorms that mainly induced flash floods, but also shallow landslides and debris-flows. Thus a method is proposed - based on the overcoming of heuristically predetermined threshold values of cumulated rainfall, maximum intensity, and kinetic energy of the rainfall event - to select and characterize the rainstorms able to induce flash floods in the Mediterranean-climate Countries. Therefore the obtained (heavy) rainstorms were automatically classified and studied according to their structure in time, localization and extension. Rainfall-runoff watershed models can consequently benefit from the enhanced identification of design storms, with a realistic time structure integrated with the results of the spatial analysis. A survey of flash flood events recorded in the last decades provides a preliminary validation of the method proposed to identify the heavy rainstorms and synthetically describe their characteristics. The notable size of the employed sample, including data with a very detailed resolution in time, that relate to several rain gauges well-distributed throughout the region, give robustness to the obtained results.

  8. Rainstorms able to induce flash floods in a Mediterranean-climate region (Calabria, southern Italy)

    NASA Astrophysics Data System (ADS)

    Terranova, O. G.; Gariano, S. L.

    2014-09-01

    Heavy rainstorms often induce flash flooding, one of the natural disasters most responsible for damage to man-made infrastructures and loss of lives, also adversely affecting the opportunities for socio-economic development of Mediterranean countries. The frequently dramatic damage of flash floods are often detected, with sufficient accuracy, by post-event surveys, but rainfall causing them are still only roughly characterized. With the aim of improving the understanding of the temporal structure and spatial distribution of heavy rainstorms in the Mediterranean context, a statistical analysis was carried out in Calabria (southern Italy) concerning rainstorms that mainly induced flash floods, but also shallow landslides and debris flows. Thus, a method is proposed - based on the overcoming of heuristically predetermined threshold values of cumulated rainfall, maximum intensity, and kinetic energy of the rainfall event - to select and characterize the rainstorms able to induce flash floods in the Mediterranean-climate countries. Therefore, the obtained (heavy) rainstorms were automatically classified and studied according to their structure in time, localization, and extension. Rainfall-runoff watershed models can consequently benefit from the enhanced identification of design storms, with a realistic time structure integrated with the results of the spatial analysis. A survey of flash flood events recorded in the last decades provides a preliminary validation of the method proposed to identify the heavy rainstorms and synthetically describe their characteristics. The notable size of the employed sample, including data with a very detailed resolution in time that relate to several rain gauges well-distributed throughout the region, gives robustness to the obtained results.

  9. Helium shell flashes and evolution of accreting white dwarfs

    NASA Astrophysics Data System (ADS)

    Fujimoto, M. Y.; Sugimoto, D.

    1982-06-01

    The evolution of accreting white dwarfs is investigated from the onset of accretion through the helium shell flash. Properties of the helium shell flashes are studied by means of a generalized theory of shell flash and by numerical computations, and it is found that the shell flash grows up to the strength of a supernova explosion when the mass of the helium zone is large enough on a massive white dwarf. Although accretion onto a hot white dwarf causes a weaker shell flash than those onto cool ones, a strong tendency exists for the strength to be determined mainly by the accretion rate. For fast accretion, the shell flashes are weak and triggered recurrently, while for slow accretion the helium shell flash, once triggered, develops into a detonation supernova.

  10. Ceramide-tamoxifen regimen targets bioenergetic elements in acute myelogenous leukemia1

    PubMed Central

    Morad, Samy A. F.; Ryan, Terence E.; Neufer, P. Darrell; Zeczycki, Tonya N.; Davis, Traci S.; MacDougall, Matthew R.; Fox, Todd E.; Tan, Su-Fern; Feith, David J.; Loughran, Thomas P.; Kester, Mark; Claxton, David F.; Barth, Brian M.; Deering, Tye G.; Cabot, Myles C.

    2016-01-01

    The objective of our study was to determine the mechanism of action of the short-chain ceramide analog, C6-ceramide, and the breast cancer drug, tamoxifen, which we show coactively depress viability and induce apoptosis in human acute myelogenous leukemia cells. Exposure to the C6-ceramide-tamoxifen combination elicited decreases in mitochondrial membrane potential and complex I respiration, increases in reactive oxygen species (ROS), and release of mitochondrial proapoptotic proteins. Decreases in ATP levels, reduced glycolytic capacity, and reduced expression of inhibitors of apoptosis proteins also resulted. Cytotoxicity of the drug combination was mitigated by exposure to antioxidant. Cells metabolized C6-ceramide by glycosylation and hydrolysis, the latter leading to increases in long-chain ceramides. Tamoxifen potently blocked glycosylation of C6-ceramide and long-chain ceramides. N-desmethyltamoxifen, a poor antiestrogen and the major tamoxifen metabolite in humans, was also effective with C6-ceramide, indicating that traditional antiestrogen pathways are not involved in cellular responses. We conclude that cell death is driven by mitochondrial targeting and ROS generation and that tamoxifen enhances the ceramide effect by blocking its metabolism. As depletion of ATP and targeting the “Warburg effect” represent dynamic metabolic insult, this ceramide-containing combination may be of utility in the treatment of leukemia and other cancers. PMID:27140664

  11. Optimizing tamoxifen-inducible Cre/loxp system to reduce tamoxifen effect on bone turnover in long bones of young mice.

    PubMed

    Zhong, Zhendong A; Sun, Weihua; Chen, Haiyan; Zhang, Hongliang; Lay, Yu-An E; Lane, Nancy E; Yao, Wei

    2015-12-01

    For tamoxifen-dependent Cre recombinase, also known as CreER recombinase, tamoxifen (TAM) is used to activate the Cre to generate time- and tissue-specific mouse mutants. TAM is a potent CreER system inducer; however, TAM is also an active selective estrogen receptor modulator (SERM) that can influence bone homeostasis. The purpose of this study was to optimize the TAM dose for Cre recombinase activation while minimizing the effects of TAM on bone turnover in young growing mice. To evaluate the effects of TAM on bone turnover and bone mass, 1-month-old wild-type male and female mice were intraperitoneally injected with TAM at 0, 1, 10 or 100mg/kg/day for four consecutive days, or 100, 300 mg/kg/day for one day. The distal femurs were analyzed one month after the last TAM injection by microCT, mechanical test, and surface-based bone histomorphometry. Similar doses of TAM were used in Col1 (2.3 kb)-CreERT2; mT/mG reporter male mice to evaluate the dose-dependent efficacy of Cre-ER activation in bone tissue. A TAM dose of 100 mg/kg × 4 days significantly increased trabecular bone volume/total volume (BV/TV) of the distal femur, femur length, bone strength, and serum bone turnover markers compared to the 0mg control group. In contrast, TAM doses ≤ 10 mg/kg did not significantly change any of these parameters compared to the 0mg group, although a higher bone strength was observed in the 10mg group. Surface-based histomorphometry revealed that the 100mg/kg dose of TAM dose significantly increased trabecular bone formation and decreased periosteal bone formation at 1-week post-TAM treatment. Using the reporter mouse model Col1-CreERT2; mT/mG, we found that 10mg/kg TAM induced Col1-CreERT2 activity in bone at a comparable level to the 100mg/kg dose. TAM treatment at 100mg/kg/day × 4 days significantly affects bone homeostasis, resulting in an anabolic bone effect on trabecular bone in 1-month-old male mice. However, a lower dose of TAM at 10 mg/kg/day × 4 days can

  12. TAMOXIFEN RETINOPATHY DURING TREATMENT OF AN INOPERABLE DESMOID TUMOR.

    PubMed

    Furst, Meredith; Somogyi, Marie B; Wong, Robert W; Araujo, Dejka; Harper, Clio A

    2017-12-08

    To evaluate the clinical significance and rarity of tamoxifen retinopathy after a long-term tamoxifen treatment for an inoperable desmoid tumor. Case report. Tamoxifen retinopathy is a condition rarely observed in clinical practice. Although tamoxifen is typically a treatment for breast cancer patients, we present a 68-year-old woman taking tamoxifen for an inoperable desmoid tumor, an equally rare condition. She presented with bilaterally deteriorating vision over the course of a year. Fundoscopic examination revealed parafoveal deposits bilaterally. Spectral domain optical coherence tomography exhibited hyperreflective deposits in all layers of the retina. She had a cumulative treatment dose of 292 g of tamoxifen, and the medication was subsequently stopped. Her vision remained stable 3 months after the cessation of tamoxifen. The development of tamoxifen retinopathy in the treatment of a desmoid tumor makes this case a rare entity, and this is the first reported case of these two concomitant conditions to our knowledge. With the use of long-term tamoxifen as a primary treatment, we recommend screening at regular intervals by an ophthalmologist as an integral part of treatment.

  13. Therapeutic drug monitoring of tamoxifen using LC-MS/MS.

    PubMed

    Tchu, Simone M; Lynch, Kara L; Wu, Alan H B

    2012-01-01

    Tamoxifen is a selective estrogen receptor modulator (SERM) that is used widely in the treatment of estrogen receptor positive breast cancer (ER+). Therapeutic monitoring of tamoxifen, and its metabolites N-desmethyltamoxifen (NDTam) and 4-hydroxy-N-desmethyltamoxifen (endoxifen), may be clinically useful for guiding treatment decisions. Two significant barriers to tamoxifen efficacy are: (1) variability in conversion of tamoxifen into the potent antiestrogenic metabolite, endoxifen, and (2) poor compliance and adherence to tamoxifen therapy. Therapeutic monitoring can be used to address both of these issues. Low levels of endoxifen indicate either poor compliance or poor metabolism of tamoxifen. Low tamoxifen levels would suggest poor compliance while a low ratio of endoxifen to NDTam would be indicative of poor metabolism. Solid phase extraction of patient serum followed by liquid chromatography tandem mass spectrometry (LC-MS/MS) detection enables rapid, accurate, detection of tamoxifen, N-desmethyltamoxifen, and endoxifen.

  14. Sex hormone concentrations and the risk of breast cancer recurrence in postmenopausal women without hot flashes.

    PubMed

    Emond, Jennifer A; Patterson, Ruth E; Natarajan, Loki; Laughlin, Gail A; Gold, Ellen B; Pierce, John P

    2011-05-01

    We examined if the reduced risk of breast cancer events seen among women without baseline hot flash symptoms in the Women's Healthy Eating and Living (WHEL) dietary intervention trial was related to changes in sex hormone concentrations. Baseline and year one concentrations of total and bioavailable estradiol, and testosterone and sex hormone-binding globulin (SHBG) were compared by intervention arm among 447 postmenopausal women without hot flashes. Cox proportional hazard models tested interaction terms between study arm and baseline hormone concentrations adjusted for study site, antiestrogen use, positive nodes, tumor size, oophorectomy status, and hormone replacement therapy use. Sex hormone concentrations did not differ by study arm at baseline nor at year one. Twenty-two (9.8%) events occurred in the intervention arm versus 42 (18.9%) in the comparison arm (P = 0.009). Baseline bioavailable testosterone was significantly, positively associated with additional events (HR 1.69, 95% CI: 1.00-2.84; P = 0.049). There were significant interactions between the intervention and total (P = 0.015), and bioavailable (P = 0.050) testosterone: the intervention was more protective among participants with higher baseline total (HR 0.3, 95% CI: 0.2-0.7) or bioavailable (HR 0.4, 95% CI: 0.2-0.7) testosterone than for participants with lower baseline total (HR 0.8, 95% CI: 0.4-1.5) or bioavailable (HR 0.8, 95% CI: 0.4-1.5) testosterone. No significant effects were seen for estradiol or SHBG. The WHEL dietary intervention may have modified other risk factors of recurrence correlated with testosterone. Sex hormones should be considered as part of a larger biological system related to the risk of breast cancer recurrence. ©2011 AACR.

  15. Long-term effects of levonorgestrel-releasing intrauterine system on tamoxifen-treated breast cancer patients: a meta-analysis

    PubMed Central

    Fu, Yun; Zhuang, Zhigang

    2014-01-01

    Objective: The aim of the study is to assess the efficacy of the levonorgestrel-releasing intrauterine system (LNG-IUS) on the tamoxifen-induced endometrial lesions in breast cancer patients. Methods: PubMed and EMBASE databases were searched for eligible studies. Odds ratios were obtained to estimate the association between the LNG-IUS and tamoxifen-induced endometrial lesions. The fixed effects or random-effects model was used to combine data depending on heterogeneity. Results: With three eligible randomized clinical trials involving 359 patients, this analysis demonstrated tamoxifen-treated breast cancer patients using the LNG-IUS derived benefit from de novo polyps prevention (P < 0.0001, OR 0.18, 95% CI: 0.08-0.42). However, the LNG-IUS only showed a trend of maintaining endometrial proliferation or secretory status (P = 0.05, OR 0.36, 95% CI 0.13-1.02) and no statistical difference in atrophic or inactive changes (P = 0.13, OR 0.24, 95% CI 0.04-1.53) or endometrial hyperplasia without atypia (P = 0.08, OR 0.20, 95% CI 0.04-1.18). The LNG-IUS didn’t have an increased incidence in breast cancer recurrence (P = 0.28, OR 1.75, 95% CI: 0.64-4.80) and cancer-induced death (P = 0.71, OR 1.22, 95% CI: 0.42-3.52). Bleeding in the treatment group was statistically more frequent than that in the control group (OR 6.20, 95% CI: 2.99-12.85, P < 0.00001). Conclusions: This analysis verifies the efficacy of the LNG-IUS in preventing tamoxifen-induced polyps. The LNG-IUS didn’t have an increased incidence in breast cancer recurrence and cancer-induced death. Long-term, large randomized studies of the LNG-IUS will be necessary to determine the benefit and risk in tamoxifen-treated breast cancer patients. PMID:25400720

  16. Tamoxifen inhibits macrophage FABP4 expression through the combined effects of the GR and PPARγ pathways.

    PubMed

    Jiang, Meixiu; Zhang, Ling; Ma, Xingzhe; Hu, Wenquan; Chen, Yuanli; Yu, Miao; Wang, Qixue; Li, Xiaoju; Yin, Zhinan; Zhu, Yan; Gao, Xiumei; Hajjar, David P; Duan, Yajun; Han, Jihong

    2013-09-15

    Macrophage adipocyte fatty acid-binding protein (FABP4) plays an important role in foam cell formation and development of atherosclerosis. Tamoxifen inhibits this disease process. In the present study, we determined whether the anti-atherogenic property of tamoxifen was related to its inhibition of macrophage FABP4 expression. We initially observed that tamoxifen inhibited macrophage/foam cell formation, but the inhibition was attenuated when FABP4 expression was selectively inhibited by siRNA.We then observed that tamoxifen and 4-hydroxytamoxifen inhibited FABP4 protein expression in primary macrophages isolated from both the male and female wild-type mice, suggesting that the inhibition is sex-independent. Tamoxifen and 4-hydroxytamoxifen inhibited macrophage FABP4 protein expression induced either by activation of GR (glucocorticoid receptor) or PPARγ (peroxisome-proliferator-activated receptor γ). Associated with the decreased protein expression, Fabp4 mRNA expression and promoter activity were also inhibited by tamoxifen and 4-hydroxytamoxifen, indicating transcriptional regulation. Analysis of promoter activity and EMSA/ChIP assays indicated that tamoxifen and 4-hydroxytamoxifen activated the nGRE (negative glucocorticoid regulatory element), but inhibited the PPRE (PPARγ regulatory element) in the Fabp4 gene. In vivo, administration of tamoxifen to ApoE (apolipoprotein E)-deficient (apoE-/-) mice on a high-fat diet decreased FABP4 expression in macrophages and adipose tissues as well as circulating FABP4 levels. Tamoxifen also inhibited FABP4 protein expression by human blood monocyte-derived macrophages. Taken together, the results of the present study show that tamoxifen inhibited FABP4 expression through the combined effects of GR and PPARγ signalling pathways. Our findings suggest that the inhibition of macrophage FABP4 expression can be attributed to the antiatherogenic properties of tamoxifen.

  17. [GPER silence inhibits the stimulation of growth and inhibition of apoptosis induced by tamoxifen in breast cancer-associated fibroblasts].

    PubMed

    Yan, Yuzhao; Yu, Tenghua; Tu, Gang; Liu, Manran; Yuan, Jie; Yang, Guanglun

    2015-09-01

    To construct a lentiviral vector (Lenti-GPER-shRNA) targeting G-protein coupled estrogen receptor (GPER) and explore the role of GPER in the effect of tamoxifen on cell proliferation and apoptosis in breast cancer associated fibroblasts (BCAFs). The target sequence of GPER gene and negative control were cloned into lentiviral vectors. The recombinant lentivirus and control were extracted after HEK293T cells were transfected with the recombinant vector and helper vectors. After infection of BCAFs with the GPER lentiviral vector under the best interfering condition, GPER expression was detected by real-time quantitative PCR and Western blotting. BCAFs were divided into negative control group, GPER-RNAi group, negative control combined with tamoxifen (10(-8) mmol/L) group and GPER-RNAi combined with tamoxifen (10(-8) mmol/L) group. CCK-8 assay was used to detect the proliferation and annexin V-fluorescein isothiocyanate/propidium iodide (annexin V-FITC/PI) combined with flow cytometry was used to detect the apoptosis of BCAFs after the treatment of tamoxifen. Lenti-GPER-shRNA significantly interfered the expression of GPER in BCAFs. Tamoxifen promoted the growth of BCAFs, which could be attenuated by knockdown of GPER. Moreover, the apoptosis of BCAFs was reduced by tamoxifen, which was also reversed by knockdown of GPER. Lenti-GPER-shRNA could effectively silence the GPER expression in BCAFs. The ability of tamoxifen to accelerate cell proliferation and decrease cell apoptosis could be weakened by knockdown of GPER.

  18. Tamoxifen resistance: from cell culture experiments towards novel biomarkers.

    PubMed

    Nass, Norbert; Kalinski, Thomas

    2015-03-01

    Tamoxifen is still the most frequently used antiestrogen for the treatment of patients with premenopausal, estrogen receptor positive breast cancer. However, in 20-30% of these cases, tamoxifen therapy fails due to an existing or developing resistance. The prediction of tamoxifen resistance by appropriate biomarker analysis and the development of novel therapies for tamoxifen resistance in premenopausal breast cancer is, therefore, an important goal of ongoing research. Tamoxifen resistance is associated with altered estrogen receptor expression especially on the plasma membrane, including the alternative G-protein coupled receptor GPR-30 (GPER) and estrogen receptor splice products, such as ERα36. Tamoxifen resistant cells often use alternative pathways to promote proliferation in the absence of genomic estrogen signaling. These pathways involve the epidermal growth factor EGF, the inflammation associated transcription factor NF-κB- and the IGF-1 pathway. Tamoxifen resistant mamma carcinoma cell lines are useful models to understand tamoxifen resistance in-vitro and to search for prognostic or predictive biomarkers. Furthermore, such cell lines can be used to identify potential targets for therapy. Copyright © 2015 Elsevier GmbH. All rights reserved.

  19. Estradiol and tamoxifen induce cell migration through GPR30 and activation of focal adhesion kinase (FAK) in endometrial cancers with low or without nuclear estrogen receptor α (ERα).

    PubMed

    Tsai, Chia-Lung; Wu, Hsien-Ming; Lin, Chiao-Yun; Lin, Yi-Jun; Chao, Angel; Wang, Tzu-Hao; Hsueh, Swei; Lai, Chyong-Huey; Wang, Hsin-Shih

    2013-01-01

    Estrogens and tamoxifen (an antiestrogen) exert their actions by activation of estrogen receptor (ER) through genomic and non-genomic mechanisms and are implicated in the development of endometrial cancer. Previous reports have demonstrated that estradiol and tamoxifen induce proliferation of human endometrial cancer cells through GPR30 (non-genomic ER) signaling pathway. Herein, we demonstrate that phosphorylation of focal adhesion kinase (FAK) is involved in cell migration induced by estradiol, tamoxifen and G1 (a GPR30 agonist) through the transmembrane ER (GPR30) in endometrial cancer cell lines with or without ERα (Ishikawa and RL95-2). Additionally, the GPR30-mediated cell migration was further abolished by administration of either specific RNA interference targeting GPR30 or an FAK inhibitor. Moreover, we have validated that the signaling between GPR30 and phosphorylated FAK is indeed mediated by the EGFR/PI3K/ERK pathway. Clinically, a significant correlation between levels of GPR30 and phophorylated FAK (pFAK) observed in human endometrial cancer tissues with low or without ERα further suggested that estrogen-induced phosphorylation of FAK and cell migration were most likely triggered by GPR30 activation. These results provided new insights for understanding the pathophysiological functions of GPR30 in human endometrial cancers.

  20. Light flash phenomena induced by HzE particles

    NASA Technical Reports Server (NTRS)

    Mcnulty, P. J.; Pease, V. P.

    1980-01-01

    Astronauts and Apollo and Skylab missions have reported observing a variety of visual phenomena when their eyes are closed and adapted to darkness. These phenomena have been collectively labelled as light flashes. Visual phenomena which are similar in appearance to those observed in space have been demonstrated at the number of accelerator facilities by expressing the eyes of human subjects to beams of various types of radiation. In some laboratory experiments Cerenkov radiation was found to be the basis for the flashes observed while in other experiments Cerenkov radiation could apparently be ruled out. Experiments that differentiate between Cerenkov radiation and other possible mechanisms for inducing visual phenomena was then compared. The phenomena obtained in the presence and absence of Cerenkov radiation were designed and conducted. A new mechanism proposed to explain the visual phenomena observed by Skylab astronauts as they passed through the South Atlantic Anomaly, namely nuclear interactions in and near the sensitive layer of the retina, is covered. Also some studies to search for similar transient effects of space radiation on sensors and microcomputer memories are described.

  1. Role of GPR30 in the mechanisms of tamoxifen resistance in breast cancer MCF-7 cells.

    PubMed

    Ignatov, Atanas; Ignatov, Tanja; Roessner, Albert; Costa, Serban Dan; Kalinski, Thomas

    2010-08-01

    Tamoxifen is the most frequently used anti-hormonal drug for treatment of women with hormone-dependent breast cancer. The aim of this study is to investigate the mechanism of tamoxifen resistance and the impact of the new estrogen G-protein coupled receptor (GPR30). MCF-7 cells were continuously exposed to tamoxifen for 6 months to induce resistance to the inhibitory effect of tamoxifen. These tamoxifen-resistant cells (TAM-R) exhibited enhanced sensitivity to 17-ss-estradiol and GPR30 agonist, G1, when compared to the parental cells. In TAM-R cells, tamoxifen was able to stimulate the cell growth and MAPK phosphorylation. These effects were abolished by EGFR inhibitor AG1478, GPR30 anti-sense oligonucleotide, and the selective c-Src inhibitor PP2. Only EGFR basal expression was slightly elevated in the TAM-R cells, whereas GPR30 expression and the basal phosphorylation of Akt and MAPK remained unchanged when compared to the parental cells. Interestingly, estrogen treatment significantly increased GPR30 translocation to the cell surface, which was stronger in TAM-R cells. Continuous treatment of MCF-7 cells with GPR30 agonist G1 mimics the long-term treatment with tamoxifen and increases drastically its agonistic activity. This data suggests the important role of GPR30/EGFR receptor signaling in the development of tamoxifen resistance. The inhibition of this pathway is a valid option to improve anti-hormone response in breast cancer.

  2. 17β-estradiol and Tamoxifen prevent gastric cancer by modulating leukocyte recruitment and oncogenic pathways in Helicobacter pylori-infected INS-GAS male mice

    PubMed Central

    Sheh, Alexander; Ge, Zhongming; Parry, Nicola M.A.; Muthupalani, Sureshkumar; Rager, Julia E.; Raczynski, Arkadiusz R.; Mobley, Melissa W.; McCabe, Amanda F.; Fry, Rebecca C.; Wang, Timothy C.; Fox, James G.

    2011-01-01

    Helicobacter pylori infection promotes male-predominant gastric adenocarcinoma in humans. Estrogens reduce gastric cancer risk and previous studies demonstrated that prophylactic 17β-estradiol (E2) in INS-GAS mice decreases H. pylori-induced carcinogenesis. We examined the effect of E2 and Tamoxifen, on H. pylori-induced gastric cancer in male and female INS-GAS mice. After confirming robust gastric pathology at 16 weeks post-infection (WPI), mice were implanted with E2, Tamoxifen, both E2 and Tamoxifen, or placebo pellets for 12 weeks. At 28 WPI, gastric histopathology, gene expression and immune cell infiltration were evaluated, and serum inflammatory cytokines measured. After treatment, no gastric cancer was observed in H. pylori-infected males receiving E2 and/or Tamoxifen, while 40% of infected untreated males developed gastric cancer. E2, Tamoxifen and their combination significantly reduced gastric precancerous lesions in infected males compared to infected untreated males (P<0.001, 0.01 and 0.01, respectively). However, Tamoxifen did not alter female pathology regardless of infection status. Differentially expressed genes from males treated with E2 or Tamoxifen (n=363 and n=144, Q<0.05) associated highly with cancer and cellular movement, indicating overlapping pathways in the reduction of gastric lesions. E2 or Tamoxifen deregulated genes associated with metastasis (PLAUR and MMP10) and Wnt inhibition (FZD6 and SFRP2). Compared to controls, E2 decreased gastric mRNA (Q<0.05) and serum levels (P<0.05) of CXCL1, a neutrophil chemokine, leading to decreased neutrophil infiltration (P<0.01). Prevention of H. pylori-induced gastric cancer by E2 and Tamoxifen may be mediated by estrogen signaling and is associated with decreased CXCL1, decreased neutrophil counts and downregulation of oncogenic pathways. PMID:21680705

  3. 17β-estradiol and tamoxifen protect mice from manganese-induced dopaminergic neurotoxicity.

    PubMed

    Pajarillo, Edward; Johnson, James; Kim, Judong; Karki, Pratap; Son, Deok-Soo; Aschner, Michael; Lee, Eunsook

    2018-03-01

    Chronic exposure to manganese (Mn) causes neurotoxicity, referred to as manganism, with common clinical features of parkinsonism. 17β-estradiol (E2) and tamoxifen (TX), a selective estrogen receptor modulator (SERM), afford neuroprotection in several neurological disorders, including Parkinson's disease (PD). In the present study, we tested if E2 and TX attenuate Mn-induced neurotoxicity in mice, assessing motor deficit and dopaminergic neurodegeneration. We implanted E2 and TX pellets in the back of the neck of ovariectomized C57BL/6 mice two weeks prior to a single injection of Mn into the striatum. One week later, we assessed locomotor activity and molecular mechanisms by immunohistochemistry, real-time quantitative PCR, western blot and enzymatic biochemical analyses. The results showed that both E2 and TX attenuated Mn-induced motor deficits and reversed the Mn-induced loss of dopaminergic neurons in the substantia nigra. At the molecular level, E2 and TX reversed the Mn-induced decrease of (1) glutamate aspartate transporter (GLAST) and glutamate transporter 1 (GLT-1) mRNA and protein levels; (2) transforming growth factor-α (TGF-α) and estrogen receptor-α (ER-α) protein levels; and (3) catalase (CAT) activity and glutathione (GSH) levels, and Mn-increased (1) malondialdehyde (MDA) levels and (2) the Bax/Bcl-2 ratio. These results indicate that E2 and TX afford protection against Mn-induced neurotoxicity by reversing Mn-reduced GLT1/GLAST as well as Mn-induced oxidative stress. Our findings may offer estrogenic agents as potential candidates for the development of therapeutics to treat Mn-induced neurotoxicity. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Identification of the major tamoxifen-DNA adducts in rat liver by mass spectroscopy.

    PubMed

    Rajaniemi, H; Rasanen, I; Koivisto, P; Peltonen, K; Hemminki, K

    1999-02-01

    We present here the first mass spectroscopic (MS) identification of the main tamoxifen-induced DNA adducts in rat liver. The two main adducts were isolated by high-performance liquid chromatography (HPLC) and identified by MS, MS-MS and ultraviolet spectroscopy. Adduct 1 was the N-desmethyltamoxifen-deoxyguanosine adduct in which the alpha-position of the metabolite N-desmethyltamoxifen is linked covalently to the amino group of deoxyguanosine. Adduct 2 was confirmed to be the trans isomer of alpha-(N2-deoxyguanosinyl)tamoxifen, as previously suggested by co-chromatography.

  5. Tamoxifen enhances stemness and promotes metastasis of ERα36+ breast cancer by upregulating ALDH1A1 in cancer cells

    PubMed Central

    Wang, Qiang; Jiang, Jun; Ying, Guoguang; Xie, Xiao-Qing; Zhang, Xia; Xu, Wei; Zhang, Xuemin; Song, Erwei; Bu, Hong; Ping, Yi-Fang; Yao, Xiao-Hong; Wang, Bin; Xu, Shilei; Yan, Ze-Xuan; Tai, Yanhong; Hu, Baoquan; Qi, Xiaowei; Wang, Yan-Xia; He, Zhi-Cheng; Wang, Yan; Wang, Ji Ming; Cui, You-Hong; Chen, Feng; Meng, Kun; Wang, Zhaoyi; Bian, Xiu-Wu

    2018-01-01

    The 66 kDa estrogen receptor alpha (ERα66) is the main molecular target for endocrine therapy such as tamoxifen treatment. However, many patients develop resistance with unclear mechanisms. In a large cohort study of breast cancer patients who underwent surgery followed by tamoxifen treatment, we demonstrate that ERα36, a variant of ERα66, correlates with poor prognosis. Mechanistically, tamoxifen directly binds and activates ERα36 to enhance the stemness and metastasis of breast cancer cells via transcriptional stimulation of aldehyde dehydrogenase 1A1 (ALDH1A1). Consistently, the tamoxifen-induced stemness and metastasis can be attenuated by either ALDH1 inhibitors or a specific ERα36 antibody. Thus, tamoxifen acts as an agonist on ERα36 in breast cancer cells, which accounts for hormone therapy resistance and metastasis of breast cancer. Our study not only reveals ERα36 as a stratifying marker for endocrine therapy but also provides a promising therapeutic avenue for tamoxifen-resistant breast cancer. PMID:29393296

  6. Effects of exemestane and tamoxifen on hormone levels within the Tamoxifen Exemestane Adjuvant Multicentre (TEAM) trial: results of a German substudy.

    PubMed

    Hadji, P; Kauka, A; Bauer, T; Tams, J; Hasenburg, A; Kieback, D G

    2012-10-01

    The aim of this study was to compare the effects of exemestane and tamoxifen on hormone levels in postmenopausal patients with hormone receptor-positive breast cancer within a Germany substudy of the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. Within the TEAM trial, patients were randomized to receive adjuvant treatment with exemestane for 5 years or tamoxifen for 2.5-3 years followed by exemestane for 2-2.5 years. Serum levels of testosterone, dehydroepiandrosterone sulfate (DHEAS), sex hormone binding globulin (SHBG), follicle stimulating hormone (FSH) and parathyroid hormone (PTH)-intact were measured at screening and after 3, 6 and 12 months of treatment. Data on hormone levels were available from 63 patients in the tamoxifen arm and 68 patients in the exemestane arm. Treatment with exemestane resulted in decreases from baseline in SHBG and PTH-intact levels, and increases from baseline in testosterone, DHEAS and FSH levels. Tamoxifen treatment resulted in increases from baseline in SHBG and PTH-intact, whereas levels of testosterone and FSH decreased and DHEAS levels did not change. At all time points assessed, the absolute change from baseline was significantly different between tamoxifen and exemestane for testosterone, SHBG, FSH and PTH-intact (all p < 0.0001). Exemestane and tamoxifen had statistically significantly different effects on hormone levels, including testosterone, SHBG, FSH and PTH-intact.

  7. The formation of estrogen-like tamoxifen metabolites and their influence on enzyme activity and gene expression of ADME genes.

    PubMed

    Johänning, Janina; Kröner, Patrick; Thomas, Maria; Zanger, Ulrich M; Nörenberg, Astrid; Eichelbaum, Michel; Schwab, Matthias; Brauch, Hiltrud; Schroth, Werner; Mürdter, Thomas E

    2018-03-01

    Tamoxifen, a standard therapy for breast cancer, is metabolized to compounds with anti-estrogenic as well as estrogen-like action at the estrogen receptor. Little is known about the formation of estrogen-like metabolites and their biological impact. Thus, we characterized the estrogen-like metabolites tamoxifen bisphenol and metabolite E for their metabolic pathway and their influence on cytochrome P450 activity and ADME gene expression. The formation of tamoxifen bisphenol and metabolite E was studied in human liver microsomes and Supersomes™. Cellular metabolism and impact on CYP enzymes was analyzed in upcyte® hepatocytes. The influence of 5 µM of tamoxifen, anti-estrogenic and estrogen-like metabolites on CYP activity was measured by HPLC MS/MS and on ADME gene expression using RT-PCR analyses. Metabolite E was formed from tamoxifen by CYP2C19, 3A and 1A2 and from desmethyltamoxifen by CYP2D6, 1A2 and 3A. Tamoxifen bisphenol was mainly formed from (E)- and (Z)-metabolite E by CYP2B6 and CYP2C19, respectively. Regarding phase II metabolism, UGT2B7, 1A8 and 1A3 showed highest activity in glucuronidation of tamoxifen bisphenol and metabolite E. Anti-estrogenic metabolites (Z)-4-hydroxytamoxifen, (Z)-endoxifen and (Z)-norendoxifen inhibited the activity of CYP2C enzymes while tamoxifen bisphenol consistently induced CYPs similar to rifampicin and phenobarbital. On the transcript level, highest induction up to 5.6-fold was observed for CYP3A4 by tamoxifen, (Z)-4-hydroxytamoxifen, tamoxifen bisphenol and (E)-metabolite E. Estrogen-like tamoxifen metabolites are formed in CYP-dependent reactions and are further metabolized by glucuronidation. The induction of CYP activity by tamoxifen bisphenol and the inhibition of CYP2C enzymes by anti-estrogenic metabolites may lead to drug-drug-interactions.

  8. Electrospray ionization-tandem mass spectrometry and 32P-postlabeling analyses of tamoxifen-DNA adducts in humans.

    PubMed

    Beland, Frederick A; Churchwell, Mona I; Doerge, Daniel R; Parkin, Daniel R; Malejka-Giganti, Danuta; Hewer, Alan; Phillips, David H; Carmichael, Paul L; Gamboa da Costa, Gonçalo; Marques, M Matilde

    2004-07-21

    Although the nonsteroidal antiestrogen tamoxifen is used as an adjuvant chemotherapeutic agent to treat hormone-dependent breast cancer and as a chemopreventive agent in women with elevated risk of breast cancer, it has also been reported to increase the risk of endometrial cancer. Reports of low levels of tamoxifen-DNA adducts in human endometrial tissue have suggested that tamoxifen induces endometrial cancer by a genotoxic mechanism. However, these findings have been controversial. We used electrospray ionization-tandem mass spectrometry (ES-MS/MS) and 32P-postlabeling analyses to investigate the presence of tamoxifen-DNA adducts in human endometrial tissue. Endometrial DNA from eight tamoxifen-treated women and eight untreated women was hydrolyzed to nucleosides and assayed for (E)-alpha-(deoxyguanosin-N2-yl)-tamoxifen (dG-Tam) and (E)-alpha-(deoxyguanosin-N2-yl)-N-desmethyltamoxifen (dG-desMeTam), the two major tamoxifen-DNA adducts that have been reported to be present in humans and/or experimental animals treated with tamoxifen, using on-line sample preparation coupled with high-performance liquid chromatography (HPLC) and ES-MS/MS. The same DNA samples were assayed for the presence of dG-Tam and dG-desMeTam by (32)P-postlabeling methodology, using two different DNA digestion and labeling protocols, followed by both thin-layer chromatography and HPLC. We did not detect either tamoxifen-DNA adduct by HPLC-ES-MS/MS analyses (limits of detection for dG-Tam and dG-desMeTam were two adducts per 10(9) nucleotides and two adducts per 10(8) nucleotides, respectively) or by 32P-postlabeling analyses (limit of detection for both adducts was one adduct per 10(9) nucleotides) in any of the endometrial DNA samples. The initiation of endometrial cancer by tamoxifen is probably not due to a genotoxic mechanism involving the formation of dG-Tam or dG-desMeTam.

  9. Oral low dose and topical tamoxifen for breast cancer prevention: modern approaches for an old drug

    PubMed Central

    2012-01-01

    Tamoxifen is a drug that has been in worldwide use for the treatment of estrogen receptor (ER)-positive breast cancer for over 30 years; it has been used in both the metastatic and adjuvant settings. Tamoxifen's approval for breast cancer risk reduction dates back to 1998, after results from the Breast Cancer Prevention Trial, co-sponsored by the National Cancer Institute and the National Surgical Adjuvant Breast and Bowel Project, showed a 49% reduction in the incidence of invasive, ER-positive breast cancer in high-risk women. Despite these positive findings, however, the public's attitude toward breast cancer chemoprevention remains ambivalent, and the toxicities associated with tamoxifen, particularly endometrial cancer and thromboembolic events, have hampered the drug's uptake by high-risk women who should benefit from its preventive effects. Among the strategies to overcome such obstacles to preventive tamoxifen, two novel and potentially safer modes of delivery of this agent are discussed in this paper. Low-dose tamoxifen, expected to confer fewer adverse events, is being investigated in both clinical biomarker-based trials and observational studies. A series of systemic biomarkers (including lipid and insulin-like growth factor levels) and tissue biomarkers (including Ki-67) are known to be favorably affected by conventional tamoxifen dosing and have been shown to be modulated in a direction consistent with a putative anti-cancer effect. These findings suggest possible beneficial clinical preventive effects by low-dose tamoxifen regimens and they are supported by observational studies. An alternative approach is topical administration of active tamoxifen metabolites directly onto the breast, the site where the cancer is to be prevented. Avoidance of systemic administration is expected to reduce the distribution of drug to tissues susceptible to tamoxifen-induced toxicity. Clinical trials of topical tamoxifen with biological endpoints are still ongoing

  10. Tamoxifen-induced non-alcoholic steatohepatitis in patients with breast cancer: determination of a suitable biopsy site for diagnosis.

    PubMed

    Murata, Yoriko; Ogawa, Yasuhiro; Saibara, Toshiji; Nishioka, Akihito; Takeuchi, Naoko; Kariya, Shinji; Onishi, Saburo; Yoshida, Shoji

    2003-01-01

    We have evaluated the distribution of fatty infiltration in the liver for determination of a suitable biopsy site for diagnosis of tamoxifen-induced non-alcoholic steatohepatitis (NASH) in patients with breast cancer. Thirty-eight consecutive breast cancer patients undergoing tamoxifen treatment were analyzed by CT to identify hepatic steatosis (HS) via calculation of the liver/spleen CT ratio in Couinaud's 8 areas. We defined hepatic fatty infiltration as a liver/spleen ratio of less than 0.9. The extent and distribution of the fatty infiltration was assessed using the liver/spleen ratio of the patients who had the lowest CT ratio below 0.9 in the 8 areas. Thirteen (34.2%) of the 38 patients had hepatic fatty infiltration. The liver/spleen ratios of each area differed significantly in all patients (p<0.0001). The CT ratio of these 13 patients was significantly lower in the right lobe than the left lobe (p<0.0001), although the ratios did not differ significantly among the 4 areas of the right lobe (p=0.52). Needle biopsy for diagnosis of NASH should be performed at the right lobe, which contains significantly more infiltrated fat than the left lobe in the liver.

  11. Depression, quality of life, work productivity, resource use, and costs among women experiencing menopause and hot flashes: a cross-sectional study.

    PubMed

    Dibonaventura, Marco Dacosta; Wagner, Jan-Samuel; Alvir, Jose; Whiteley, Jennifer

    2012-01-01

    To examine the effect of depression on health-related quality of life, work productivity, resource use, and costs among women experiencing menopausal symptoms, including hot flashes. The study included data from the 2005 US National Health and Wellness Survey (N = 41,184), a cross-sectional, Internet-based survey representative of the adult US population. Among women who reported experiencing menopausal symptoms, including hot flashes, women who reported experiencing depression in the last year (n = 1,165) were compared with women who did not report experiencing depression in the last year (n = 2,467), controlling for demographic and health characteristics. Outcome measures included health-related quality of life (Medical Outcomes Study 8-item Short-Form Health Survey [SF-8]), work productivity within the past 7 days, self-reported health care resource use within the past 6 months, and indirect and direct costs. Women experiencing depression were significantly more likely to be white, to be unemployed, to be uninsured, to currently smoke, to not exercise, and to be obese (all P < .05). After controlling for these differences, women experiencing depression reported significantly lower mental (39.66 vs 50.85, P < .05) and physical (44.05 vs 46.38, P < .05) SF-8 component summary scores. Similarly, the prevalences of time missed from work (5.31% vs 2.80%, P < .05), impairment while at work (25.00% vs 14.32%, P < .05), and impairment of daily activities (37.32% vs 23.16%, P < .05) due to health were greater among women experiencing depression. The numbers of physician visits (2.47 vs 1.77, P < .05), emergency room visits (0.27 vs 0.16, P < .05), and days hospitalized (0.36 vs 0.18, P < .05) in the past 6 months were also higher among women experiencing depression. Per woman per year indirect and direct costs were $3,066 and $1,075 higher, respectively, for women experiencing depression compared with those not experiencing depression. Approximately one-third of women

  12. AMPK activation and metabolic reprogramming by tamoxifen through estrogen receptor-independent mechanisms suggests new uses for this therapeutic modality in cancer treatment

    PubMed Central

    Daurio, Natalie A.; Tuttle, Stephen W.; Worth, Andrew J.; Song, Ethan Y.; Davis, Julianne M.; Snyder, Nathaniel W.; Blair, Ian A.; Koumenis, Constantinos

    2016-01-01

    Tamoxifen is the most widely used adjuvant chemotherapeutic for the treatment of estrogen receptor (ER) positive breast cancer, yet a large body of clinical and preclinical data indicates that tamoxifen can modulate multiple cellular processes independently of ER status. Here, we describe the ER-independent effects of tamoxifen on tumor metabolism. Using combined pharmacological and genetic knockout approaches, we demonstrate that tamoxifen inhibits oxygen consumption via inhibition of mitochondrial complex I, resulting in an increase in the AMP/ATP ratio and activation of the AMPK signaling pathway in vitro and in vivo. AMPK in turn promotes glycolysis, and alters fatty acid metabolism. We also show that tamoxifen-induced cytotoxicity is modulated by isoform-specific effects of AMPK signaling, in which AMPKα1 promotes cell death through inhibition of the mTOR pathway and translation. By using agents which concurrently target distinct adaptive responses to tamoxifen-mediated metabolic reprogramming, we demonstrate increased cytotoxicity through synergistic therapeutic approaches. Our results demonstrate novel metabolic perturbations by tamoxifen in tumor cells which can be exploited to expand the therapeutic potential of tamoxifen treatment beyond ER+ breast cancer. PMID:27020861

  13. Tamoxifen treatment of bleeding irregularities associated with Norplant use.

    PubMed

    Abdel-Aleem, Hany; Shaaban, Omar M; Amin, Ahmed F; Abdel-Aleem, Aly M

    2005-12-01

    To evaluate the possible role of tamoxifen (selective estrogen receptor modulators, SERM) in treating bleeding irregularities associated with Norplant contraceptive use. Randomized clinical trial including 100 Norplant users complaining of vaginal bleeding irregularities. The trial was conducted in the Family Planning Clinic of Assiut University Hospital. Women were assigned at random to receive tamoxifen tablets (10 mg) twice daily for 10 days or similar placebo. Women were followed-up for 3 months. The end points were percentage of women who stopped bleeding during treatment, bleeding/spotting days during the period of follow-up, effect of treatment on their lifestyle, and side effects and discontinuation of contraception. There was good compliance with treatment. At the end of treatment, a significantly higher percentage of tamoxifen users stopped bleeding in comparison to the control group (88% vs. 68%, respectively; p=.016). Women who used tamoxifen had significantly less bleeding and/or spotting days than women who used placebo, during the first and second months. During the third month, there were no significant differences between the two groups. Women who used tamoxifen reported improvement in performing household activities, religious duties and in sexual life, during the first 2 months. In the third month, there were no differences between the two groups. There were no significant differences between tamoxifen and placebo groups in reporting side effects. In the group who used tamoxifen, two women discontinued Norplant use because of bleeding vs. nine women in the placebo group. Tamoxifen use at a dose of 10 mg twice daily orally, for 10 days, has a beneficial effect on vaginal bleeding associated with Norplant use. In addition, the bleeding pattern was better in women who used tamoxifen for the following 2 months after treatment. However, these results have to be confirmed in a larger trial before advocating this line of treatment.

  14. Dietary change and reduced breast cancer events among women without hot flashes after treatment of early-stage breast cancer: subgroup analysis of the Women's Healthy Eating and Living Study1234

    PubMed Central

    Pierce, John P; Natarajan, Loki; Caan, Bette J; Flatt, Shirley W; Kealey, Sheila; Gold, Ellen B; Hajek, Richard A; Newman, Vicky A; Rock, Cheryl L; Pu, Minya; Saquib, Nazmus; Stefanick, Marcia L; Thomson, Cynthia A; Parker, Barbara

    2009-01-01

    Background: A diet high in vegetables, fruit, and fiber and low in fat decreased additional risk of secondary breast cancer events in women without hot flashes (HF−) compared with that in women with hot flashes (HF+), possibly through lowered concentrations of circulating estrogens. Objective: The objective was to investigate the intervention effect by baseline quartiles of dietary pattern among breast cancer survivors in the HF− subgroup of the Women's Healthy Eating and Living Study. Design: A randomized controlled trial compared a putative cancer prevention diet with a diet of 5 servings of vegetables and fruit daily in early-stage breast cancer survivors. Participants did not experience hot flashes at baseline (n = 896). We confirmed cancer status for 96% of participants ≈7.3 y after enrollment. Results: The study intervention achieved a large between-group difference in dietary pattern that, at 4 y, was not significantly different across baseline quartiles of dietary pattern. The intervention group experienced fewer breast cancer events than did the comparison group for all of the baseline quartiles. This difference was significant only in upper baseline quartiles of intake of vegetables, fruit, and fiber and in the lowest quartile of fat. A significant trend for fewer breast cancer events was observed across quartiles of vegetable-fruit and fiber consumption. Conclusions: The secondary analysis showing the decreased risk in the HF− subgroup was not explained by amount of change in dietary pattern achieved. The difference was strongest in the quartile with the most putatively cancer-preventive dietary pattern at baseline. PMID:19339393

  15. Multi- and unisensory visual flash illusions.

    PubMed

    Courtney, Jon R; Motes, Michael A; Hubbard, Timothy L

    2007-01-01

    The role of stimulus structure in multisensory and unisensory interactions was examined. When a flash (17 ms) was accompanied by multiple tones (each 7 ms, SOA < or =100 ms) multiple flashes were reported, and this effect has been suggested to reflect the role of stimulus continuity in multisensory interactions. In experiments 1 and 2 we examined if stimulus continuity would affect concurrently presented stimuli. When a relatively longer flash (317 ms) was accompanied by multiple tones (each 7 ms), observers reported perceiving multiple flashes. In experiment 3 we tested whether a flash presented near fixation would induce an illusory flash further in the periphery. One flash (17 ms) presented 5 degrees below fixation was reported as multiple flashes if presented with two flashes (each 17 ms, SOA =100 ms) 2 degrees above fixation. The extent to which these data support a phenomenological continuity principle and whether this principle applies to unisensory perception is discussed.

  16. Follow-up CT findings of tamoxifen-induced non-alcoholic steatohepatitis (NASH) of breast cancer patients treated with bezafibrate.

    PubMed

    Ogawa, Yasuhiro; Murata, Yoriko; Saibara, Toshiji; Nishioka, Akihito; Kariya, Shinji; Yoshida, Shoji

    2003-01-01

    One-third of the breast cancer patients who underwent tamoxifen intake showed less than 0.9 of their liver/spleen CT (computed tomography) ratio on their annual CT study, and were diagnosed as having fatty liver (hepatic steatosis). Among them, patients who showed a lower liver/spleen CT ratio of less than 0.5 were recommended to undergo needle biopsy of the liver in order to obtain histopathological confirmation of non-alcoholic steatohepatitis (NASH), with 15 patients undergoing needle biopsy of the liver. As a result, 14 out of the 15 patients were diagnosed as having NASH, and these patients were additionally administered bezafibrate in order to prevent possible progressive changes of NASH into liver cirrhosis. In this study, we show the changes of follow-up CT findings of 6 patients with histopathologically-proven NASH who continued to undergo bezafibrate intake after the diagnosis of NASH. Two patients showed almost complete improvement as indicated by the liver/spleen CT ratio several months after completion of a tamoxifen intake of 5 years, and another 3 showed partial improvement on their liver/spleen CT ratio by bezafibrate intake in spite of continuing tamoxifen intake. Another patient with diabetes mellitus (type II) showed a continually decreasing liver/spleen CT ratio during adjuvant tamoxifen in spite of bezafibrate intake. Therefore, we concluded that the progression of NASH could be prevented by bezafibrate without any interruption of adjuvant tamoxifen treatment. For patients with diabetes mellitus, critical follow-up using CT study and laboratory tests is considered essential.

  17. Comparison of tamoxifen and letrozole response in mammary preneoplasia of ER and aromatase overexpressing mice defines an immune-associated gene signature linked to tamoxifen resistance

    PubMed Central

    Dabydeen, Sarah A.; Kang, Keunsoo; Díaz-Cruz, Edgar S.; Alamri, Ahmad; Axelrod, Margaret L.; Bouker, Kerrie B.; Al-Kharboosh, Rawan; Clarke, Robert; Hennighausen, Lothar; Furth, Priscilla A.

    2015-01-01

    Response to breast cancer chemoprevention can depend upon host genetic makeup and initiating events leading up to preneoplasia. Increased expression of aromatase and estrogen receptor (ER) is found in conjunction with breast cancer. To investigate response or resistance to endocrine therapy, mice with targeted overexpression of Esr1 or CYP19A1 to mammary epithelial cells were employed, representing two direct pathophysiological interventions in estrogen pathway signaling. Both Esr1 and CYP19A1 overexpressing mice responded to letrozole with reduced hyperplastic alveolar nodule prevalence and decreased mammary epithelial cell proliferation. CYP19A1 overexpressing mice were tamoxifen sensitive but Esr1 overexpressing mice were tamoxifen resistant. Increased ER expression occurred with tamoxifen resistance but no consistent changes in progesterone receptor, pSTAT3, pSTAT5, cyclin D1 or cyclin E levels in association with response or resistance were found. RNA-sequencing (RNA-seq) was employed to seek a transcriptome predictive of tamoxifen resistance using these models and a second tamoxifen-resistant model, BRCA1 deficient/Trp53 haploinsufficient mice. Sixty-eight genes associated with immune system processing were upregulated in tamoxifen-resistant Esr1- and Brca1-deficient mice, whereas genes related to aromatic compound metabolic process were upregulated in tamoxifen-sensitive CYP19A1 mice. Interferon regulatory factor 7 was identified as a key transcription factor regulating these 68 immune processing genes. Two loci encoding novel transcripts with high homology to human immunoglobulin lambda-like polypeptide 1 were uniquely upregulated in the tamoxifen-resistant models. Letrozole proved to be a successful alternative to tamoxifen. Further study of transcriptional changes associated with tamoxifen resistance including immune-related genes could expand our mechanistic understanding and lead to biomarkers predictive of escape or response to endocrine therapies

  18. Sox2 promotes tamoxifen resistance in breast cancer cells

    PubMed Central

    Piva, Marco; Domenici, Giacomo; Iriondo, Oihana; Rábano, Miriam; Simões, Bruno M; Comaills, Valentine; Barredo, Inmaculada; López-Ruiz, Jose A; Zabalza, Ignacio; Kypta, Robert; Vivanco, Maria d M

    2014-01-01

    Development of resistance to therapy continues to be a serious clinical problem in breast cancer management. Cancer stem/progenitor cells have been shown to play roles in resistance to chemo- and radiotherapy. Here, we examined their role in the development of resistance to the oestrogen receptor antagonist tamoxifen. Tamoxifen-resistant cells were enriched for stem/progenitors and expressed high levels of the stem cell marker Sox2. Silencing of the SOX2 gene reduced the size of the stem/progenitor cell population and restored sensitivity to tamoxifen. Conversely, ectopic expression of Sox2 reduced tamoxifen sensitivity in vitro and in vivo. Gene expression profiling revealed activation of the Wnt signalling pathway in Sox2-expressing cells, and inhibition of Wnt signalling sensitized resistant cells to tamoxifen. Examination of patient tumours indicated that Sox2 levels are higher in patients after endocrine therapy failure, and also in the primary tumours of these patients, compared to those of responders. Together, these results suggest that development of tamoxifen resistance is driven by Sox2-dependent activation of Wnt signalling in cancer stem/progenitor cells. PMID:24178749

  19. Evaluation of Tamoxifen and metabolites by LC-MS/MS and HPLC Methods

    PubMed Central

    Heath, D.D.; Flatt, S.W.; Wu, A.H.B.; Pruitt, M.A.; Rock, C.L.

    2015-01-01

    Epidemiological and laboratory evidence suggests that quantification of serum or plasma levels of tamoxifen and the metabolites of tamoxifen, 4-hydroxy-N-desmethyl-tamoxifen (endoxifen), Z-4-hydroxy-tamoxifen (4HT), N-desmethyl-tamoxifen (ND-tam) is a clinically useful tool in the assessment and monitoring of breast cancer status in patients taking adjuvant tamoxifen. A liquid chromatographic mass spectrometric method (LC-MS/MS) was used to measure the blood levels of tamoxifen and the metabolites of tamoxifen. This fully automated analytical method is specific, accurate and sensitive. The LC-MS/MS automated technique has now become a widely accepted reference method. We analyzed a randomly selected batch of blood samples from participants enrolled in a breast cancer study to compare results from this reference method in 40 samples with those obtained from a recently developed high performance liquid chromatography (HPLC) method with fluorescence detection. The mean (SD) concentration for the LC-MS/MS (endoxifen 12.6 [7.5] ng/mL, tamoxifen 105 [44] ng/mL, 4-HT 1.9 [1.0] ng/mL, ND-tam 181 [69] ng/mL) and the HPLC (endoxifen 13.1 [7.8] ng/mL, tamoxifen 108[55]ng/mL, 4-HT 1.8 [0.8] ng/mL, ND-tam 184 [81] ng/mL), the methods did not show any significant differences. Our results confirm that the HPLC method offers an accurate and comparable alternative for the quantification of tamoxifen and tamoxifen metabolites. PMID:24693573

  20. Association of tamoxifen with meningioma: a population-based study in Sweden

    PubMed Central

    Sundquist, Jan; Sundquist, Kristina

    2016-01-01

    Previous studies suggest that hormone therapy may play an important role in the development of meningioma. However, it is unclear whether medication with tamoxifen can prevent meningioma. Our study cohort included all women who were diagnosed with breast cancer between 1961 and 2010, and a total of 227 535 women were identified with breast cancer with a median age at diagnosis of 63 years. Women diagnosed with breast cancer after 1987 were defined as tamoxifen exposed; those diagnosed with breast cancer before or during 1987 were defined as not exposed to tamoxifen. Standardized incidence ratios (SIRs) were used to calculate the risk of subsequent meningioma. Of these women, 223 developed meningioma. For women without tamoxifen exposure, the risk of meningioma was significantly increased, with an SIR of 1.54 (95% confidence interval 1.30–1.81); the risk was not increased in those with tamoxifen exposure (SIR=1.06, 95% confidence interval 0.84–1.32). The increased risk of meningioma in women without tamoxifen exposure persisted during 10 years of follow-up. In this historical cohort study, we found that women diagnosed with breast cancer but not treated with tamoxifen had an increased incidence of meningioma, whereas the incidence was close to that of the general population in patients treated with tamoxifen. This suggests that tamoxifen may prevent the development of meningioma. PMID:25642792

  1. Tumor characteristics and survival outcomes of women with tamoxifen-related uterine carcinosarcoma.

    PubMed

    Matsuo, Koji; Ross, Malcolm S; Bush, Stephen H; Yunokawa, Mayu; Blake, Erin A; Takano, Tadao; Ueda, Yutaka; Baba, Tsukasa; Satoh, Shinya; Shida, Masako; Ikeda, Yuji; Adachi, Sosuke; Yokoyama, Takuhei; Takekuma, Munetaka; Takeuchi, Satoshi; Nishimura, Masato; Iwasaki, Keita; Yanai, Shiori; Klobocista, Merieme M; Johnson, Marian S; Machida, Hiroko; Hasegawa, Kosei; Miyake, Takahito M; Nagano, Tadayoshi; Pejovic, Tanja; Shahzad, Mian Mk; Im, Dwight D; Omatsu, Kohei; Ueland, Frederick R; Kelley, Joseph L; Roman, Lynda D

    2017-02-01

    To examine tumor characteristics and survival outcome of women with uterine carcinosarcoma who had a history of tamoxifen use. This is a multicenter retrospective study examining stage I-IV uterine carcinosarcoma cases based on history of tamoxifen use. Patient demographics, tumor characteristics, treatment pattern, and survival outcomes were compared between tamoxifen users and non-users. Sixty-six cases of tamoxifen-related uterine carcinosarcoma were compared to 1009 cases with no history of tamoxifen use. Tamoxifen users were more likely to be older (mean age, 69 versus 64, P<0.001) and had a past history of malignancy (100% versus 12.7%, P<0.001). Tamoxifen-related uterine carcinosarcoma was significantly associated with a higher proportion of stage IA disease (48.4% versus 29.9%) and a lower risk of stage IVB disease (7.8% versus 16.0%) compared to tamoxifen-unrelated carcinosarcoma (P=0.034). Deep myometrial tumor invasion was less common in uterine carcinosarcoma related to tamoxifen use (28.3% versus 48.8%, P=0.002). On univariate analysis, tamoxifen use was not associated with progression-free survival (5-year rates 44.5% versus 46.8%, P=0.48) and disease-specific survival (64.0% versus 59.1%, P=0.39). After adjusting for age, past history of malignancy, stage, residual disease status at surgery, and postoperative treatment patterns, tamoxifen use was not associated with progression-free survival (adjusted-hazard ratio 0.86, 95% confidence interval 0.50 to 1.50, P=0.60) and disease-specific survival (adjusted-hazard ratio 0.68, 95% confidence interval 0.36 to 1.29, P=0.24). Our study suggests that tamoxifen-related uterine carcinosarcoma may have favorable tumor characteristics but have comparable stage-specific survival outcomes compared to tamoxifen-unrelated uterine carcinosarcoma. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Effects of Tamoxifen and Raloxifene on Memory and Other Cognitive Abilities: Cognition in the Study of Tamoxifen and Raloxifene

    PubMed Central

    Legault, Claudine; Maki, Pauline M.; Resnick, Susan M.; Coker, Laura; Hogan, Patricia; Bevers, Therese B.; Shumaker, Sally A.

    2009-01-01

    Purpose To compare the effects of two selective estrogen receptor modulators, tamoxifen and raloxifene, on global and domain-specific cognitive function. Patients and Methods The National Surgical Adjuvant Breast and Bowel Project's Study of Tamoxifen and Raloxifene (STAR) study was a randomized clinical trial of tamoxifen 20 mg/d or raloxifene 60 mg/d in healthy postmenopausal women at increased risk of breast cancer. The 1,498 women who were randomly assigned in STAR were age 65 years and older, were not diagnosed with dementia, and were enrolled onto the Cognition in the Study of Tamoxifen and Raloxifene (Co-STAR) trial, beginning 18 months after STAR enrollment started. A cognitive test battery modeled after the one used in the Women's Health Initiative Study of Cognitive Aging (WHISCA) was administered. Technicians were centrally trained to administer the battery and recertified every 6 months. Analyses were conducted on all participants and on 273 women who completed the first cognitive battery before they started taking their medications. Results Overall, there were no significant differences in adjusted mean cognitive scores between the two treatment groups across visits. There were significant time effects across the three visits for some of the cognitive measures. Similar results were obtained for the subset of women with true baseline measures. Conclusion Tamoxifen and raloxifene are associated with similar patterns of cognitive function in postmenopausal women at increased risk of breast cancer. Future comparisons between these findings and patterns of cognitive function in hormone therapy and placebo groups in WHISCA should provide additional insights into the effects of tamoxifen and raloxifene on cognitive function in older women. PMID:19770382

  3. Tamoxifen has a proliferative effect in endometrial carcinoma mediated via the GPER/EGFR/ERK/cyclin D1 pathway: A retrospective study and an in vitro study.

    PubMed

    Zhang, Lizhi; Li, Yanmin; Lan, Lan; Liu, Rong; Wu, Yanhong; Qu, Quanxin; Wen, Ke

    2016-12-05

    Tamoxifen has been widely used to treat breast cancer as an endocrine therapy. However, tamoxifen is known to enhance the risk of developing endometrial cancer. We want to examine the effect of tamoxifen on endometrial cancer. In our retrospective study, we found that high grade, high stage, and lymph node metastasis were more common in tamoxifen users. In vitro 4-hydroxytamoxifen (OHT) induced cell proliferation and cell cycle promotion in type I and type II endometrial cancer cell lines, and this proliferation was blocked by GPER silencing. Treatment with OHT increased EGFR and ERK phosphorylation and the mRNA and protein levels of cyclin D1 and GPER. Taken together, our data demonstrate that endometrial cancer patients with tamoxifen treatment exhibit more aggressive histological subtypes and worse prognosis. OHT is a proliferation-inducing agent for endometrial cancer cells, and the GPER/EFGR/ERK/cyclin D1 pathway is involved in this process. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  4. The endometrium in breast cancer patients on tamoxifen.

    PubMed

    Dallenbach-Hellweg, G; Schmidt, D; Hellberg, P; Bourne, T; Kreuzwieser, E; Dören, M; Rydh, W; Rudenstam, G; Granberg, S

    2000-04-01

    We restudied histologically and immunohistochemically 17 endometrial carcinomas, 2 malignant mixed tumors and 180 endometria with benign changes during or after tamoxifen therapy. The carcinomas were subtyped according to the 1994 WHO-classification. Endometrial biopsies were taken only if the endometrial thickness was > 8 mm sonographically, when a polyp was seen, or for postmenopausal bleeding. About half of the endometrial specimens showed simple or cystic atrophy, 55-76% had cystic-atrophic polyps or regressive hyperplasia. Depending upon the dose of tamoxifen, 7-19% (30 mg) to 27-36% (20 mg) showed moderate glandular proliferation. 20-33% had foci of mucinous, clear cell or serous-papillary metaplasia. 68-70% revealed diffuse extensive fibrosis of the endometrial stroma. None of 11 patients biopsied before starting tamoxifen therapy had advanced endometrial glandular proliferation in the second endometrial biopsy after tamoxifen treatment. None of the 19 endometrial neoplasms after tamoxifen therapy was of the endometrioid type: 11 were mucinous adenocarcinomas, 4 clear cell carcinomas, 2 serous-papillary carcinomas, one carcinosarcoma and one malignant Mullerian mixed tumor. The reasons for discrepancies between suspicious sonograms and endometrial atrophy are discussed.

  5. Genotype-guided tamoxifen therapy; time to pause for reflection?

    PubMed Central

    Lash, Timothy L.; Lien, Ernst A.; Sørensen, Henrik Toft; Hamilton-Dutoit, Stephen

    2010-01-01

    Tamoxifen remains a cornerstone of adjuvant therapy for early stage breast cancer patients with estrogen receptor-positive tumors. Accurate markers of tamoxifen resistance would allow prediction of tamoxifen response and personalization of combined therapies. Recently, it has been suggested that patients with inherited nonfunctional alleles of the cytochrome P450 CYP2D6 may be poor candidates for adjuvant tamoxifen therapy because women with these variant alleles have reduced concentrations of the tamoxifen metabolites that most strongly bind the estrogen receptor. In some studies, women with these alleles have a higher risk of recurrence than women with two functional alleles. However, dose-setting studies with clinical and biomarker outcomes, studies associating clinical outcomes with serum concentrations of tamoxifen and its metabolites, and a simple model of receptor binding, all suggest that tamoxifen and its metabolites should reach concentrations sufficient to achieve the therapeutic effect regardless of CYP2D6 inhibition. The ten epidemiology studies of the association between CYP2D6 genotype and breast cancer recurrence report widely heterogeneous results with relative risk estimates outside the range of reasonable bounds. None of the explanations proposed for the heterogeneity of results account adequately for the observed variability and no design feature sets apart any study or subset of studies as most likely to be accurate. The studies reporting a positive association may receive the most attention because they reported a result consistent with the profile of metabolite concentrations; not because they are more reliable by design. We argue that a recommendation for CYP2D6 genotyping of candidates for tamoxifen therapy, and its implicit conclusion regarding the association between genotype and recurrence risk, is premature. PMID:19647203

  6. Endocrine effects of adjuvant letrozole + triptorelin compared with tamoxifen + triptorelin in premenopausal patients with early breast cancer.

    PubMed

    Rossi, Emanuela; Morabito, Alessandro; De Maio, Ermelinda; Di Rella, Francesca; Esposito, Giuseppe; Gravina, Adriano; Labonia, Vincenzo; Landi, Gabriella; Nuzzo, Francesco; Pacilio, Carmen; Piccirillo, Maria Carmela; D'Aiuto, Giuseppe; D'Aiuto, Massimiliano; Rinaldo, Massimo; Botti, Gerardo; Gallo, Ciro; Perrone, Francesco; de Matteis, Andrea

    2008-01-10

    To compare the endocrine effects of 6 months of adjuvant treatment with letrozole + triptorelin or tamoxifen + triptorelin in premenopausal patients with early breast cancer within an ongoing phase 3 trial (Hormonal Adjuvant Treatment Bone Effects study). Prospectively collected hormonal data were available for 81 premenopausal women, of whom 30 were assigned to receive tamoxifen + triptorelin and 51 were assigned letrozole + triptorelin +/- zoledronate. Serum 17-beta-estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), Delta4-androstenedione, testosterone, dehydroepiandrosterone-sulfate, progesterone, adrenocorticotropic hormone (ACTH), and cortisol were measured at baseline and after 6 months of treatment. For each hormone, 6-month values were compared between treatment groups by the Wilcoxon-Mann-Whitney exact test. Median age was 44 years for both groups of patients. Letrozole + triptorelin (+/- zoledronate) induced a stronger suppression of median E2 serum levels (P = .0008), LH levels (P = .0005), and cortisol serum levels (P < .0001) compared with tamoxifen + triptorelin. Median FSH serum levels were suppressed in both groups, but such suppression was lower among patients receiving letrozole, who showed significantly higher median FSH serum levels (P < .0001). No significant differences were observed for testosterone, progesterone, ACTH, androstenedione, and dehydroepiandrosterone between the two groups of patients. Letrozole in combination with triptorelin induces a more intense estrogen suppression than tamoxifen + triptorelin in premenopausal patients with early breast cancer.

  7. [Comparison between manual acupuncture and electroacupuncture for hot flashes and sex hormone of perimenopausal syndrome].

    PubMed

    Cao, Zhiliang; Tang, Jian; Xue, Yuting; Wang, Qiong; Li, Saiqun; Zhou, Youjun; Zhang, Wei

    2017-03-12

    To compare the effect and differences sex the influence of hormone levels of perimenopau-sal syndrome patients between manual acupuncture and electroacupuncture (EA). A total of 50 cases with perimenopausal syndrome were randomly assigned into an manual acupuncture group (27 cases) and an EA group (23 cases), and 1 case dropped in the EA group. The acupoints in the two groups were Guanyuan (CV 4), Zigong (EX-CA 1), Tianshu (ST 25), and Sanyinjiao (SP 6). Acupuncture with 3-time small and even manipulation of lifting, thrusting and twirling was used in the acupuncture group, once 10 min. EA with sparse-dense wave and 10 Hz/50 Hz was applied in the EA group for 30 min. The treatments in the two groups were for continuous 8 weeks (24 times in total), once the other day, 3 times a week. The scores of 24-hour hot flashes even, menopausal rating scale (MRS) and menopause-specific quality of life questionnaire (MENQOL) were recorded before treatment and after 4-week and 8-week treatment, as well as 12 and 24 weeks after treatment. Serum sex hormone levels were tested before and after 8-week treatment as well as 12 weeks after treatment, including serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estracliol (E 2 ). Compared with those before treatment, the 24-hour hot flashes even score, MRS and MENQOL scores were significantly lower after 4-week and 8-week treatments, 12 and 24 weeks after treatment (all P <0.05). All the above scores after 8-week treatment were lower than those after 4-week treatment (all P <0.05); and the scores 12 and 24 weeks after treatment were lower than those after 4-week and 8-week treatments (all P <0.05); all the scores after treatment were not significantly different at any time between the two groups (all P >0.05). Compared with those before treatment, serum FSH and E 2 apparently improved in the two groups after 8-week treatment and 12 weeks after treatment (all P <0.05). LH levels did not significantly change in the

  8. Antrodia cinnamomea extract inhibits the proliferation of tamoxifen-resistant breast cancer cells through apoptosis and skp2/microRNAs pathway.

    PubMed

    Lin, Yu-Shih; Lin, Yin-Yin; Yang, Yao-Hsu; Lin, Chun-Liang; Kuan, Feng-Che; Lu, Cheng-Nan; Chang, Geng-He; Tsai, Ming-Shao; Hsu, Cheng-Ming; Yeh, Reming-Albert; Yang, Pei-Rung; Lee, I-Yun; Shu, Li-Hsin; Cheng, Yu-Ching; Liu, Hung-Te; Lee, Kuan-Der; Chang, De-Ching; Wu, Ching-Yuan

    2018-05-09

    Breast cancer is the most common cancer in women and affects 1.38 million women worldwide per year. Antiestrogens such as tamoxifen, a selective estrogen receptor (ER) modulator, are widely used in clinics to treat ER-positive breast tumors. However, remissions of breast cancer are often followed by resistance to tamoxifen and disease relapse. Despite the increasing understanding of the resistance mechanisms, effective regimens for treating tamoxifen-resistant breast cancer are limited. Antrodia cinnamomea is a traditional medicinal mushroom native only to Taiwan. In this study, we aimed to examine in vitro effect of antrodia cinnamomea in the tamoxifen-resistant cancer. Antrodia cinnamomea was studied for its biological activity against proliferation of tamoxifen-resistant breast cancer by XTT assay. Next, the underlying mechanism was studied by flow cytometry, qPCR and Western's blotting assay. Our results revealed that the ethanol extract of antrodia cinnamomea (AC) can inhibit the growth of breast cancer cells, including MCF-7 cell and tamoxifen-resistant MCF-7 cell lines. Combination treatment with AC and 10 - 6  M tamoxifen have the better inhibitory effect on the proliferation of tamoxifen-resistant MCF-7 cells than only AC did. AC can induce apoptosis in these breast cancer cells. Moreover, it can suppress the mRNA expression of skp2 (S-phase kinase-associated protein 2) by increasing the expressions of miR-21-5p, miR-26-5p, and miR-30-5p in MCF-7 and tamoxifen-resistant MCF-7 cells. These results suggest that the ethanol extract of antrodia cinnamomea could be a novel anticancer agent in the armamentarium of tamoxifen-resistant breast cancer management. Moreover, we hope to identify additional pure compounds that could serve as promising anti-breast cancer candidates for further clinical trials.

  9. Tamoxifen Activation of Cre-Recombinase Has No Persisting Effects on Adult Neurogenesis or Learning and Anxiety

    PubMed Central

    Rotheneichner, Peter; Romanelli, Pasquale; Bieler, Lara; Pagitsch, Sebastian; Zaunmair, Pia; Kreutzer, Christina; König, Richard; Marschallinger, Julia; Aigner, Ludwig; Couillard-Després, Sébastien

    2017-01-01

    Adult neurogenesis is a tightly regulated process continuously taking place in the central nervous system of most mammalian species. In neuroscience research, transgenic animals bearing the tamoxifen-inducible CreERT2-Lox system are widely used. In this study, we made use of a Nestin-CreERT2/R26R-YFP transgenic mouse model in which the CreERT2 activates the expression of YFP in multipotent neural stem cells upon tamoxifen application. Humoral factors, such as the levels of estrogens, have been reported to affect the hippocampal neurogenesis. The application of tamoxifen, a mixed agonist/antagonist of the estrogen receptor that permeates the blood-brain-barrier, could thus influence adult neurogenesis. Although the functions of adult neurogenesis are yet to be fully deciphered, a reciprocal interaction between rates of neurogenesis on the one hand and learning and mood regulation on the other hand, has been suggested. The impact of tamoxifen on neurogenesis and behavior was therefore addressed following five daily applications according to the open field test, the elevated plus maze, and Morris water maze. In addition, the impact of short-term tamoxifen application on progenitor cell proliferation, morphology, and fate in the neurogenic niche of the dentate gyrus were investigated. Finally, the influence of the route of administration (oral vs. intra-peritoneal) and gender-specific response were scrutinized. The sub-acute analysis did neither reveal significant differences in behavior, such as voluntary motor activity, anxiety behavior, and spatial learning, nor in cell proliferation, cell survival, dendritic arborization or maturation rate within the dentate gyrus between saline solution-, corn oil-, and tamoxifen-treated groups. Finally, neither the route of application, nor the gender of treated mice influenced the response to tamoxifen. We conclude that short tamoxifen treatments used to activate the CreERT2 system in transgenic mouse models does not have a

  10. Phenotype anchoring in zebrafish reveals a potential role for matrix metalloproteinases (MMPs) in tamoxifen's effects on skin epithelium

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Bugel, Sean M., E-mail: Sean.Bugel@oregonstate.edu; Wehmas, Leah C., E-mail: wehmasl@onid.oregonstate.edu; La Du, Jane K., E-mail: Jane.LaDu@oregonstate.edu

    The zebrafish is a powerful alternative model used to link phenotypes with molecular effects to discover drug mode of action. Using a zebrafish embryo-larval toxicity bioassay, we evaluated the effects of tamoxifen — a widely used anti-estrogen chemotherapeutic. Zebrafish exposed to ≥ 10 μM tamoxifen exhibited a unique necrotic caudal fin phenotype that was rapidly induced regardless of developmental life-stage when treatment was applied. To define tamoxifen's bioactivity resulting in this phenotype, targeted gene expression was used to evaluate 100 transcripts involved in tissue remodeling, calcium signaling, cell cycle and cell death, growth factors, angiogenesis and hypoxia. The most robustlymore » misregulated transcripts in the tail were matrix metalloproteinases mmp9 and mmp13a, induced 127 and 1145 fold, respectively. Expression of c-fos, c-jun, and ap1s1 were also moderately elevated (3–7 fold), consistent with AP-1 activity — a transcription factor that regulates MMP expression. Immunohistochemistry confirmed high levels of induction for MMP13a in affected caudal fin skin epithelial tissue. The necrotic caudal fin phenotype was significantly attenuated or prevented by three functionally unique MMP inhibitors: EDTA (metal chelator), GM 6001 (broad MMP inhibitor), and SR 11302 (AP-1 transcription factor inhibitor), suggesting MMP-dependence. SR 11302 also inhibited induction of mmp9, mmp13a, and a putative MMP target, igfbp1a. Overall, our studies suggest that tamoxifen's effect is the result of perturbation of the MMP system in the skin leading to ectopic expression, cytotoxicity, and the necrotic caudal fin phenotype. These studies help advance our understanding of tamoxifen's non-classical mode of action and implicate a possible role for MMPs in tissues such as skin. - Highlights: • Tamoxifen rapidly induced a unique necrotic caudal fin phenotype in zebrafish. • Apoptosis co-localized temporally and spatially in the necrotic tail. • The

  11. Effect of dietary administration of letrozole and tamoxifen on gonadal development, sex differentiation and biochemical changes in common carp (Cyprinus carpio L.).

    PubMed

    Singh, Atul K; Srivastava, P P; Verma, Rita; Srivastava, Sharad C; Kumar, Dinesh; Ansari, Abubakar

    2015-03-01

    The effect of letrozole and tamoxifen on the specific growth rate (SGR; % day(-1)), gonado-somatic index (GSI), total haemoglobin (g%), gonadal and serum protein as well as lipid, sex differentiation and 17β-oestradiol levels were studied in sexually undifferentiated Cyprinus carpio fingerlings 30 days post fertilisation (30 dpf) for 60 days. Results showed decreased GSI with tamoxifen treatment whereas letrozole increased it. There were reduced protein, lipid, triglyceride and cholesterol levels after treatment with tamoxifen and letrozole during gonadal development. Tamoxifen (200mgkg(-1) feed) induced 82.5% masculinisation, whereas letrozole in the same dose produced 98.5% males. Gonadal 17β-oestradiol significantly declined from 86.0±1.41pg per 100mg (control) to 45.5±1.94pg per 100mg with tamoxifen and 36.0±0.72pg per 100mg with letrozole treatment. Similarly, serum 17β-oestradiol levels also decreased after tamoxifen and letrozole treatments. Testicular development in 37.8% of fish treated with tamoxifen and letrozole was found to be more advanced (spermatocytes) than in the control (spermatogonium); however, there was reduced ovarian growth and increased atresia. It was concluded that letrozole and tamoxifen both significantly affect sex differentiation and gonadal maturity in C. carpio leading to the production of sex-reversed males, yet the effect of letrozole was more potent.

  12. Stromal-Epithelial Interactions and Tamoxifen-Sensitivity: A Bench-to-Bedside Model of Chemoprevention

    DTIC Science & Technology

    2008-05-01

    effects of tamoxifen can be directly attributed to competitive interactions with ER. Tamox- ifen induces apoptosis in cholangiocarcinoma cells and...Pickens A, et al. Apoptosis and tumorigenesis in human cholangiocarcinoma cells. Involvement of Fas/APO-1 (CD95) and calmodulin. Am J Pathol 1999;155:193

  13. Role of human pregnane X receptor in tamoxifen- and 4-hydroxytamoxifen-mediated CYP3A4 induction in primary human hepatocytes and LS174T cells.

    PubMed

    Sane, Rucha S; Buckley, Donna J; Buckley, Arthur R; Nallani, Srikanth C; Desai, Pankaj B

    2008-05-01

    Previously we observed that the antiestrogens tamoxifen and 4-hydroxytamoxifen (4OHT) induce CYP3A4 in primary human hepatocytes and activate human pregnane X receptor (PXR) in cell-based reporter assays. Given the complex cross-talk between nuclear receptors, tissue-specific expression of CYP3A4, and the potential for tamoxifen and 4OHT to interact with a myriad of receptors, this study was undertaken to gain mechanistic insights into the inductive effects of tamoxifen and 4OHT. First, we observed that transfection of the primary cultures of human hepatocytes with PXR-specific small interfering RNA reduced the PXR mRNA expression and the extent of CYP3A4 induction by tamoxifen and 4OHT by 50%. Second, in LS174T colon carcinoma cells, which were observed to have significantly lower PXR expression relative to human hepatocytes, neither tamoxifen nor 4OHT induced CYP3A4. Third, N-desmethyltamoxifen, which did not induce CYP3A4 in human hepatocytes, also did not activate PXR in LS174T cells. We then used cell-based reporter assay to evaluate the effects of other receptors such as glucocorticoid receptor GR alpha and estrogen receptor ER alpha on the transcriptional activation of PXR. The cotransfection of GR alpha in LS174T cells augmented PXR activation by tamoxifen and 4OHT. On the other hand, the presence of ER alpha inhibited PXR-mediated basal activation of CYP3A4 promoter, possibly via competing for common cofactors such as steroid receptor coactivator 1 and glucocorticoid receptor interacting protein 1. Collectively, our findings suggest that the CYP3A4 induction by tamoxifen and 4OHT is primarily mediated by PXR but the overall stoichiometry of other nuclear receptors and transcription cofactors also contributes to the extent of the inductive effect.

  14. Tamoxifen Inhibition of Kv7.2/Kv7.3 Channels

    PubMed Central

    Ferrer, Tania; Aréchiga-Figueroa, Ivan Arael; Shapiro, Mark S.; Tristani-Firouzi, Martin; Sanchez-Chapula, José A.

    2013-01-01

    KCNQ genes encode five Kv7 K+ channel subunits (Kv7.1–Kv7.5). Four of these (Kv7.2–Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow voltage-gated M-channel, which regulates neuronal excitability. In this study, we demonstrate that tamoxifen, an estrogen receptor antagonist used in the treatment of breast cancer, inhibits Kv7.2/Kv7.3 currents heterologously expressed in human embryonic kidney HEK-293 cells. Current inhibition by tamoxifen was voltage independent but concentration-dependent. The IC50 for current inhibition was 1.68 ± 0.44 µM. The voltage-dependent activation of the channel was not modified. Tamoxifen inhibited Kv7.2 homomeric channels with a higher potency (IC50 = 0.74 ± 0.16 µM). The mutation Kv7.2 R463E increases phosphatidylinositol- 4,5-bisphosphate (PIP2) - channel interaction and diminished dramatically the inhibitory effect of tamoxifen compared with that for wild type Kv7.2. Conversely, the mutation Kv7.2 R463Q, which decreases PIP2 -channel interaction, increased tamoxifen potency. Similar results were obtained on the heteromeric Kv7.2 R463Q/Kv7.3 and Kv7.2 R463E/Kv7.3 channels, compared to Kv7.2/Kv7.3 WT. Overexpression of type 2A PI(4)P5-kinase (PIP5K 2A) significantly reduced tamoxifen inhibition of Kv7.2/Kv7.3 and Kv7.2 R463Q channels. Our results suggest that tamoxifen inhibited Kv7.2/Kv7.3 channels by interfering with PIP2-channel interaction because of its documented interaction with PIP2 and the similar effect of tamoxifen on various PIP2 sensitive channels. PMID:24086693

  15. Tamoxifen inhibition of kv7.2/kv7.3 channels.

    PubMed

    Ferrer, Tania; Aréchiga-Figueroa, Ivan Arael; Shapiro, Mark S; Tristani-Firouzi, Martin; Sanchez-Chapula, José A

    2013-01-01

    KCNQ genes encode five Kv7 K(+) channel subunits (Kv7.1-Kv7.5). Four of these (Kv7.2-Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow voltage-gated M-channel, which regulates neuronal excitability. In this study, we demonstrate that tamoxifen, an estrogen receptor antagonist used in the treatment of breast cancer, inhibits Kv7.2/Kv7.3 currents heterologously expressed in human embryonic kidney HEK-293 cells. Current inhibition by tamoxifen was voltage independent but concentration-dependent. The IC50 for current inhibition was 1.68 ± 0.44 µM. The voltage-dependent activation of the channel was not modified. Tamoxifen inhibited Kv7.2 homomeric channels with a higher potency (IC50 = 0.74 ± 0.16 µM). The mutation Kv7.2 R463E increases phosphatidylinositol- 4,5-bisphosphate (PIP2) - channel interaction and diminished dramatically the inhibitory effect of tamoxifen compared with that for wild type Kv7.2. Conversely, the mutation Kv7.2 R463Q, which decreases PIP2 -channel interaction, increased tamoxifen potency. Similar results were obtained on the heteromeric Kv7.2 R463Q/Kv7.3 and Kv7.2 R463E/Kv7.3 channels, compared to Kv7.2/Kv7.3 WT. Overexpression of type 2A PI(4)P5-kinase (PIP5K 2A) significantly reduced tamoxifen inhibition of Kv7.2/Kv7.3 and Kv7.2 R463Q channels. Our results suggest that tamoxifen inhibited Kv7.2/Kv7.3 channels by interfering with PIP2-channel interaction because of its documented interaction with PIP2 and the similar effect of tamoxifen on various PIP2 sensitive channels.

  16. Acquisition of epithelial-mesenchymal transition phenotype in the tamoxifen-resistant breast cancer cell: a new role for G protein-coupled estrogen receptor in mediating tamoxifen resistance through cancer-associated fibroblast-derived fibronectin and β1-integrin signaling pathway in tumor cells.

    PubMed

    Yuan, Jie; Liu, Manran; Yang, Li; Tu, Gang; Zhu, Qing; Chen, Maoshan; Cheng, Hong; Luo, Haojun; Fu, Weijie; Li, Zhenhua; Yang, Guanglun

    2015-05-21

    Acquired tamoxifen resistance remains the major obstacle to breast cancer endocrine therapy. β1-integrin was identified as one of the target genes of G protein-coupled estrogen receptor (GPER), a novel estrogen receptor recognized as an initiator of tamoxifen resistance. Here, we investigated the role of β1-integrin in GPER-mediated tamoxifen resistance in breast cancer. The expression of β1-integrin and biomarkers of epithelial-mesenchymal transition were evaluated immunohistochemically in 53 specimens of metastases and paired primary tumors. The function of β1-integrin was investigated in tamoxifen-resistant (MCF-7R) subclones, derived from parental MCF-7 cells, and MCF-7R β1-integrin-silenced subclones in MTT and Transwell assays. Involved signaling pathways were identified using specific inhibitors and Western blotting analysis. GPER, β1-integrin and mesenchymal biomarkers (vimentin and fibronectin) expression in metastases increased compared to the corresponding primary tumors; a close expression pattern of β1-integrin and GPER were in metastases. Increased β1-integrin expression was also confirmed in MCF-7R cells compared with MCF-7 cells. This upregulation of β1-integrin was induced by agonists of GPER and blocked by both antagonist and knockdown of it in MCF-7R cells. Moreover, the epidermal growth factor receptor/extracellular regulated protein kinase (EGFR/ERK) signaling pathway was involved in this transcriptional regulation since specific inhibitors of these kinases also reduced the GPER-induced upregulation of β1-integrin. Interestingly, silencing of β1-integrin partially rescued the sensitivity of MCF-7R cells to tamoxifen and the α5β1-integrin subunit is probably responsible for this phenomenon. Importantly, the cell migration and epithelial-mesenchymal transition induced by cancer-associated fibroblasts, or the product of cancer-associated fibroblasts, fibronectin, were reduced by knockdown of β1-integrin in MCF-7R cells. In addition

  17. Evaluation of tamoxifen and metabolites by LC-MS/MS and HPLC methods.

    PubMed

    Heath, D D; Flat, S W; Wu, A H B; Pruitt, M A; Rock, C L

    2014-01-01

    Epidemiological and laboratory evidence suggests that quantification of serum or plasma levels of tamoxifen and its metabolites, 4-hydroxy-N-desmethyl-tamoxifen (endoxifen), Z-4-hydroxytamoxifen (4HT), N-desmethyl-tamoxifen (ND-tam), is a clinically useful tool in the assessment and monitoring of breast cancer status in patients taking adjuvant tamoxifen. A liquid chromatographic mass spectrometric method (LC-MS/MS) was used to measure the blood levels of tamoxifen and its metabolites. This fully automated analytical method is specific, accurate and sensitive. The LC-MS/MS automated technique has now become a widely accepted reference method. This study analysed a randomly selected batch of blood samples from participants enrolled in a breast cancer study to compare results from this reference method in 40 samples with those obtained from a recently developed high-performance liquid chromatography (HPLC) method with fluorescence detection. The mean (SD) concentrations for the LC-MS/MS method (endoxifen 12.6 [7.5] ng/mL, tamoxifen 105 [44] ng/mL, 4-HT 1.9 [1.0] ng/mL, ND-tam 181 [69] ng/mL) and the HPLC method (endoxifen 13.1 [7.8] ng/mL, tamoxifen 108 [55] ng/mL, 4-HT 1.8 [0.8] ng/mL, ND-tam 184 [81] ng/mL) did not show any significant differences. The results confirm that the HPLC method offers an accurate and comparable alternative for the quantification of tamoxifen and tamoxifen metabolites.

  18. A misdiagnosed Riedel's thyroiditis successfully treated by thyroidectomy and tamoxifen.

    PubMed

    Wang, Chih-Jung; Wu, Ta-Jen; Lee, Chung-Ta; Huang, Shih-Ming

    2012-12-01

    Riedel's thyroiditis, known as invasive fibrous thyroiditis, is a very rare form of chronic thyroiditis. It is hard to make the diagnosis without surgical biopsy. We present a case of Riedel's thyroiditis in a 52-year-old female with past history of Hashimoto's thyroiditis. She suffered from bilateral neck pain, which radiated to both lower jaws. The erythrocyte sedimentation rate was 125 mm/hour. Subacute thyroiditis superimposed on Hashimoto's thyroiditis was diagnosed and treated with steroid. However the response was poor and she had a history of severe peptic ulcer. To avoid inducing the peptic ulcer by steroid, she received bilateral subtotal thyroidectomy. During surgery, the thyroid had severe adhesion to surrounding soft tissue and the pathology showed Riedel's thyroiditis. The neck pain improved after thyroidectomy. Tamoxifen has been given for 8 months and the size of remnant thyroid decreased to 8 mm. We concluded that combined thyroidectomy and tamoxifen successfully cured a patient with Riedel's thyroiditis. Copyright © 2012. Published by Elsevier B.V.

  19. Identification of tamoxifen and metabolites in human male urine by GC/MS.

    PubMed

    Mihailescu, R; Aboul-Enein, H Y; Efstatide, M D

    2000-05-01

    Tamoxifen is an antiestrogenic drug which is used in the treatment of breast cancer and nonmalignant breast disorders. It also has a stimulating effect on the secretion of hypofisar gonadotropic hormones and is generally used in the treatment of infertility. In males, tamoxifen causes an increase of endogenous production of androgenic steroids, and therefore is used by athletes. A method for identification of tamoxifen and metabolites in urine, using the gas chromatography and mass spectrometry system (GC/MS) is described. This study also reports the extraction methodology of tamoxifen and metabolites in urine samples of healthy male volunteers and the GC/MS conditions used to identify tamoxifen and its metabolites.

  20. Long Non-Coding RNA (lncRNA) Urothelial Carcinoma-Associated 1 (UCA1) Enhances Tamoxifen Resistance in Breast Cancer Cells via Inhibiting mTOR Signaling Pathway.

    PubMed

    Wu, Chihua; Luo, Jing

    2016-10-21

    BACKGROUND Long non-coding RNA (lncRNA) UCA1 is an oncogene in breast cancer. The purpose of this study was to investigate the role of UCA1 in tamoxifen resistance of estrogen receptor positive breast cancer cells. MATERIAL AND METHODS Tamoxifen sensitive MCF-7 cells were transfected for UCA1 overexpression, while tamoxifen resistant LCC2 and LCC9 cells were transfected with UCA siRNA for UCA1 knockdown. qRT-PCR was performed to analyze UCA1 expression. CCK-8 assay, immunofluorescence staining of cleaved caspase-9, and flow cytometric analysis of Annexin V/PI staining were used to assess tamoxifen sensitivity. Western blot analysis was performed to detect p-AKT and p-mTOR expression. RESULTS LncRNA UCA1 was significantly upregulated in tamoxifen resistant breast cancer cells compared to tamoxifen sensitive cells. LCC2 and LCC9 cells transfected with UCA1 siRNA had significantly higher ratio of apoptosis after tamoxifen treatment. UCA1 siRNA significantly decreased the protein levels of p-AKT and p-mTOR in LCC2 and LCC9 cells. Enforced UCA1 expression substantially reduced tamoxifen induced apoptosis in MCF-7 cells, while rapamycin treatment abrogated the protective effect of UCA1. CONCLUSIONS UCA1 upregulation was associated with tamoxifen resistance in breast cancer. Mechanistically, UCA1 confers tamoxifen resistance to breast cancer cells partly via activating the mTOR signaling pathway.

  1. Concurrent tamoxifen-related Müllerian adenofibromas in uterus and ovary.

    PubMed

    Shi, Haiyan; Chen, Xiaoduan; Lv, Bingjian; Zhang, Xiaofei

    2015-01-01

    Tamoxifen is a widely used in anti-oestrogen treatment of breast cancer. Previous reports showed that tamoxifen is associated with proliferative endometrial lesions. We herein reported an unusual case of concurrent hyperplastic lesions in the uterine cavity and right ovary in a 45-year-old woman with tamoxifen therapy. Regular vaginal ultrasonography showed the progressive endometrial thickening and right ovary enlargement during the period of drug use. Both lesions in the uterine cavity and right ovary showed characteristics resembling that of Müllerian adenofibroma. There were also foci of endometriosis in her bilateral ovarian surfaces. We suggest that women taking tamoxifen with a known history of endometriosis should be followed with transvaginal ultrasonography periodically.

  2. Amelioration of tamoxifen-induced liver injury in rats by grape seed extract, black seed extract and curcumin.

    PubMed

    El-Beshbishy, Hesham A; Mohamadin, Ahmed M; Nagy, Ayman A; Abdel-Naim, Ashraf B

    2010-03-01

    Liver injury was induced in female rats using tamoxifen (TAM). Grape seeds (Vitis vinifera) extract (GSE), black seed (Nigella sativa) extract (NSE), curcumin (CUR) or silymarin (SYL) were orally administered to TAM-intoxicated rats. Liver histopathology of TAM-intoxicated:rats showed pathological changes. TAM-intoxication elicited declines in liver antioxidant enzymes levels (glutathione peroxidase, glutathione reductase, superoxide dismutase and catalase), reduced glutathione (GSH) and GSH/GSSG ratio plus the hepatic elevations in lipid peroxides, oxidized glutathione (GSSG), tumor necrosis factor-alpha (TNF-alpha) and serum liver enzymes; alanine transaminase, aspartate transaminase, alkaline phosphatase, lactate dehydrogenase and gamma glutamyl transferase levels. Oral intake of NSE, GSE, CUR or SYL to TAM-intoxicated rats, attenuated histopathological changes and corrected all parameters mentioned above. Improvements were prominent in case of NSE (similarly SYL) > CUR > GSE. Data indicated that NSE, GSE or CUR act as free radicals scavengers and protect TAM-induced liver injury in rats.

  3. Effects of Yoga and Aerobic Exercise on Actigraphic Sleep Parameters in Menopausal Women with Hot Flashes.

    PubMed

    Buchanan, Diana Taibi; Landis, Carol A; Hohensee, Chancellor; Guthrie, Katherine A; Otte, Julie L; Paudel, Misti; Anderson, Garnet L; Caan, Bette; Freeman, Ellen W; Joffe, Hadine; LaCroix, Andrea Z; Newton, Katherine M; Reed, Susan D; Ensrud, Kristine E

    2017-01-15

    To determine effects of yoga and aerobic exercise compared with usual activity on objective assessments of sleep in midlife women. Secondary analyses of a randomized controlled trial in the Menopause Strategies: Finding Lasting Answers for Symptoms and Health (MsFLASH) network conducted among 186 late transition and postmenopausal women aged 40-62 y with hot flashes. Women were randomized to 12 w of yoga, supervised aerobic exercise, or usual activity. The mean and coefficient of variation (CV) of change in actigraph sleep measures from each intervention group were compared to the usual activity group using linear regression models. Baseline values of the primary sleep measures for the entire sample were mean total sleep time (TST) = 407.5 ± 56.7 min; mean wake after sleep onset (WASO) = 54.6 ± 21.8 min; mean CV for WASO = 37.7 ± 18.7 and mean CV for number of long awakenings > 5 min = 81.5 ± 46.9. Changes in the actigraphic sleep outcomes from baseline to weeks 11-12 were small, and none differed between groups. In an exploratory analysis, women with baseline Pittsburgh Sleep Quality Index higher than 8 had significantly reduced TST-CV following yoga compared with usual activity. This study adds to the currently scant literature on objective sleep outcomes from yoga and aerobic exercise interventions for this population. Although small effects on self-reported sleep quality were previously reported, the interventions had no statistically significant effects on actigraph measures, except for potentially improved sleep stability with yoga in women with poor self-reported sleep quality. © 2017 American Academy of Sleep Medicine

  4. Targeting of EGFR, VEGFR2, and Akt by Engineered Dual Drug Encapsulated Mesoporous Silica-Gold Nanoclusters Sensitizes Tamoxifen-Resistant Breast Cancer.

    PubMed

    Kumar, B N Prashanth; Puvvada, Nagaprasad; Rajput, Shashi; Sarkar, Siddik; Mahto, Madhusudan Kr; Yallapu, Murali M; Pathak, Amita; Emdad, Luni; Das, Swadesh K; Reis, Rui L; Kundu, S C; Fisher, Paul B; Mandal, Mahitosh

    2018-05-30

    Tamoxifen administration enhanced overall disease-free survival and diminished mortality rates in cancer patients. However, patients with breast cancer often fail to respond for tamoxifen therapy due to the development of a drug-resistant phenotype. Functional analysis and molecular studies suggest that protein mutation and dysregulation of survival signaling molecules such as epidermal growth factor receptor, vascular endothelial growth factor receptor 2, and Akt contribute to tamoxifen resistance. Various strategies, including combinatorial therapies, show chemosensitize tamoxifen-resistant cancers. Based on chemotoxicity issues, researchers are actively investigating alternative therapeutic strategies. In the current study, we fabricate a mesoporous silica gold cluster nanodrug delivery system that displays exceptional tumor-targeting capability, thus promoting accretion of drug indices at the tumor site. We employ dual drugs, ZD6474, and epigallocatechin gallate (EGCG) that inhibit EGFR2, VEGFR2, and Akt signaling pathways since changes in these signaling pathways confer tamoxifen resistance in MCF 7 and T-47D cells. Mesoporous silica gold cluster nanodrug delivery of ZD6474 and EGCG sensitize tamoxifen-resistant cells to apoptosis. Western and immune-histochemical analyses confirmed the apoptotic inducing properties of the nanoformulation. Overall, results with these silica gold nanoclusters suggest that they may be a potent nanoformulation against chemoresistant cancers.

  5. Imaging, biodistribution and therapy potential of halogenated tamoxifen analogues.

    PubMed

    Yang, D J; Li, C; Kuang, L R; Price, J E; Buzdar, A U; Tansey, W; Cherif, A; Gretzer, M; Kim, E E; Wallace, S

    1994-01-01

    Tamoxifen binds to estrogen receptors (ERs) and prevents breast cancer cell proliferation. This study is aimed at developing a ligand for imaging ER (+) breast tumors by positron emission tomography (PET) or single photon emission computed tomography (SPECT). [18F]-Labeled tamoxifen analogue ([18F]FTX) was prepared in 30-40% yield and [131I]-labeled tamoxifen analogue ([131I]ITX) was prepared in 20-25% yield. In mammary tumor-bearing rats, the biodistribution of [18F]FTX at 2 h showed a tumor uptake value (% injected dose/gram tissue) of 0.41 +/- 0.07; when rats were pretreated with diethylstilbestrol (DES), the value changed to 0.24 +/- 0.017. [131I]ITX at 6 h showed a tumor uptake value of 0.26 +/- 0.166; when rats were pretreated with DES, the value changed to 0.22 +/- 0.044. Priming tumor-bearing rats with estradiol, a tumor uptake value for [131I]ITX was increased to 0.48 +/- 0.107 at 6 h. In the [3H]estradiol receptor assay, tumors had a mean estrogen receptor density of 7.5 fmol/mg of protein. In gamma scintigraphic imaging studies with [131I]ITX, the rabbit uterus uptake can be blocked by pretreatment with DES. Both iodo-tamoxifen and tamoxifen reduced ER(+) breast tumor growth at the dose of 50 micrograms in tumor-bearing mice. The findings indicate that tamoxifen analogue uptake in tumors occurs via an ER-mediated process. Both analogues should have potential for diagnosing functioning ER(+) breast cancer.

  6. Experimental study of flash boiling spray vaporization through quantitative vapor concentration and liquid temperature measurements

    NASA Astrophysics Data System (ADS)

    Zhang, Gaoming; Hung, David L. S.; Xu, Min

    2014-08-01

    Flash boiling sprays of liquid injection under superheated conditions provide the novel solutions of fast vaporization and better air-fuel mixture formation for internal combustion engines. However, the physical mechanisms of flash boiling spray vaporization are more complicated than the droplet surface vaporization due to the unique bubble generation and boiling process inside a superheated bulk liquid, which are not well understood. In this study, the vaporization of flash boiling sprays was investigated experimentally through the quantitative measurements of vapor concentration and liquid temperature. Specifically, the laser-induced exciplex fluorescence technique was applied to distinguish the liquid and vapor distributions. Quantitative vapor concentration was obtained by correlating the intensity of vapor-phase fluorescence with vapor concentration through systematic corrections and calibrations. The intensities of two wavelengths were captured simultaneously from the liquid-phase fluorescence spectra, and their intensity ratios were correlated with liquid temperature. The results show that both liquid and vapor phase of multi-hole sprays collapse toward the centerline of the spray with different mass distributions under the flash boiling conditions. Large amount of vapor aggregates along the centerline of the spray to form a "gas jet" structure, whereas the liquid distributes more uniformly with large vortexes formed in the vicinity of the spray tip. The vaporization process under the flash boiling condition is greatly enhanced due to the intense bubble generation and burst. The liquid temperature measurements show strong temperature variations inside the flash boiling sprays with hot zones present in the "gas jet" structure and vortex region. In addition, high vapor concentration and closed vortex motion seem to have inhibited the heat and mass transfer in these regions. In summary, the vapor concentration and liquid temperature provide detailed information

  7. Energy transfer dynamics in strongly inhomogeneous hot-dense-matter systems

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Stillman, C. R.; Nilson, P. M.; Sefkow, A. B.

    Direct measurements of energy transfer across steep density and temperature gradients in a hot-dense-matter system are presented. Hot dense plasma conditions were generated by high-intensity laser irradiation of a thin-foil target containing a buried metal layer. Energy transfer to the layer was measured using picosecond time-resolved x-ray emission spectroscopy. Here, the data show two x-ray flashes in time. Fully explicit, coupled particle-in-cell and collisional-radiative atomic kinetics model predictions reproduce these observations, connecting the two x-ray flashes with staged radial energy transfer within the target.

  8. Energy transfer dynamics in strongly inhomogeneous hot-dense-matter systems

    DOE PAGES

    Stillman, C. R.; Nilson, P. M.; Sefkow, A. B.; ...

    2018-06-25

    Direct measurements of energy transfer across steep density and temperature gradients in a hot-dense-matter system are presented. Hot dense plasma conditions were generated by high-intensity laser irradiation of a thin-foil target containing a buried metal layer. Energy transfer to the layer was measured using picosecond time-resolved x-ray emission spectroscopy. Here, the data show two x-ray flashes in time. Fully explicit, coupled particle-in-cell and collisional-radiative atomic kinetics model predictions reproduce these observations, connecting the two x-ray flashes with staged radial energy transfer within the target.

  9. The effect of exemestane and tamoxifen on bone health within the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial: a meta-analysis of the US, German, Netherlands, and Belgium sub-studies.

    PubMed

    Hadji, Peyman; Asmar, Lina; van Nes, Johanna G H; Menschik, Thomas; Hasenburg, Annette; Kuck, Joachim; Nortier, Johan W R; van de Velde, Cornelis J H; Jones, Stephen E; Ziller, May

    2011-06-01

    We performed a meta-analysis of three sub-studies of the randomized Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial to determine the effects of exemestane and tamoxifen on bone health. Patients received exemestane or tamoxifen as adjuvant therapy for hormone receptor-positive breast cancer. Bone mineral density (BMD) was assessed at baseline and after 12 and 24 months of treatment. Bone turnover markers were also measured. Patients receiving tamoxifen showed a mean increase from baseline in lumbar spine BMD of 1.2% at month 12 and 0.2% at month 24. Patients receiving exemestane showed a mean decrease from baseline of 2.6% after 12 months and 3.5% after 24 months. There were significant differences in the changes in lumbar spine BMD between treatment groups (P < 0.0001 at both time points). Changes in BMD from baseline at the total hip were also significantly different between exemestane and tamoxifen (P < 0.05 at both time points). Bone turnover markers decreased from baseline with tamoxifen and increased with exemestane. Exemestane resulted in decreases in BMD and increases in bone turnover markers. BMD increased and bone turnover markers decreased with tamoxifen.

  10. Mammographic density changes following discontinuation of tamoxifen in premenopausal women with oestrogen receptor-positive breast cancer.

    PubMed

    Kim, Won Hwa; Cho, Nariya; Kim, Young-Seon; Yi, Ann

    2018-04-06

    To evaluate the changes in mammographic density after tamoxifen discontinuation in premenopausal women with oestrogen receptor-positive breast cancers and the underlying factors METHODS: A total of 213 consecutive premenopausal women with breast cancer who received tamoxifen treatment after curative surgery and underwent three mammograms (baseline, after tamoxifen treatment, after tamoxifen discontinuation) were included. Changes in mammographic density after tamoxifen discontinuation were assessed qualitatively (decrease, no change, or increase) by two readers and measured quantitatively by semi-automated software. The association between % density change and clinicopathological factors was evaluated using univariate and multivariate regression analyses. After tamoxifen discontinuation, a mammographic density increase was observed in 31.9% (68/213, reader 1) to 22.1% (47/213, reader 2) by qualitative assessment, with a mean density increase of 1.8% by quantitative assessment compared to density before tamoxifen discontinuation. In multivariate analysis, younger age (≤ 39 years) and greater % density decline after tamoxifen treatment (≥ 17.0%) were independent factors associated with density change after tamoxifen discontinuation (p < .001 and p = .003, respectively). Tamoxifen discontinuation was associated with mammographic density change with a mean density increase of 1.8%, which was associated with younger age and greater density change after tamoxifen treatment. • Increased mammographic density after tamoxifen discontinuation can occur in premenopausal women. • Mean density increase after tamoxifen discontinuation was 1.8%. • Density increase is associated with age and density decrease after tamoxifen.

  11. G-protein-coupled estrogen receptor GPR30 and tamoxifen resistance in breast cancer.

    PubMed

    Ignatov, Atanas; Ignatov, Tanja; Weissenborn, Christine; Eggemann, Holm; Bischoff, Joachim; Semczuk, Andrzej; Roessner, Albert; Costa, Serban Dan; Kalinski, Thomas

    2011-07-01

    Recently, we have shown that the new G-protein-coupled estrogen receptor GPR30 plays an important role in the development of tamoxifen resistance in vitro. This study was undertaken to evaluate the correlation between GPR30 and tamoxifen resistance in breast cancer patients. GPR30 protein expression was evaluated by immunohistochemical analysis in 323 patients with primary operable breast cancer. The association between GPR30 expression and tamoxifen resistance was confirmed in a second cohort of 103 patients treated only with tamoxifen. Additionally, we evaluated GPR30 expression in 33 primary tumors and in recurrent tumors from the same patients. GPR30 expression was detected in 56.7% of the breast cancer specimens investigated and it correlated with overexpression of HER-2 (P = 0.021), EGFR (P = 0.024) and lymph node status (P = 0.047). In a first cohort, survival analysis showed that GPR30 was negatively correlated with relapse-free survival (RFS) only in patients treated with tamoxifen (tamoxifen with or without chemotherapy). GPR30 expression was associated with shorter RFS (HR = 1.768; 95% CI, 1.156-2.703; P = 0.009). In a subset of patients treated only with tamoxifen, multivariate analysis revealed that GPR30 expression is an independent unfavorable factor for RFS (HR = 4.440; 95% CI, 1.408-13.997; P = 0.011). In contrast, GPR30 tended to be a favorable factor regarding RFS in patients who did not receive tamoxifen. In 33 paired biopsies obtained before and after adjuvant therapy, GPR30 expression significantly increased only under tamoxifen treatment (P = 0.001). GPR30 expression in breast cancer independently predicts a poor RFS in patients treated with tamoxifen.

  12. Proteomics of xenografted human breast cancer indicates novel targets related to tamoxifen resistance.

    PubMed

    Besada, Vladimir; Diaz, Maylin; Becker, Michael; Ramos, Yassel; Castellanos-Serra, Lila; Fichtner, Iduna

    2006-02-01

    Tamoxifen is the most frequently used drug for hormone therapy of breast cancer patients, even though a high percentage of women are (or become) refractory to this treatment. The proteins involved in tamoxifen resistance of breast tumor cells as well as the mechanisms by which they interact, are still unknown. Some years ago, we established the xenograft breast tumor 3366, sensitive to tamoxifen and the 3366/TAM, resistant to tamoxifen, derived after two years of in vivo passages of the parental 3366 under tamoxifen treatment. Here, we compare the protein expression levels of both xenografts. 2-DE of proteins from total cell extracts showed very high reproducibility among tumors from each group (tamoxifen sensitive and tamoxifen resistant). The heuristic clustering analysis of these gels pooled them correctly in both groups. Twelve proteins were found up-regulated in the tamoxifen-resistant line, while nine were down-regulated. The proteins differentially expressed were identified by MS and sequence database analysis. Biological functions of these proteins are related to cell-cell adhesion and interaction, signal transduction, DNA and protein synthesis machinery, mitochondrial respiratory chain, oxidative stress processes and apoptosis. Three of the identified proteins (ALG-2 interacting protein and two GDP-dissociation inhibitors) could be directly involved in the resistance phenomenon.

  13. Tamoxifen enhances choline acetyltransferase mRNA expression in rat basal forebrain cholinergic neurons.

    PubMed

    McMillan, Pamela J; LeMaster, Ann M; Dorsa, Daniel M

    2002-06-30

    Novel estrogen-like molecules known as SERMs (selective estrogen receptor modulators) produce many of the beneficial estrogen-like actions without the detrimental side-effects. The SERM, tamoxifen, an estrogen-like molecule with both agonist and antagonist properties, is widely prescribed for the treatment of breast cancer. While the effects of tamoxifen are being evaluated in many peripheral tissues, its effects in the central nervous system (CNS) have been largely ignored. In the present study, we begin to evaluate the effects of tamoxifen in the rat basal forebrain, a region known to be highly responsive to estrogen. We compared the effects of short-term (24 h) tamoxifen treatment to that of estrogen on ChAT mRNA expression in cholinergic neurons. In addition, we examined the effect of tamoxifen in the presence and absence of estrogen. Our results indicate that tamoxifen enhances ChAT expression in a manner similar to that of estrogen in several basal forebrain regions. In contrast, tamoxifen exhibits antagonist properties with respect to estrogen-induction of progesterone receptor mRNA in the medial preoptic nucleus. These results indicate tamoxifen has estrogenic properties with respect to cholinergic neurons, suggesting a previously unidentified effect of this agent in the CNS. Copyright 2002 Elsevier Science B.V.

  14. Gamma shielding properties of Tamoxifen drug

    NASA Astrophysics Data System (ADS)

    Kanberoglu, Gulsah Saydan; Oto, Berna; Gulebaglan, Sinem Erden

    2017-02-01

    Tamoxifen (MW=371 g/mol) is an endocrine therapeutic drug widely prescribed as chemopreventive in women to prevent and to treat all stages of breast cancer. It is also being studied for other types of cancer. In this study, we have calculated some gamma shielding parameters such as mass attenuation coefficient (μρ), effective atomic number (Zeff) and electron density (Nel) for Tamoxifen drug. The values of μρ were calculated using WinXCom computer program and then the values of Zeff and Nel were derived using μρ values in the wide energy range (1 keV - 100 GeV).

  15. Treatment with tamoxifen reduces hypoxic-ischemic brain injury in neonatal rats.

    PubMed

    Feng, Yangzheng; Fratkins, Jonathan D; LeBlanc, Michael H

    2004-01-19

    Tamoxifen, an estrogen receptor modulator, is neuroprotective in adult rats. Does tamoxifen reduce brain injury in the rat pup? Seven-day-old rat pups had the right carotid artery permanently ligated followed by 2.5 h of hypoxia (8% oxygen). Tamoxifen (10 mg/kg) or vehicle was given i.p. 5 min prior to hypoxia, or 5 min after reoxygenation, with a second dose given 6 h after the first. Brain damage was evaluated by weight deficit of the right hemisphere 22 days following hypoxia and gross and microscopic morphology. Tamoxifen pre-treatment reduced brain weight loss from 21.5+/-4.0% in vehicle pups (n=27) to 2.6+/-2.5% in the treated pups (n=22, P<0.05). Treatment 5 min after reoxygenation reduced brain weight loss from 27.5+/-4.0% in vehicle pups (n=42) to 12.0+/-3.9% in the treated pups (n=30, P<0.05). Tamoxifen reduces brain injury in the neonatal rat.

  16. The Study of Tamoxifen and Raloxifene (STAR): Questions and Answers

    Cancer.gov

    Learn about the Study of Tamoxifen and Raloxifene (STAR) clinical trial, which is comparing the drug raloxifene (Evista®) with the drug tamoxifen (Nolvadex®) in reducing the incidence of breast cancer in at-risk postmenopausal women.

  17. Inhibition of Macrophage CD36 Expression and Cellular Oxidized Low Density Lipoprotein (oxLDL) Accumulation by Tamoxifen: A PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR)γ-DEPENDENT MECHANISM.

    PubMed

    Yu, Miao; Jiang, Meixiu; Chen, Yuanli; Zhang, Shuang; Zhang, Wenwen; Yang, Xiaoxiao; Li, Xiaoju; Li, Yan; Duan, Shengzhong; Han, Jihong; Duan, Yajun

    2016-08-12

    Macrophage CD36 binds and internalizes oxidized low density lipoprotein (oxLDL) to facilitate foam cell formation. CD36 expression is activated by peroxisome proliferator-activated receptor γ (PPARγ). Tamoxifen, an anti-breast cancer medicine, has demonstrated pleiotropic functions including cardioprotection with unfully elucidated mechanisms. In this study, we determined that treatment of ApoE-deficient mice with tamoxifen reduced atherosclerosis, which was associated with decreased CD36 and PPARγ expression in lesion areas. At the cellular level, we observed that tamoxifen inhibited CD36 protein expression in human THP-1 monocytes, THP-1/PMA macrophages, and human blood monocyte-derived macrophages. Associated with decreased CD36 protein expression, tamoxifen reduced cellular oxLDL accumulation in a CD36-dependent manner. At the transcriptional level, tamoxifen decreased CD36 mRNA expression, promoter activity, and the binding of the PPARγ response element in CD36 promoter to PPARγ protein. Tamoxifen blocked ligand-induced PPARγ nuclear translocation and CD36 expression, but it increased PPARγ phosphorylation, which was due to that tamoxifen-activated ERK1/2. Furthermore, deficiency of PPARγ expression in macrophages abolished the inhibitory effect of tamoxifen on CD36 expression or cellular oxLDL accumulation both in vitro and in vivo Taken together, our study demonstrates that tamoxifen inhibits CD36 expression and cellular oxLDL accumulation by inactivating the PPARγ signaling pathway, and the inhibition of macrophage CD36 expression can be attributed to the anti-atherogenic properties of tamoxifen. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  18. Adjuvant tamoxifen influences the lipid profile in breast cancer patients.

    PubMed

    Lin, Che; Chen, Li-Sheng; Kuo, Shou-Jen; Chen, Dar-Ren

    2014-02-01

    Currently there is a debate regarding whether tamoxifen used in breast cancer has an impact on lipid profiles. The aim of this study was to determine whether tamoxifen has an impact on the serum lipid profile in Taiwanese women. Data of 109 patients were collected from the routine clinical follow-up for women with hormone receptor-positive breast cancer who were treated between July 2005 and March 2008. These patients were divided into 2 subgroups, based on their tumor grade and lymph node status. Subgroup 1 patients had tumor grade I/II and a negative lymph node status. Those patients with tumor grade III or a positive lymph node status were defined as subgroup 2. In the 109 patients, the mean serum total cholesterol (TC) levels after tamoxifen treatment, as well as the serum low-density lipoprotein cholesterol (LDL-C) levels, were lower than the baseline levels, with statistically significant differences. Treatment with tamoxifen lowered the serum TC and LDL-C levels in both subgroups. The results indicate that tamoxifen has an impact on the serum lipid profile of breast cancer patients in Taiwan. Physicians should follow up the lipid profile in these patients.

  19. C-Cbl reverses HER2-mediated tamoxifen resistance in human breast cancer cells.

    PubMed

    Li, Wei; Xu, Ling; Che, Xiaofang; Li, Haizhou; Zhang, Ye; Song, Na; Wen, Ti; Hou, Kezuo; Yang, Yi; Zhou, Lu; Xin, Xing; Xu, Lu; Zeng, Xue; Shi, Sha; Liu, Yunpeng; Qu, Xiujuan; Teng, Yuee

    2018-05-02

    Tamoxifen is a frontline therapy for estrogen receptor (ER)-positive breast cancer in premenopausal women. However, many patients develop resistance to tamoxifen, and the mechanism underlying tamoxifen resistance is not well understood. Here we examined whether ER-c-Src-HER2 complex formation is involved in tamoxifen resistance. MTT and colony formation assays were used to measure cell viability and proliferation. Western blot was used to detect protein expression and protein complex formations were detected by immunoprecipitation and immunofluorescence. SiRNA was used to examine the function of HER2 in of BT474 cells. An in vivo xenograft animal model was established to examine the role of c-Cbl in tumor growth. MTT and colony formation assay showed that BT474 cells are resistant to tamoxifen and T47D cells are sensitive to tamoxifen. Immunoprecipitation experiments revealed ER-c-Src-HER2 complex formation in BT474 cells but not in T47D cells. However, ER-c-Src-HER2 complex formation was detected after overexpressing HER2 in T47D cells and these cells were more resistant to tamoxifen. HER2 knockdown by siRNA in BT474 cells reduced ER-c-Src-HER2 complex formation and reversed tamoxifen resistance. ER-c-Src-HER2 complex formation was also disrupted and tamoxifen resistance was reversed in BT474 cells by the c-Src inhibitor PP2 and HER2 antibody trastuzumab. Nystatin, a lipid raft inhibitor, reduced ER-c-Src-HER2 complex formation and partially reversed tamoxifen resistance. ER-c-Src-HER2 complex formation was disrupted by overexpression of c-Cbl but not by the c-Cbl ubiquitin ligase mutant. In addition, c-Cbl could reverse tamoxifen resistance in BT474 cells, but the ubiquitin ligase mutant had no effect. The effect of c-Cbl was validated in BT474 tumor-bearing nude mice in vivo. Immunofluorescence also revealed ER-c-Src-HER2 complex formation was reduced in tumor tissues of nude mice with c-Cbl overexpression. Our results suggested that c-Cbl can reverse tamoxifen

  20. Heavy rainfall induced flash flood management

    NASA Astrophysics Data System (ADS)

    Weiler, Markus; Steinbrich, Andreas; Stölzle, Michael; Leistert, Hannes

    2016-04-01

    Heavy rain induced flash floods are still a serious hazard. In context of climate change even a rise of threat potential of flash flood must be suspected. To improve prediction of endangered areas hydraulic models was developed in the past that implement topography information in heigh resolution, gathered by laser scan applications. To run such models it is crucial to estimate the runoff input spatial distributed. However, this information is usually derived with relatively simple models lacking the process rigour that is required for prediction in engaged basins. Though available rain runoff models are able to model runoff response integral for measured catchments they do not indicate the spatial distribution of processes. Moreover they are commonly calibrated to measured runoff data and not applicable in other environments. Since runoff generation is commonly not measured, a calibration on it is hardly possible. In this study, we present a new approach for quantification of runoff generation in height spatial and temporal resolution. A suited model needs to work without calibration in every given environment under any given conditions. It is possible to develop such a model by combining spatial distributed input data of land surface properties (e.g. soil, geology, land use, …) with worldwide findings of runoff generation research. We developed such a model for the state of Baden-Württemberg, what has an extensive pool of spatial data. E.g. a digital elevation model of 1*1m² resolution, degree of sealing of the earth surface in 1*1m² resolution, soil properties (1:50.000) and geology (1:200.000). Within the state of Baden-Württemberg different regions are situated, with distinct environmental characteristics concerning as well climate, soil properties, land use, topography and geology. The model was tested and validated by modelling 36 observed flood events in 13 mesoscale catchments representing the different regions of Baden-Württemberg as well as by

  1. Tamoxifen with ovarian function suppression versus tamoxifen alone as an adjuvant treatment for premenopausal breast cancer: a meta-analysis of published randomized controlled trials

    PubMed Central

    Yan, Shunchao; Li, Kai; Jiao, Xin; Zou, Huawei

    2015-01-01

    Background Ovarian function suppression (OFS) significantly downregulates the concentration of plasma estrogens. However, it is unclear whether it offers any survival benefits if combined with adjuvant tamoxifen treatment in premenopausal women. This meta-analysis was designed to assess data from previous studies involving adjuvant tamoxifen treatment plus OFS in premenopausal breast cancer. Methods Electronic literature databases (PubMed, Embase, the Web of Science, and the Cochrane Library) were searched for relevant randomized controlled trials published prior to February 1, 2015. Only randomized controlled trials that compared tamoxifen alone with tamoxifen plus OFS for premenopausal women with breast cancer were selected. The evaluated endpoints were disease-free survival and overall survival. Results Four randomized controlled trials comprising 6,279 patients (OFS combination, n=3,133; tamoxifen alone, n=3,146) were included in the meta-analysis. There was no significant improvement in disease-free survival or overall survival with addition of OFS in either the whole population or the hormone receptor-positive subgroup. The risk of distant recurrence was not reduced with the addition of OFS in the whole population. A subgroup analysis showed that addition of OFS significantly improved overall survival in patients who were administered chemotherapy. Conclusion Based on the available studies, concurrent administration of OFS and adjuvant tamoxifen treatment for premenopausal women with breast cancer has no effect on prolonging disease-free survival and overall survival, excluding patients who were administered chemotherapy. It should not be widely recommended, except perhaps for women who were hormone-receptor positive and who were also administered adjuvant chemotherapy. PMID:26109867

  2. Analysis of tamoxifen-DNA adducts in endometrial explants by MS and 32P-postlabeling.

    PubMed

    Beland, Frederick A; Churchwell, Mona I; Hewer, Alan; Phillips, David H; Gamboa da Costa, Gonçalo; Marques, M Matilde

    2004-07-23

    The nonsteroidal antiestrogen tamoxifen increases the risk of endometrial cancer; however, the mechanism for the induction of these tumors is not known. Recently, Sharma et al. [Biochem. Biophys. Res. Commun. 307 (2003) 157], using high performance liquid chromatography (HPLC) with online postcolumn photochemical activation and fluorescence detection, reported the presence of (E)-alpha-(deoxyguanosin- N2-yl)tamoxifen in DNA from human endometrial explants incubated with tamoxifen. Inasmuch as the methodology used by these investigators does not allow unambiguous characterization of tamoxifen-DNA adducts, we have used two additional techniques (HPLC coupled with electrospray ionization tandem mass spectrometry and 32P-postlabeling analyses) to assay for the presence of tamoxifen-DNA adducts in the human endometrial explant DNA. Tamoxifen-DNA adducts were not detected by either method.

  3. Impact Flash Physics: Modeling and Comparisons With Experimental Results

    NASA Astrophysics Data System (ADS)

    Rainey, E.; Stickle, A. M.; Ernst, C. M.; Schultz, P. H.; Mehta, N. L.; Brown, R. C.; Swaminathan, P. K.; Michaelis, C. H.; Erlandson, R. E.

    2015-12-01

    Hypervelocity impacts frequently generate an observable "flash" of light with two components: a short-duration spike due to emissions from vaporized material, and a long-duration peak due to thermal emissions from expanding hot debris. The intensity and duration of these peaks depend on the impact velocity, angle, and the target and projectile mass and composition. Thus remote sensing measurements of planetary impact flashes have the potential to constrain the properties of impacting meteors and improve our understanding of impact flux and cratering processes. Interpreting impact flash measurements requires a thorough understanding of how flash characteristics correlate with impact conditions. Because planetary-scale impacts cannot be replicated in the laboratory, numerical simulations are needed to provide this insight for the solar system. Computational hydrocodes can produce detailed simulations of the impact process, but they lack the radiation physics required to model the optical flash. The Johns Hopkins University Applied Physics Laboratory (APL) developed a model to calculate the optical signature from the hot debris cloud produced by an impact. While the phenomenology of the optical signature is understood, the details required to accurately model it are complicated by uncertainties in material and optical properties and the simplifications required to numerically model radiation from large-scale impacts. Comparisons with laboratory impact experiments allow us to validate our approach and to draw insight regarding processes that occur at all scales in impact events, such as melt generation. We used Sandia National Lab's CTH shock physics hydrocode along with the optical signature model developed at APL to compare with a series of laboratory experiments conducted at the NASA Ames Vertical Gun Range. The experiments used Pyrex projectiles to impact pumice powder targets with velocities ranging from 1 to 6 km/s at angles of 30 and 90 degrees with respect to

  4. Exemestane Following Tamoxifen Reduces Breast Cancer Recurrences and Prolongs Survival

    Cancer.gov

    Postmenopausal women with early-stage hormone receptor-positive breast cancer had delayed disease recurrence and longer survival after taking 2-3 years of tamoxifen followed by exemestane for a total of 5 years compared to taking tamoxifen for 5 years.

  5. An ultra performance liquid chromatography-tandem MS assay for tamoxifen metabolites profiling in plasma: first evidence of 4'-hydroxylated metabolites in breast cancer patients.

    PubMed

    Dahmane, E; Mercier, T; Zanolari, B; Cruchon, S; Guignard, N; Buclin, T; Leyvraz, S; Zaman, K; Csajka, C; Decosterd, L A

    2010-12-15

    There is increasing evidence that the clinical efficacy of tamoxifen, the first and most widely used targeted therapy for estrogen-sensitive breast cancer, depends on the formation of the active metabolites 4-hydroxy-tamoxifen and 4-hydroxy-N-desmethyl-tamoxifen (endoxifen). Large inter-individual variability in endoxifen plasma concentrations has been observed and related both to genetic and environmental (i.e. drug-induced) factors altering CYP450s metabolizing enzymes activity. In this context, we have developed an ultra performance liquid chromatography-tandem mass spectrometry method (UPLC-MS/MS) requiring 100 μL of plasma for the quantification of tamoxifen and three of its major metabolites in breast cancer patients. Plasma is purified by a combination of protein precipitation, evaporation at room temperature under nitrogen, and reconstitution in methanol/20 mM ammonium formate 1:1 (v/v), adjusted to pH 2.9 with formic acid. Reverse-phase chromatographic separation of tamoxifen, N-desmethyl-tamoxifen, 4-hydroxy-tamoxifen and 4-hydroxy-N-desmethyl-tamoxifen is performed within 13 min using elution with a gradient of 10 mM ammonium formate and acetonitrile, both containing 0.1% formic acid. Analytes quantification, using matrix-matched calibration samples spiked with their respective deuterated internal standards, is performed by electrospray ionization-triple quadrupole mass spectrometry using selected reaction monitoring detection in the positive mode. The method was validated according to FDA recommendations, including assessment of relative matrix effects variability, as well as tamoxifen and metabolites short-term stability in plasma and whole blood. The method is precise (inter-day CV%: 2.5-7.8%), accurate (-1.4 to +5.8%) and sensitive (lower limits of quantification comprised between 0.4 and 2.0 ng/mL). Application of this method to patients' samples has made possible the identification of two further metabolites, 4'-hydroxy-tamoxifen and 4'-hydroxy-N-desmethyl-tamoxifen

  6. Flash Inactivation of Oxygen Evolution

    PubMed Central

    Frasch, Wayne D.; Cheniae, George M.

    1980-01-01

    Brief saturating light flashes were used to probe the mechanism of inactivation of O2 evolution by Tris in chloroplasts. Maximum inactivation with a single flash and an oscillation with period of four on subsequent flashes was observed. Analyses of the oscillations suggested that only the charge-collecting O2-evolving catalyst of photosystem II (S2-state) was a target of inactivation by Tris. This conclusion was supported by the following observations: (a) hydroxylamine preequilibration caused a three-flash delay in the inactivation pattern; (b) the lifetimes of the Tris-inactivable and S2-states were similar; and (c) reagents accelerating S2 deactivation decreased the lifetime of the inactivable state. Inactivation proved to be moderated by F, the precursor of Signal IIs, as shown by a one flash delay with chloroplasts having high abundance of F. Evidence was obtained for cooperativity effects in inactivation and NH3 was shown to be a competitive inhibitor of the Tris-induced inactivation. S2-dependent inactivation was inhibited by glutaraldehyde fixation of chloroplasts, possibly suggesting that inactivation proceeds via conformational changes of the S2-state. PMID:16661270

  7. Shock compression and flash-heating of molecular adsorbates on the picosecond time scale

    NASA Astrophysics Data System (ADS)

    Berg, Christopher Michael

    An ultrafast nonlinear coherent laser spectroscopy termed broadband multiplex vibrational sum-frequency generation (SFG) with nonresonant suppression was employed to monitor vibrational transitions of molecular adsorbates on metallic substrates during laser-driven shock compression and flash-heating. Adsorbates were in the form of well-ordered self-assembled monolayers (SAMs) and included molecular explosive simulants, such as nitroaromatics, and long chain-length alkanethiols. Based on reflectance measurements of the metallic substrates, femtosecond flash-heating pulses were capable of producing large-amplitude temperature jumps with DeltaT = 500 K. Laser-driven shock compression of SAMs produced pressures up to 2 GPa, where 1 GPa ≈ 1 x 104 atm. Shock pressures were estimated via comparison with frequency shifts observed in the monolayer vibrational transitions during hydrostatic pressure measurements in a SiC anvil cell. Molecular dynamics during flash-heating and shock loading were probed with vibrational SFG spectroscopy with picosecond temporal resolution and sub-nanometer spatial resolution. Flash-heating studies of 4-nitrobenzenethiolate (NBT) on Au provided insight into effects from hot-electron excitation of the molecular adsorbates at early pump-probe delay times. At longer delay times, effects from the excitation of SAM lattice modes and lower-energy NBT vibrations were shown. In addition, flash-heating studies of alkanethiolates demonstrated chain disordering behaviors as well as interface thermal conductances across the Au-SAM junction, which was of specific interest within the context of molecular electronics. Shock compression studies of molecular explosive simulants, such as 4-nitrobenzoate (NBA), demonstrated the proficiency of this technique to observe shock-induced molecular dynamics, in this case orientational dynamics, on the picosecond time scale. Results validated the utilization of these refined shock loading techniques to probe the shock

  8. The Space Shuttle Orbiter molecular environment induced by the supplemental flash evaporator system

    NASA Technical Reports Server (NTRS)

    Ehlers, H. K. F.

    1985-01-01

    The water vapor environment of the Space Shuttle Orbiter induced by the supplemental flash evaporator during the on-orbit flight phase has been analyzed based on Space II model predictions and orbital flight measurements. Model data of local density, column density, and return flux are presented. Results of return flux measurements with a mass spectrometer during STS-2 and of direct flux measurements during STS-4 are discussed and compared with model predictions.

  9. Flash-induced nanowelding of silver nanowire networks for transparent stretchable electrochromic devices.

    PubMed

    Lee, Chihak; Oh, Youngsu; Yoon, In Seon; Kim, Sun Hong; Ju, Byeong-Kwon; Hong, Jae-Min

    2018-02-09

    Electrochromic devices (ECDs) are emerging as a novel technology for various applications like commercialized smart window glasses, and auto-dimming rear-view mirrors. Recently, the development of low-power, lightweight, flexible, and stretchable devices has been accelerated to meet the growing demand in the new wearable devices market. Silver nanowires (AgNWs) can become new primary transparent conducting electrode (TCE) materials to replace indium tin oxide (ITO) for ECDs. However, issues such as substrate adhesion, delamination, and higher resistance still exist with AgNWs. Herein, we report a high-performance stretchable flash-induced AgNW-network-based TCE on surface-treated polydimethylsiloxane (PDMS) substrates. A Xe flash light method was used to create nanowelded networks of AgNWs. Surface silane treatments increased the adhesion and durability of the films as well. Finally, ECDs were fabricated under the optimal conditions and examined under strained conditions to demonstrate the resistance and mechanical behaviours of the devices. Results showed a flexible and durable film maintaining a high level of conductivity and reversible resistance behaviour, beyond those currently achievable with standard ITO/PET flexible TCEs.

  10. Generation of knock-in mice that express nuclear enhanced green fluorescent protein and tamoxifen-inducible Cre recombinase in the notochord from Foxa2 and T loci.

    PubMed

    Imuta, Yu; Kiyonari, Hiroshi; Jang, Chuan-Wei; Behringer, Richard R; Sasaki, Hiroshi

    2013-03-01

    The node and the notochord are important embryonic signaling centers that control embryonic pattern formation. Notochord progenitor cells present in the node and later in the posterior end of the notochord move anteriorly to generate the notochord. To understand the dynamics of cell movement during notochord development and the molecular mechanisms controlling this event, analyses of cell movements using time-lapse imaging and conditional manipulation of gene activities are required. To achieve this goal, we generated two knock-in mouse lines that simultaneously express nuclear enhanced green fluorescent protein (EGFP) and tamoxifen-inducible Cre, CreER(T2) , from two notochord gene loci, Foxa2 and T (Brachury). In Foxa2(nEGFP-CreERT2/+) and T(nEGFP-CreERT2/+) embryos, nuclei of the Foxa2 or T-expressing cells, which include the node, notochord, and endoderm (Foxa2) or wide range of posterior mesoderm (T), were labeled with EGFP at intensities that can be used for live imaging. Cre activity was also induced in cells expressing Foxa2 and T 1 day after tamoxifen administration. These mice are expected to be useful tools for analyzing the mechanisms of notochord development. Copyright © 2013 Wiley Periodicals, Inc.

  11. Induction of cytochrome P450 3A4 in primary human hepatocytes and activation of the human pregnane X receptor by tamoxifen and 4-hydroxytamoxifen.

    PubMed

    Desai, Pankaj B; Nallani, Srikanth C; Sane, Rucha S; Moore, Linda B; Goodwin, Bryan J; Buckley, Donna J; Buckley, Arthur R

    2002-05-01

    Tamoxifen is a widely utilized antiestrogen in the treatment and chemoprevention of breast cancer. Clinical studies document that tamoxifen administration markedly enhances the systemic elimination of other drugs. Additionally, tamoxifen enhances its own clearance following repeated dosing. The mechanisms that underlie these clinically important events remain unresolved. Here, we report that tamoxifen and its metabolite 4-hydroxytamoxifen markedly induce cytochrome P450 3A4, a drug-metabolizing enzyme of central importance, in primary cultures of human hepatocytes. Tamoxifen and 4-hydroxytamoxifen (1-10 microM) significantly increased the CYP3A4 expression and activity (measured as the rate of testosterone 6beta-hydroxylation). Maximal induction was achieved at the 5 microM level. At this level, tamoxifen and 4-hydroxytamoxifen caused a 1.5- to 3.3-fold (mean, 2.1-fold) and 3.4- to 17-fold (mean, 7.5-fold) increase in the CYP3A4 activity, respectively. In comparison, rifampicin treatment resulted in a 6- to 16-fold (mean, 10.5-fold) increase. We also observed corresponding increase in the CYP3A4 immunoreactive protein and mRNA levels. Furthermore, tamoxifen and 4-hydroxytamoxifen efficaciously activated the human pregnane X receptor (hPXR; also known as the steroid xenobiotic receptor), a key regulator of CYP3A4 expression. The efficacy of tamoxifen and 4-hydroxytamoxifen relative to rifampicin for hPXR activation was approximately 30 and 60%, respectively. Our results indicate that the mechanism of tamoxifen-mediated alteration in drug clearance pathways in humans may involve CYP3A4 induction by the parent drug and/or its metabolite. Furthermore, the CYP3A4 induction may be a result of hPXR activation. These findings have important implications for optimizing the use of tamoxifen and in the development of newer antiestrogens.

  12. Safety and efficacy of low-dose esterified estrogens and methyltestosterone, alone or combined, for the treatment of hot flashes in menopausal women: a randomized, double-blind, placebo-controlled study.

    PubMed

    Liu, James; Allgood, Adam; Derogatis, Leonard R; Swanson, Stephen; O'Mahony, Michael; Nedoss, Bertrand; Soper, Herbert; Zbella, Edward; Prokofieva, Svetlana Vladimirovna; Zipfel, Lisa; Guo, Chun-Yuan

    2011-01-01

    This study evaluated safety and efficacy of esterified estrogens and methyltestosterone administered alone or in combination for the treatment of hot flashes in menopausal women. The 0.30-mg esterified estrogens and 0.30-mg methyltestosterone combination was the lowest effective dose, and our results are consistent with the known safety profile of estrogen and androgen combination products. Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  13. Long-Term Data from 20 Trials Confirm Tamoxifen's Long-Lasting Benefit

    Cancer.gov

    Women with estrogen receptor-positive breast cancer who received about 5 years of adjuvant tamoxifen had a lower risk of recurrence in the 15 years after treatment than women who did not receive tamoxifen.

  14. An Integrated Bioinformatics Approach Identifies Elevated Cyclin E2 Expression and E2F Activity as Distinct Features of Tamoxifen Resistant Breast Tumors

    PubMed Central

    Huang, Lei; Zhao, Shuangping; Frasor, Jonna M.; Dai, Yang

    2011-01-01

    Approximately half of estrogen receptor (ER) positive breast tumors will fail to respond to endocrine therapy. Here we used an integrative bioinformatics approach to analyze three gene expression profiling data sets from breast tumors in an attempt to uncover underlying mechanisms contributing to the development of resistance and potential therapeutic strategies to counteract these mechanisms. Genes that are differentially expressed in tamoxifen resistant vs. sensitive breast tumors were identified from three different publically available microarray datasets. These differentially expressed (DE) genes were analyzed using gene function and gene set enrichment and examined in intrinsic subtypes of breast tumors. The Connectivity Map analysis was utilized to link gene expression profiles of tamoxifen resistant tumors to small molecules and validation studies were carried out in a tamoxifen resistant cell line. Despite little overlap in genes that are differentially expressed in tamoxifen resistant vs. sensitive tumors, a high degree of functional similarity was observed among the three datasets. Tamoxifen resistant tumors displayed enriched expression of genes related to cell cycle and proliferation, as well as elevated activity of E2F transcription factors, and were highly correlated with a Luminal intrinsic subtype. A number of small molecules, including phenothiazines, were found that induced a gene signature in breast cancer cell lines opposite to that found in tamoxifen resistant vs. sensitive tumors and the ability of phenothiazines to down-regulate cyclin E2 and inhibit proliferation of tamoxifen resistant breast cancer cells was validated. Our findings demonstrate that an integrated bioinformatics approach to analyze gene expression profiles from multiple breast tumor datasets can identify important biological pathways and potentially novel therapeutic options for tamoxifen-resistant breast cancers. PMID:21789246

  15. Relationship between hot flashes and ambulatory blood pressure: the Hilo women's health study.

    PubMed

    Brown, Daniel E; Sievert, Lynnette L; Morrison, Lynn A; Rahberg, Nichole; Reza, Angela

    2011-01-01

    To examine ambulatory blood pressure (BP) differences between women who report hot flashes (HFs) and those who do not, and to observe whether an objectively measured HF is associated with transient changes in BP. HFs have been associated with elevated BP, but studies have not examined the relationship between objectively measured HFs and blood pressure during normal daily activities. A sample of 202 women in Hilo, Hawaii, aged 45 to 55 years, were asked to fill out a questionnaire that included demographic information and an inventory of symptoms. The women underwent simultaneous 24-hour monitoring of ambulatory BP and HFs, at the same time keeping a diary that included mood and HF reports. No significant difference was present in mean BP between women who reported having an HF during the last 2 weeks and those who did not. When measurements controlled for negative mood reports and posture, there was a highly significant elevation in Z scores of systolic BP when a measured, objective HF occurred within 10 minutes before a BP reading, and a significant elevation of Z scores of diastolic BP when a subjectively reported HF occurred within 10 minutes after a BP reading. These results suggest that objectively measured HFs precede transient elevations of systolic BP, but it is unclear if there is a causal relationship. These results also suggest that women experience subjective HFs within 10 minutes after a transient increase in diastolic BP. Again, the causal relationship is not understood.

  16. Estrous cycle and ovarian changes in a rat mammary carcinogenesis model after irradiation, tamoxifen chemoprevention, and aging.

    PubMed

    Karim, Baktiar O; Landolfi, Jennifer A; Christian, Archie; Ricart-Arbona, Rodolfo; Qiu, Weiping; McAlonis, Melissa; Eyabi, Paul O; Khan, Khalid A; Dicello, John F; Mann, Jill F; Huso, David L

    2003-10-01

    Variation in the effects of selective estrogen receptor modulators (SERMs) on the estrous cycle and reproductive organs during aging could play an important role in the observed heterogeneity of tamoxifen chemoprevention efficacy against breast cancer. Of the 1,022 female Sprague Dawley rats enrolled in a long-term tamoxifen chemoprevention study, 87 were randomly chosen from four groups (irradiated, irradiated and tamoxifen treated, tamoxifen treated, and control). Vaginal smears were evaluated for determination of cycle stage, and vaginal pathologic changes. Correlation with the histologic features of reproductive tissues in 43 animals was made. More tamoxifen-treated (21.9%; 7/32) rats had irregular cycling than did control (9%; 3/23) rats. Ovarian granulosa cell hyperplasia was present in 50% (3/6) of tamoxifen-treated rats, and 20% (2/10) of control rats. Endometrial-type cells (ETCs) were present only in tamoxifen-treated (tamoxifen alone 6.25% [2/32]) and tamoxifen/ radiation-treated (28.6% [4/14]) rats. The modified Papanicolaou stain used here provided excellent morphologic detail for evaluating the estrous cycle in rodents. Tamoxifen altered vaginal cytologic and ovarian histologic features during aging. Results indicated that tamoxifen had direct and indirect effects on the reproductive tract, causing disturbance of the estrous cycle, shedding of ETCs, and promoting granulosa cell hyperplasia. Understanding of the heterogeneous response to tamoxifen chemoprevention during aging in rodents may provide important insights into the basis for tamoxifen chemoprevention failures in humans.

  17. The advantage of letrozole over tamoxifen in the BIG 1-98 trial is consistent in younger postmenopausal women and in those with chemotherapy-induced menopause.

    PubMed

    Chirgwin, Jacquie; Sun, Zhuoxin; Smith, Ian; Price, Karen N; Thürlimann, Beat; Ejlertsen, Bent; Bonnefoi, Hervé; Regan, Meredith M; Goldhirsch, Aron; Coates, Alan S

    2012-01-01

    Letrozole, an aromatase inhibitor, is ineffective in the presence of ovarian estrogen production. Two subpopulations of apparently postmenopausal women might derive reduced benefit from letrozole due to residual or returning ovarian activity: younger women (who have the potential for residual subclinical ovarian estrogen production), and those with chemotherapy-induced menopause who may experience return of ovarian function. In these situations tamoxifen may be preferable to an aromatase inhibitor. Among 4,922 patients allocated to the monotherapy arms (5 years of letrozole or tamoxifen) in the BIG 1-98 trial we identified two relevant subpopulations: patients with potential residual ovarian function, defined as having natural menopause, treated without adjuvant or neoadjuvant chemotherapy and age ≤ 55 years (n = 641); and those with chemotherapy-induced menopause (n = 105). Neither of the subpopulations examined showed treatment effects differing from the trial population as a whole (interaction P values are 0.23 and 0.62, respectively). Indeed, both among the 641 patients aged ≤ 55 years with natural menopause and no chemotherapy (HR 0.77 [0.51, 1.16]) and among the 105 patients with chemotherapy-induced menopause (HR 0.51 [0.19, 1.39]), the disease-free survival (DFS) point estimate favoring letrozole was marginally more beneficial than in the trial as a whole (HR 0.84 [0.74, 0.95]). Contrary to our initial concern, DFS results for young postmenopausal patients who did not receive chemotherapy and patients with chemotherapy-induced menopause parallel the letrozole benefit seen in the BIG 1-98 population as a whole. These data support the use of letrozole even in such patients.

  18. The advantage of letrozole over tamoxifen in the BIG 1-98 trial is consistent in younger postmenopausal women and in those with chemotherapy-induced menopause

    PubMed Central

    Sun, Zhuoxin; Smith, Ian; Price, Karen N.; Thürlimann, Beat; Ejlertsen, Bent; Bonnefoi, Hervé; Regan, Meredith M.; Goldhirsch, Aron; Coates, Alan S.

    2016-01-01

    Letrozole, an aromatase inhibitor, is ineffective in the presence of ovarian estrogen production. Two subpopulations of apparently postmenopausal women might derive reduced benefit from letrozole due to residual or returning ovarian activity: younger women (who have the potential for residual subclinical ovarian estrogen production), and those with chemotherapy-induced menopause who may experience return of ovarian function. In these situations tamoxifen may be preferable to an aromatase inhibitor. Among 4,922 patients allocated to the monotherapy arms (5 years of letrozole or tamoxifen) in the BIG 1-98 trial we identified two relevant subpopulations: patients with potential residual ovarian function, defined as having natural menopause, treated without adjuvant or neoadjuvant chemotherapy and age ≤55 years (n = 641); and those with chemotherapy-induced menopause (n = 105). Neither of the subpopulations examined showed treatment effects differing from the trial population as a whole (interaction P values are 0.23 and 0.62, respectively). Indeed, both among the 641 patients aged ≤55 years with natural menopause and no chemotherapy (HR 0.77 [0.51, 1.16]) and among the 105 patients with chemotherapy-induced menopause (HR 0.51 [0.19, 1.39]), the disease-free survival (DFS) point estimate favoring letrozole was marginally more beneficial than in the trial as a whole (HR 0.84 [0.74, 0.95]). Contrary to our initial concern, DFS results for young postmenopausal patients who did not receive chemotherapy and patients with chemotherapy-induced menopause parallel the letrozole benefit seen in the BIG 1-98 population as a whole. These data support the use of letrozole even in such patients. PMID:21892704

  19. Bioanalytical methods for determination of tamoxifen and its phase I metabolites: a review.

    PubMed

    Teunissen, S F; Rosing, H; Schinkel, A H; Schellens, J H M; Beijnen, J H

    2010-12-17

    The selective estrogen receptor modulator tamoxifen is used in the treatment of early and advanced breast cancer and in selected cases for breast cancer prevention in high-risk subjects. The cytochrome P450 enzyme system and flavin-containing monooxygenase are responsible for the extensive metabolism of tamoxifen into several phase I metabolites that vary in toxicity and potencies towards estrogen receptor (ER) alpha and ER beta. An extensive overview of publications on the determination of tamoxifen and its phase I metabolites in biological samples is presented. In these publications techniques were used such as capillary electrophoresis, liquid, gas and thin layer chromatography coupled with various detection techniques (mass spectrometry, ultraviolet or fluorescence detection, liquid scintillation counting and nuclear magnetic resonance spectroscopy). A trend is seen towards the use of liquid chromatography coupled to mass spectrometry (LC-MS). State-of-the-art LC-MS equipment allowed for identification of unknown metabolites and quantification of known metabolites reaching lower limit of quantification levels in the sub pg mL(-1) range. Although tamoxifen is also metabolized into phase II metabolites, the number of publications reporting on phase II metabolism of tamoxifen is scarce. Therefore the focus of this review is on phase I metabolites of tamoxifen. We conclude that in the past decades tamoxifen metabolism has been studied extensively and numerous metabolites have been identified. Assays have been developed for both the identification and quantification of tamoxifen and its metabolites in an array of biological samples. This review can be used as a resource for method transfer and development of analytical methods used to support pharmacokinetic and pharmacodynamic studies of tamoxifen and its phase I metabolites. Copyright © 2010 Elsevier B.V. All rights reserved.

  20. Effects of Topical Tamoxifen on Wound Healing of Burned Skin in Rats

    PubMed Central

    Mehrvarz, Shaban; Ebrahimi, Ali; Sahraei, Hedayat; Bagheri, Mohammad Hasan; Fazili, Sima; Manoochehry, Shahram; Rasouli, Hamid Reza

    2017-01-01

    Background This study aimed to assess the effects of the topical application of tamoxifen on wound healing of burned skin in Wistar rats by evaluating 3 healing characteristics: fibrotic tissue thickness (FTT), scar surface area (SSA), and angiogenesis in the healed scar tissue. Methods Eighteen male Wistar rats were used in this study. A third-degree burn wound was made on the shaved animals’ back, measuring 2×2×2 cm. In the first group, a 2% tamoxifen ointment was applied to the wound twice daily for 8 weeks. The second group received a placebo ointment during the same period. The third group did not receive any treatment and served as the control group. Results The median (interquartile range=[Q1, Q3]) FTT was 1.35 (1.15, 1.62) mm, 1.00 (0.95, 1.02) mm, and 1.25 (0.8, 1.5) mm in the control, tamoxifen, and placebo groups, respectively (P=0.069). However, the FTT in the tamoxifen group was less than in the placebo and control groups. The median angiogenesis was 3.5 (3.00, 6.25), 8.00 (6.75, 9.25), and 7.00 (5.50, 8.25) vessels per high-power field for the control, tamoxifen, and placebo groups, respectively (P=0.067). However, the median angiogenesis was higher in the tamoxifen group than in the control group. No significant difference was observed in the mean SSA between the tamoxifen group and the control group (P=0.990). Conclusions Local application of tamoxifen increased angiogenesis and decreased the FTT, with no change in the SSA in burned skin areas. These effects are expected to expedite the wound healing process, reducing contracture and preventing hypertrophic scar and keloid formation. PMID:28946718

  1. A comparison of colour, shape, and flash induced illusory line motion.

    PubMed

    Hamm, Jeff P

    2017-04-01

    When a bar suddenly appears between two boxes, the bar will appear to shoot away from the box that matches it in colour or in shape-a phenomenon referred to as attribute priming of illusory line motion (ILM; colour ILM and shape ILM, respectively). If the two boxes are identical, ILM will still occur away from a box if it changes luminance shortly before the presentation of the bar ( flash ILM). This flash condition has been suggested to produce the illusory motion due to the formation of an attentional gradient surrounding the flashed location. However, colour ILM and shape ILM cannot be explained by an attentional gradient as there is no way for attention to select the matching box prior to the presentation of the bar. These findings challenge the attentional gradient explanation for ILM, but only if it is assumed that ILM arises for the same underlying reason. Two experiments are presented that address the question of whether or not flash ILM is the same as colour ILM or shape ILM. The results suggest that while colour ILM and shape ILM reflect a common illusion, flash ILM arises for a different reason. Therefore, the attentional gradient explanation for flash ILM is not refuted by the occurrence of colour ILM or shape ILM, which may reflect transformational apparent motion (TAM).

  2. An UPLC-MS/MS method for separation and accurate quantification of tamoxifen and its metabolites isomers.

    PubMed

    Arellano, Cécile; Allal, Ben; Goubaa, Anwar; Roché, Henri; Chatelut, Etienne

    2014-11-01

    A selective and accurate analytical method is needed to quantify tamoxifen and its phase I metabolites in a prospective clinical protocol, for evaluation of pharmacokinetic parameters of tamoxifen and its metabolites in adjuvant treatment of breast cancer. The selectivity of the analytical method is a fundamental criteria to allow the quantification of the main active metabolites (Z)-isomers from (Z)'-isomers. An UPLC-MS/MS method was developed and validated for the quantification of (Z)-tamoxifen, (Z)-endoxifen, (E)-endoxifen, Z'-endoxifen, (Z)'-endoxifen, (Z)-4-hydroxytamoxifen, (Z)-4'-hydroxytamoxifen, N-desmethyl tamoxifen, and tamoxifen-N-oxide. The validation range was set between 0.5ng/mL and 125ng/mL for 4-hydroxytamoxifen and endoxifen isomers, and between 12.5ng/mL and 300ng/mL for tamoxifen, tamoxifen N-desmethyl and tamoxifen-N-oxide. The application to patient plasma samples was performed. Copyright © 2014 Elsevier B.V. All rights reserved.

  3. Characterization of flash floods induced by tropical cyclones in Mexico

    NASA Astrophysics Data System (ADS)

    Real-Rangel, R. A.; Pedrozo-Acuña, A.

    2015-12-01

    This study investigates the role of tropical cyclones (hurricanes, tropical storms and depressions) in the generation of flash floods in Mexico. For this, a severity assessment during several cyclonic events for selected catchments was estimated through the evaluation of a flash flood index recently proposed by Kim and Kim (2014). This classification is revised, considering the forcing and areal extent of torrential rainfall generated by the incidence of tropical cyclones on the studied catchments, enabling the further study of the flood regime in catchments located in tropical regions. The analysis incorporates characteristics of the flood hydrographs such as the hydrograph shape (rising curve gradient, magnitude of the peak discharge and flood response time) in order to identify flash-flood prone areas. Results show the Qp-A scaling relationship in catchments that were impacted by tropical cyclones, enabling their comparison against floods generated by other meteorological events (e.g. convective and orographic storms). Results will inform on how peak flows relationships are modified by cyclonic events and highlighting the contribution of cyclonic precipitation to flash-flooding susceptibility.

  4. Smart coumarin-tagged imprinted polymers for the rapid detection of tamoxifen.

    PubMed

    Ray, Judith V; Mirata, Fosca; Pérollier, Celine; Arotcarena, Michel; Bayoudh, Sami; Resmini, Marina

    2016-03-01

    A signalling molecularly imprinted polymer was synthesised for easy detection of tamoxifen and its metabolites. 6-Vinylcoumarin-4-carboxylic acid (VCC) was synthesised from 4-bromophenol to give a fluorescent monomer, designed to switch off upon binding of tamoxifen. Clomiphene, a chlorinated analogue, was used as the template for the imprinting, and its ability to quench the coumarin fluorescence when used in a 1:1 ratio was demonstrated. Tamoxifen and 4-hydroxytamoxifen were also shown to quench coumarin fluorescence. Imprinted and non-imprinted polymers were synthesised using VCC, methacrylic acid as a backbone monomer and ethylene glycol dimethacrylate as cross-linker, and were ground and sieved to particle sizes ranging between 45 and 25 μm. Rebinding experiments demonstrate that the imprinted polymer shows very strong affinity for both clomiphene and tamoxifen, while the non-imprinted polymer shows negligible rebinding. The fluorescence of the imprinted polymer is quenched by clomiphene, tamoxifen and 4-hydroxytamoxifen. The switch off in fluorescence of the imprinted polymer under these conditions could also be detected under a UV lamp with the naked eye, making this matrix suitable for applications when coupled with a sample preparation system.

  5. Theoretical investigation of flash vaporisation in a screw expander

    NASA Astrophysics Data System (ADS)

    Vasuthevan, Hanushan; Brümmer, Andreas

    2017-08-01

    In the present study flash vaporisation of liquid injection in a twin screw expander for a Trilateral Flash Cycle (TFC) is examined theoretically. The TFC process comprises a pressure increase in the working fluid, followed by heating the liquid close to boiling point. The hot liquid is injected into the working chamber of a screw expander. During this process the pressure of the liquid drops below the saturation pressure, while the temperature of the liquid remains virtually constant. Hence the liquid is superheated and in a metastable state. The liquid jet seeks to achieve a stable state in thermodynamic equilibrium and is therefore partially vaporised. This effect is referred to as flash vaporisation. Accordingly, a two-phase mixture, consisting of vapour and liquid, exists in the working chamber. Thermodynamic simulations were carried out using water as the working fluid for representative screw expander geometry. The simulations presented are performed from two different aspects during the filling process of a screw expander. The first case is the vaporisation of the injected liquid in a state of thermodynamic equilibrium, whereby the two-phase mixture is treated entirely as a compressible and homogeneous gas. The second case considers flashing efficiency. It describes the quantity of flashed vapour and consists of a liquid and vapour domain. Both models are compared and analysed with respect to the operational behaviour of a screw expander.

  6. Pulsed photoacoustic detection of flash-induced oxygen evolution from intact leaves and its oscillations

    PubMed Central

    Canaani, Ora; Malkin, Shmuel; Mauzerall, David

    1988-01-01

    Photoacoustic signals from intact leaves, produced upon excitation with single-turnover flashes, were shown to be dependent on their position in the flash sequence. Compared to the signal obtained from the first flash, all the others were time-shifted and had increased amplitudes. The signal from the third flash had the largest deviation, whereas that from the second flash deviated only minimally. The amplitude difference of the signals relative to that from the first flash was measured at a convenient time point (5 ms) and showed oscillations of period 4, similar to the O2-evolution pattern from algae. These oscillations were strongly damped, tending to a steady state from about the seventh flash on. The extra photoacoustic signal (relative to the first flash) was shown to be inhibited by 3-(3,4-dichlorophenyl)-1,1-dimethylurea, heat treatment, or water infiltration. Its change with flash number, its saturation with increasing flash energy, and the above inhibition criteria indicate that it originates in pulsed O2 evolution. The sound wave produced by the first flash, however, arose by a photothermal mechanism only, as shown by its linear dependence on the flash intensity and insensitivity to the above treatments. The above flash pattern demonstrates that the photocycle of the S states (i.e., positive charge accumulation before two water molecules can be oxidized in a concerted way to produce molecular oxygen) occurs in intact leaves. It proves the applicability of the photoacoustic method for mechanistic studies of O2 evolution in leaves under physiological conditions. Water content of leaves is readily measured by this method. Images PMID:16593952

  7. Tamoxifen-Dependent Induction of AGR2 Is Associated with Increased Aggressiveness of Endometrial Cancer Cells.

    PubMed

    Hrstka, Roman; Podhorec, Jan; Nenutil, Rudolf; Sommerova, Lucia; Obacz, Joanna; Durech, Michal; Faktor, Jakub; Bouchal, Pavel; Skoupilova, Hana; Vojtesek, Borivoj

    2017-05-28

    Tamoxifen treatment in breast cancer patients is associated with increased risk of endometrial malignancies. Significantly, higher AGR2 expression was found in endometrial cancers that developed in women previously treated with tamoxifen compared to those who had not been exposed to tamoxifen. An association of elevated AGR2 level with myometrial invasion occurrence and invasion depth was also found. In vitro analyses identified a stimulatory effect of AGR2 on cellular proliferation. Although adverse tamoxifen effects on endometrial cells remain elusive, our work identifies elevated AGR2 as a candidate tamoxifen-dependent mechanism of action responsible for increased incidence of endometrial cancer.

  8. On the Solar Stimuli That Initiate Makkah Al Mukaramah, Al-Madinah Al-Munawarah And Jeddah Flash Floods

    NASA Astrophysics Data System (ADS)

    Elfaki, H.; Yousef, S.; Mawad, Ramy; Algafari, Y. H. O.; Amer, M.; Abdel-Sattar, W.

    2017-12-01

    Severe solar events manifested as highly energetic X-Ray events accompanied by coronal mass ejections ( CMEs) and proton flares caused flash floods in Makkah Al-Mukaramah, Al-Madinah Al-Munawarah and Jeddah. In the case of the 20 January 2005 CME that initiated severe flash on the 22 of January. it is shown that the CME lowered the pressure in the polar region and extended the low pressure regime to Saudi Arabia passing by the Mediterranean. Such passage accelerated evaporation and caused Cumulonimbus clouds to form and discharge flash floods over Makkah Al-Mukaramah. On the other hand, solar forcing due coronal holes have a different technique in initiating flash floods. The November 25 2009 and the 13-15 January 2011 Jeddah flash floods are attributed to prompt events due to fast solar streams emanated from two coronal holes that arrived the Earth on 24 November 2009 and 13 January 2011. We present evidences that those streams penetrated the Earth's magnetosphere and hit the troposphere at the western part of the Red Sea, dissipated their energy at 925mb geopotential height and left two hot spots. It follows that the air in the hot spots expanded and developed spots of low pressure air that spread over the Red Sea to its eastern coast. Accelerated evaporation due to reduced pressure caused quick formation of Cumulonimbus clouds that caused flash floods over Makkah Al-Mukaramah and Jeddah.

  9. Targeting glycolysis by 3-bromopyruvate improves tamoxifen cytotoxicity of breast cancer cell lines.

    PubMed

    Attia, Yasmin M; El-Abhar, Hanan S; Al Marzabani, Mahmoud M; Shouman, Samia A

    2015-11-03

    Tamoxifen is the standard endocrine therapy for ER+ breast cancer; however, many women still relapse after long-term therapy. 3-Bromopyruvate, a glycolytic inhibitor, has shown high selective anti-tumor activity in vitro, and in vivo. The aim of this study was to evaluate the possible augmentation of the effect of tamoxifen via reprograming cancer cell metabolism using 3-bromopyruvate. An in vitro screening of antitumor activity as well as the apoptotic, anti-metastatic, and anti-angiogenic potentials of the combination therapy were carried out using different techniques on breast cancer cell lines MCF7and T47D. In addition the antitumor effect of the combined therapy was done on mice bearing tumor. Our results showed modulation in apoptosis, angiogenesis and metastatic potential by either drug alone; however, their combination has surpassed that of the individual one. Combination regimen enhanced activated caspases-3, 7 and 9, as well as oxidative stress, signified by increased malondialdehyde and decreased glutathione level. Additionally, the angiogenesis and metastasis markers, including hypoxia inducing factor-1α, vascular endothelia growth factor, and metaloproteinases-2 and 9 were decreased after using the combination regimen. These results were further confirmed by the in vivo study, which depicted a decrease in the tumor volume and angiogenesis and an increase in oxidative stress as well. 3-bromopyruvate could be a valuable compound when added with tamoxifen in breast cancer treatment.

  10. From the Cover: Potentiation of Drug-Induced Phospholipidosis In Vitro through PEGlyated Graphene Oxide as the Nanocarrier.

    PubMed

    Yang, Liecheng; Zhong, Xiaoyan; Li, Qian; Zhang, Xihui; Wang, Yangyun; Yang, Kai; Zhang, Leshuai W

    2017-03-01

    Cationic amphiphilic drugs (CADs) are small molecules that can induce phospholipidosis (PLD), causing the intracellular accumulation of phospholipid in the lamellar bodies. Nanotechnology based drug delivery systems have been used widely, while it is unknown if drug-induced PLD (DIP) can be potentiated through drug retention by indigestible nanocarriers. Due to the high drug loading capacity of graphene, we investigated if PEGylated graphene oxide (PEG-GO) loaded with CAD could potentiate DIP. Tamoxifen induced the accumulation of NBD-PE, a fluorescence labeled phospholipid in human hepatoma HepG2 cells, while PEG-GO loaded with tamoxifen (PEG-GO/tamoxifen) further potentiated PLD. PEG-GO/tamoxifen induced more gene expression of PLD marker than tamoxifen alone. PEG-GO enhanced DIP was also observed for other CAD, indicating that nanocarrier potentiated DIP could be universal. More lamellar bodies were observed in PEG-GO/tamoxifen treated cells than tamoxifen alone by transmission electron microscopy. When compared with tamoxifen alone, PEG-GO/tamoxifen showed a delayed but potent PLD. In addition, the retarded PLD recovery by PEG-GO/tamoxifen indicated that the reversibility of DIP was interfered. Confocal microscopy revealed the increased number of lysosomes, greater expression of lysosomal associated membrane protein 2 (LAMP2) (a PLD marker), and an increase in the co-localization between lysosome/LAMP2 and NBD-PE by PEG-GO/tamoxifen rather than tamoxifen alone. Finally, we found that PEG-GO or/and tamoxifen-induced PLD seemed to have no correlation with autophagy. This research suggests pharmaceutical companies and regulatory agencies that if nanoparticles are used as the vectors for drug delivery, the adverse drug effects may be further potentiated probably through the long-term accumulation of nanocarriers. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e

  11. Tamoxifen Therapy to Treat Pulmonary Arterial Hypertension

    ClinicalTrials.gov

    2018-05-16

    Hypertension; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Primary Pulmonary Hypertension; Lung Diseases; Tamoxifen; Estrogen Receptor Antagonist; Hormone Antagonists; Estrogens

  12. Ex vivo permeation of tamoxifen and its 4-OH metabolite through rat intestine from lecithin/chitosan nanoparticles.

    PubMed

    Barbieri, S; Buttini, F; Rossi, A; Bettini, R; Colombo, P; Ponchel, G; Sonvico, F; Colombo, G

    2015-08-01

    Tamoxifen citrate is an anticancer drug slightly soluble in water. Administered orally, it shows great intra- and inter-patient variations in bioavailability. We developed a nanoformulation based on phospholipid and chitosan able to efficiently load tamoxifen and showing an enzyme triggered release. In this work the permeation of tamoxifen released from lecithin/chitosan nanoparticles across excised rat intestinal wall mounted in an Ussing chamber was investigated. Compared to tamoxifen citrate suspension, the amount of the drug permeated using the nanoformulation was increased from 1.5 to 90 times, in absence or in presence of pancreatin or lipase, respectively. It was also evidenced the formation of an active metabolite of tamoxifen, 4-hydroxy tamoxifen, however, the amount of metabolite permeated remained roughly constant in all experiments. The effect of enzymes on intestinal permeation of tamoxifen was shown only when tamoxifen-loaded nanoparticles were in intimate contact with the mucosal surface. The encapsulation of tamoxifen in lecithin/chitosan nanoparticles improved the non-metabolized drug passing through the rat intestinal tissue via paracellular transport. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. Lecithin/chitosan controlled release nanopreparations of tamoxifen citrate: loading, enzyme-trigger release and cell uptake.

    PubMed

    Barbieri, Stefano; Sonvico, Fabio; Como, Caterina; Colombo, Gaia; Zani, Franca; Buttini, Francesca; Bettini, Ruggero; Rossi, Alessandra; Colombo, Paolo

    2013-05-10

    Tamoxifen citrate (TAM), an anticancer drug with amphiphilic properties, was loaded in lecithin/chitosan nanoparticles (LCN) with a view to oral administration. The influence of tamoxifen loading on the physico-chemical properties of nanoparticles was studied. Size, surface charge and morphological properties of tamoxifen-loaded nanoparticles (LCN-TAM) were assessed. The increase in the tamoxifen amount in the LCN-TAM preparation up to 60 mg/100 ml maintained the positive zeta potential value of about +45 mV. A statistically significant decrease in particle size was observed for TAM amounts between 5 and 20mg. A strong influence of loaded tamoxifen on the structure of lecithin/chitosan nanoparticles was observed, supported by the quantification of free chitosan and morphological analysis. A loading of tamoxifen in nanoparticles of around 19% was obtained. The release of the drug from the LCN-TAM colloidal dispersion was measured, showing that tamoxifen citrate was released very slowly in simulated gastro-intestinal fluids without enzymes. When enzymes able to dismantle the nanoparticle structure were added to the dissolution medium, drug release was triggered and continued in a prolonged manner. Tamoxifen-loaded nanoparticles showed cytotoxicity towards MCF-7 cells comparable to that obtained with tamoxifen citrate solution, but the rate of this toxic effect was dependent on drug release. Caco-2 cells, used as a model of the intestinal epithelium, were shown to take up the TAM loaded nanoparticles extensively. Copyright © 2013 Elsevier B.V. All rights reserved.

  14. Therapeutic Effects of a Traditional Chinese Medicine Formula Plus Tamoxifen vs. Tamoxifen for the Treatment of Mammary Gland Hyperplasia: A Meta-Analysis of Randomized Trials

    PubMed Central

    Li, Hao-Tian; Liu, Hong-Hong; Yang, Yu-Xue; Wang, Tao; Zhou, Xue-Lin; Yu, Yang; Li, Su-Na; Zheng, Yi; Zhang, Ping; Wang, Rui-Lin; Li, Jian-Yu; Wei, Shi-Zhang; Li, Kun; Li, Peng-Yan; Qian, Li-Qi

    2018-01-01

    As a common disorder that accounts for over 70% of all breast disease cases, mammary gland hyperplasia (MGH) causes a severe problem for the quality of patients' life, and confers an increased risk of breast carcinoma. However, the etiology and pathogenesis of MGH remain unclear, and the safety and efficacy of current western drug therapy for MGH still need to be improved. Therefore, a meta-analysis was conducted by our team to determine whether a TCM formula named Ru-Pi-Xiao in combination with tamoxifen or Ru-Pi-Xiao treated alone can show more prominent therapeutic effects against MGH with fewer adverse reactions than that of tamoxifen. Studies published before June 2017 were searched based on standardized searching rules in several mainstream medical databases. A total of 27 articles with 4,368 patients were enrolled in this meta-analysis. The results showed that the combination of Ru-Pi-Xiao and tamoxifen could exhibit better therapeutic effects against MGH than that of tamoxifen (OR: 3.79; 95% CI: 3.09–4.65; P < 0.00001) with a lower incidence of adverse reactions (OR: 0.35; 95% CI: 0.28–0.43; P < 0.00001). The results also suggested that this combination could improve the level of progesterone (MD: 2.22; 95% CI: 1.72–2.71; P < 0.00001) and decrease the size of breast lump (MD: −0.67; 95% CI: −0.86 to −0.49; P < 0.00001) to a greater extent, which might provide a possible explanation for the pharmacodynamic mechanism of Ru-Pi-Xiao plus tamoxifen. In conclusion, Ru-Pi-Xiao and related preparations could be recommended as auxiliary therapy combined tamoxifen for the treatment of MGH. PMID:29456506

  15. Epigenetic Mechanisms of Tamoxifen Resistance in Luminal Breast Cancer.

    PubMed

    Abdel-Hafiz, Hany A

    2017-07-06

    Breast cancer is one of the most common cancers and the second leading cause of cancer death in the United States. Estrogen receptor (ER)-positive cancer is the most frequent subtype representing more than 70% of breast cancers. These tumors respond to endocrine therapy targeting the ER pathway including selective ER modulators (SERMs), selective ER downregulators (SERDs) and aromatase inhibitors (AIs). However, resistance to endocrine therapy associated with disease progression remains a significant therapeutic challenge. The precise mechanisms of endocrine resistance remain unclear. This is partly due to the complexity of the signaling pathways that influence the estrogen-mediated regulation in breast cancer. Mechanisms include ER modifications, alteration of coregulatory function and modification of growth factor signaling pathways. In this review, we provide an overview of epigenetic mechanisms of tamoxifen resistance in ER-positive luminal breast cancer. We highlight the effect of epigenetic changes on some of the key mechanisms involved in tamoxifen resistance, such as tumor-cell heterogeneity, ER signaling pathway and cancer stem cells (CSCs). It became increasingly recognized that CSCs are playing an important role in driving metastasis and tamoxifen resistance. Understanding the mechanism of tamoxifen resistance will provide insight into the design of novel strategies to overcome the resistance and make further improvements in breast cancer therapeutics.

  16. Spectral domain optical coherence tomography findings in tamoxifen retinopathy--a case report.

    PubMed

    Nair, Sandhya Narayanan; Anantharaman, Giridhar; Gopalakrishnan, Mahesh; Vyas, Jyothiprakash

    2013-01-01

    To report spectral domain optical coherence tomography findings in a case of typical tamoxifen retinopathy. In this observational case report, a patient with tamoxifen retinopathy was imaged with spectral domain optical coherence tomography and fundus auto fluorescence. Spectral domain optical coherence tomography showed numerous hyperreflective spots within the retina, mainly in the inner retinal layers in both the eyes. The external limiting membrane, the Inner Segment-Outer Segment junction, and the photoreceptors were not discernable at the fovea in the right eye. In the left eye, there was foveal atrophy with total loss of photoreceptors. The autofluorescent images showed macular hypofluorescence with foveal hyperfluorescence. Spectral domain optical coherence tomography demonstrated abnormalities in the outer retinal layers in tamoxifen retinopathy. There were also characteristic alterations in the autofluorescence pattern at the macula in tamoxifen retinopathy.

  17. A Hot Downflowing Model Atmosphere for Umbral Flashes and the Physical Properties of Their Dark Fibrils

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Henriques, V. M. J.; Mathioudakis, M.; Socas-Navarro, H.

    We perform non-LTE inversions in a large set of umbral flashes, including the dark fibrils visible within them, and in the quiescent umbra by using the inversion code NICOLE on a set of full Stokes high-resolution Ca ii λ 8542 observations of a sunspot at disk center. We find that the dark structures have Stokes profiles that are distinct from those of the quiescent and flashed regions. They are best reproduced by atmospheres that are more similar to the flashed atmosphere in terms of velocities, even if with reduced amplitudes. We also find two sets of solutions that finely fitmore » the flashed profiles: a set that is upflowing, featuring a transition region that is deeper than in the quiescent case and preceded by a slight dip in temperature, and a second solution with a hotter atmosphere in the chromosphere but featuring downflows close to the speed of sound at such heights. Such downflows may be related, or even dependent, on the presence of coronal loops, rooted in the umbra of sunspots, as is the case in the region analyzed. Similar loops have been recently observed to have supersonic downflows in the transition region and are consistent with the earlier “sunspot plumes,” which were invariably found to display strong downflows in sunspots. Finally, we find, on average, a magnetic field reduction in the flashed areas, suggesting that the shock pressure is moving field lines in the upper layers.« less

  18. Management of menopause-associated vasomotor symptoms: Current treatment options, challenges and future directions

    PubMed Central

    Pachman, Deirdre R; Jones, Jason M; Loprinzi, Charles L

    2010-01-01

    Hot flashes are one of the most common and distressing symptoms associated with menopause, occurring in more than 75% of postmenopausal women. They are especially problematic in breast cancer patients since some breast cancer therapies can induce hot flashes. For mild hot flashes, it is proposed that behavioral modifications are the first step in management. Hormonal therapies, including estrogens and progestogens, are the most well known effective agents in relieving hot flashes; however, the safety of these agents is controversial. There is an increasing amount of literature on nonhormonal agents for the treatment of hot flashes. The most promising data regard newer antidepressant agents such as venlafaxine, which reduces hot flashes by about 60%. Gabapentin is another nonhormonal agent that is effective in reducing hot flashes. While many complimentary therapies, including phytoestrogens, black cohosh, and dehydroepiandrosterone, have been explored for the treatment of hot flashes; none can be recommended at this time. Furthermore, there is a lack of strong evidence to support exercise, yoga, or relaxation for the treatment of hot flashes. Paced respirations and hypnosis appear to be promising enough to warrant further investigation. Another promising nonpharmacological therapy, currently under investigation, involves a stellate ganglion block. PMID:21072305

  19. Patterning of wound-induced intercellular Ca2+ flashes in a developing epithelium

    NASA Astrophysics Data System (ADS)

    Narciso, Cody; Wu, Qinfeng; Brodskiy, Pavel; Garston, George; Baker, Ruth; Fletcher, Alexander; Zartman, Jeremiah

    2015-10-01

    Differential mechanical force distributions are increasingly recognized to provide important feedback into the control of an organ’s final size and shape. As a second messenger that integrates and relays mechanical information to the cell, calcium ions (Ca2+) are a prime candidate for providing important information on both the overall mechanical state of the tissue and resulting behavior at the individual-cell level during development. Still, how the spatiotemporal properties of Ca2+ transients reflect the underlying mechanical characteristics of tissues is still poorly understood. Here we use an established model system of an epithelial tissue, the Drosophila wing imaginal disc, to investigate how tissue properties impact the propagation of Ca2+ transients induced by laser ablation. The resulting intercellular Ca2+ flash is found to be mediated by inositol 1,4,5-trisphosphate and depends on gap junction communication. Further, we find that intercellular Ca2+ transients show spatially non-uniform characteristics across the proximal-distal axis of the larval wing imaginal disc, which exhibit a gradient in cell size and anisotropy. A computational model of Ca2+ transients is employed to identify the principle factors explaining the spatiotemporal patterning dynamics of intercellular Ca2+ flashes. The relative Ca2+ flash anisotropy is principally explained by local cell shape anisotropy. Further, Ca2+ velocities are relatively uniform throughout the wing disc, irrespective of cell size or anisotropy. This can be explained by the opposing effects of cell diameter and cell elongation on intercellular Ca2+ propagation. Thus, intercellular Ca2+ transients follow lines of mechanical tension at velocities that are largely independent of tissue heterogeneity and reflect the mechanical state of the underlying tissue.

  20. Dextromethorphan as a phenotyping test to predict endoxifen exposure in patients on tamoxifen treatment.

    PubMed

    de Graan, Anne-Joy M; Teunissen, Sebastiaan F; de Vos, Filip Y F L; Loos, Walter J; van Schaik, Ron H N; de Jongh, Felix E; de Vos, Aad I; van Alphen, Robbert J; van der Holt, Bronno; Verweij, Jaap; Seynaeve, Caroline; Beijnen, Jos H; Mathijssen, Ron H J

    2011-08-20

    Tamoxifen, a widely used agent for the prevention and treatment of breast cancer, is mainly metabolized by CYP2D6 and CYP3A to form its most abundant active metabolite, endoxifen. Interpatient variability in toxicity and efficacy of tamoxifen is substantial. Contradictory results on the value of CYP2D6 genotyping to reduce the variable efficacy have been reported. In this pharmacokinetic study, we investigated the value of dextromethorphan, a known probe drug for both CYP2D6 and CYP3A enzymatic activity, as a potential phenotyping probe for tamoxifen pharmacokinetics. In this prospective study, 40 women using tamoxifen for invasive breast cancer received a single dose of dextromethorphan 2 hours after tamoxifen intake. Dextromethorphan, tamoxifen, and their respective metabolites were quantified. Exposure parameters of all compounds were estimated, log transformed, and subsequently correlated. A strong and highly significant correlation (r = -0.72; P < .001) was found between the exposures of dextromethorphan (0 to 6 hours) and endoxifen (0 to 24 hours). Also, the area under the plasma concentration-time curve of dextromethorphan (0 to 6 hours) and daily trough endoxifen concentration was strongly correlated (r = -0.70; P < .001). In a single patient using the potent CYP2D6 inhibitor paroxetine, the low endoxifen concentration was accurately predicted by dextromethorphan exposure. Dextromethorphan exposure after a single administration adequately predicted endoxifen exposure in individual patients with breast cancer taking tamoxifen. This test could contribute to the personalization and optimization of tamoxifen treatment, but it needs additional validation and simplification before being applicable in future dosing strategies.

  1. The anticancer drug tamoxifen counteracts the pathology in a mouse model of duchenne muscular dystrophy.

    PubMed

    Dorchies, Olivier M; Reutenauer-Patte, Julie; Dahmane, Elyes; Ismail, Heham M; Petermann, Olivier; Patthey- Vuadens, Ophélie; Comyn, Sophie A; Gayi, Elinam; Piacenza, Tony; Handa, Robert J; Décosterd, Laurent A; Ruegg, Urs T

    2013-02-01

    Duchenne muscular dystrophy (DMD) is a severe disorder characterized by progressive muscle wasting,respiratory and cardiac impairments, and premature death. No treatment exists so far, and the identification of active substances to fight DMD is urgently needed. We found that tamoxifen, a drug used to treat estrogen-dependent breast cancer, caused remarkable improvements of muscle force and of diaphragm and cardiac structure in the mdx(5Cv) mouse model of DMD. Oral tamoxifen treatment from 3 weeks of age for 15 months at a dose of 10 mg/kg/day stabilized myofiber membranes, normalized whole body force, and increased force production and resistance to repeated contractions of the triceps muscle above normal values. Tamoxifen improved the structure of leg muscles and diminished cardiac fibrosis by~ 50%. Tamoxifen also reduced fibrosis in the diaphragm, while increasing its thickness,myofiber count, and myofiber diameter, thereby augmenting by 72% the amount of contractile tissue available for respiratory function. Tamoxifen conferred a markedly slower phenotype to the muscles.Tamoxifen and its metabolites were present in nanomolar concentrations in plasma and muscles,suggesting signaling through high-affinity targets. Interestingly, the estrogen receptors ERa and ERb were several times more abundant in dystrophic than in normal muscles, and tamoxifen normalized the relative abundance of ERb isoforms. Our findings suggest that tamoxifen might be a useful therapy for DMD.

  2. The anticancer estrogen receptor antagonist tamoxifen impairs consolidation of inhibitory avoidance memory through estrogen receptor alpha.

    PubMed

    Lichtenfels, Martina; Dornelles, Arethuza da Silva; Petry, Fernanda Dos Santos; Blank, Martina; de Farias, Caroline Brunetto; Roesler, Rafael; Schwartsmann, Gilberto

    2017-11-01

    Over two-thirds of women with breast cancer have positive tumors for hormone receptors, and these patients undergo treatment with endocrine therapy, tamoxifen being the most widely used agent. Despite being very effective in breast cancer treatment, tamoxifen is associated with side effects that include cognitive impairments. However, the specific aspects and mechanisms underlying these impairments remain to be characterized. Here, we have investigated the effects of tamoxifen and interaction with estrogen receptors on formation of memory for inhibitory avoidance conditioning in female rats. In the first experiment, Wistar female rats received a single oral dose of tamoxifen (1, 3, or 10 mg/kg) or saline by gavage immediately after training and were tested for memory consolidation 24 h after training. In the second experiment, rats received a single dose of 1 mg/kg tamoxifen or saline by gavage 3 h after training and were tested 24 h after training for memory consolidation. In the third experiment, rats received a subcutaneous injection with estrogen receptor α agonist or estrogen receptor beta agonist 30 min before the training. After training, rats received a single oral dose of tamoxifen 1 mg/kg or saline and were tested 24 h after training. In the fourth experiment, rats were trained and tested 24 h later. Immediately after test, rats received a single dose of tamoxifen (1 mg/kg) or saline by gavage and were given four additional daily test trials followed by a re-instatement. Tamoxifen at 1 mg/kg impaired memory consolidation when given immediately after training and the estrogen receptor alpha agonist improved the tamoxifen-related memory impairment. Moreover, tamoxifen impairs memory consolidation of the test. These findings indicate that estrogen receptors regulate the early phase of memory consolidation and the effects of tamoxifen on memory consolidation.

  3. Modification of sphingolipid metabolism by tamoxifen and N-desmethyltamoxifen in acute myelogenous leukemia – Impact on enzyme activity and response to cytotoxics

    PubMed Central

    Morad, Samy A. F.; Tan, Su-Fern; Feith, David J.; Kester, Mark; Claxton, David F.; Loughran, Thomas P.; Barth, Brian M.; Fox, Todd E.; Cabot, Myles C.

    2015-01-01

    The triphenylethylene antiestrogen, tamoxifen, can be an effective inhibitor of sphingolipid metabolism. This off-target activity makes tamoxifen an interesting ancillary for boosting the apoptosis-inducing properties of ceramide, a sphingolipid with valuable tumor censoring activity. Here we show for the first time that tamoxifen and metabolite, N –desmethyltamoxifen (DMT) block ceramide glycosylation and inhibit ceramide hydrolysis (by acid ceramidase, AC) in human acute myelogenous leukemia (AML) cell lines and in AML cells derived from patients. Tamoxifen (1-10 μM) inhibition of AC in AML cells was accompanied by decreases in AC protein expression. Tamoxifen also depressed expression and activity of sphingosine kinase 1 (SphK1), the enzyme catalyzing production of mitogenic sphingosine 1-phosphate (S1-P). Results from mass spectroscopy showed that tamoxifen and DMT, i ) increased the levels of endogenous C16:0- and C24:1 ceramide molecular species, ii) nearly totally halted production of respective glucosylceramide (GC) molecular species, iii ) drastically reduced levels of sphingosine ( to 9% of control), and iv ) reduced levels of S1-P by 85%, in vincristine-resistant HL-60/VCR cells. Co-administration of tamoxifen with either N-(4-hydroxyphenyl)retinamide (4-HPR), a ceramide-generating retinoid, or a cell-deliverable form of ceramide, C6-ceramide, resulted in marked decreases in HL-60/VCR cell viability that far exceeded single agent potency. Combination treatments resulted in synergistic apoptotic cell death as gauged by increased Annexin V binding and DNA fragmentation and activation of caspase-3. These results show the versatility of adjuvant triphenylethylene with ceramide-centric therapies for magnifying therapeutic potential in AML. Such drug regimens could serve as effective strategies, even in the multidrug resistant setting. PMID:25769964

  4. Impact of CYP19A1 and ESR1 variants on early-onset side effects during combined endocrine therapy in the TEXT trial.

    PubMed

    Johansson, Harriet; Gray, Kathryn P; Pagani, Olivia; Regan, Meredith M; Viale, Giuseppe; Aristarco, Valentina; Macis, Debora; Puccio, Antonella; Roux, Susanne; Maibach, Rudolf; Colleoni, Marco; Rabaglio, Manuela; Price, Karen N; Coates, Alan S; Gelber, Richard D; Goldhirsch, Aron; Kammler, Roswitha; Bonanni, Bernardo; Walley, Barbara A

    2016-11-08

    Single nucleotide polymorphisms (SNPs) in the estrogen receptor 1 (ESR1) and cytochrome P450 19A1 (CYP19A1) genes have been associated with breast cancer risk, endocrine therapy response and side effects, mainly in postmenopausal women with early breast cancer. This analysis aimed to assess the association of selected germline CYP19A1 and ESR1 SNPs with early-onset hot flashes, sweating and musculoskeletal symptoms in premenopausal patients enrolled in the Tamoxifen and Exemestane Trial (TEXT). Blood was collected from consenting premenopausal women with hormone-responsive early breast cancer, randomly assigned to 5-years of tamoxifen plus ovarian suppression (OFS) or exemestane plus OFS. DNA was extracted with QIAamp kits and genotyped for two CYP19A1 (rs4646 and rs10046) and three ESR1 (rs2077647, rs2234693 and rs9340799) SNPs by a real-time pyrosequencing technique. Adverse events (AEs) were recorded at baseline and 3-monthly during the first year. Associations of the genotype variants with grade ≥2 early-onset targeted AEs of hot flashes/sweating or musculoskeletal events were assessed using logistic regression models. There were 2660 premenopausal patients with breast cancer in the intention-to-treat population of TEXT, and 1967 (74 %) are included in this translational study. The CYP19A1 rs10046 variant T/T, represented in 23 % of women, was associated with a reduced incidence of grade ≥2 hot flashes/sweating (univariate odds ratio (OR) = 0.78; 95 % CI 0.63-0.97; P = 0.03), more strongly in patients assigned exemestane + OFS (TT vs CT/CC: OR = 0.65, 95 % CI = 0.48-0.89) than assigned tamoxifen + OFS (OR = 0.94, 95 % CI = 0.69-1.27, interaction P = 0.03). No association with any of the CYP19A1/ESR1 genotypes and musculoskeletal AEs was found. The CYP19A1 rs10046 variant T/T favors lower incidence of hot flashes/sweating under exemestane + OFS treatment, suggesting endocrine-mediated effects. Based on findings

  5. Near infrared light induced plasmonic hot hole transfer at a nano-heterointerface.

    PubMed

    Lian, Zichao; Sakamoto, Masanori; Matsunaga, Hironori; Vequizo, Junie Jhon M; Yamakata, Akira; Haruta, Mitsutaka; Kurata, Hiroki; Ota, Wataru; Sato, Tohru; Teranishi, Toshiharu

    2018-06-13

    Localized surface plasmon resonance (LSPR)-induced hot-carrier transfer is a key mechanism for achieving artificial photosynthesis using the whole solar spectrum, even including the infrared (IR) region. In contrast to the explosive development of photocatalysts based on the plasmon-induced hot electron transfer, the hole transfer system is still quite immature regardless of its importance, because the mechanism of plasmon-induced hole transfer has remained unclear. Herein, we elucidate LSPR-induced hot hole transfer in CdS/CuS heterostructured nanocrystals (HNCs) using time-resolved IR (TR-IR) spectroscopy. TR-IR spectroscopy enables the direct observation of carrier in a LSPR-excited CdS/CuS HNC. The spectroscopic results provide insight into the novel hole transfer mechanism, named plasmon-induced transit carrier transfer (PITCT), with high quantum yields (19%) and long-lived charge separations (9.2 μs). As an ultrafast charge recombination is a major drawback of all plasmonic energy conversion systems, we anticipate that PITCT will break the limit of conventional plasmon-induced energy conversion.

  6. SUMO regulates proteasome-dependent degradation of FLASH/Casp8AP2

    PubMed Central

    Vennemann, Astrid; Hofmann, Thomas G.

    2013-01-01

    FLASH/Casp8AP2 is a huge multifunctional protein involved in multiple cellular processes, reaching from death receptor signaling to regulation of histone gene transcription and histone mRNA processing. Previous work has shown that FLASH localizes to Cajal bodies and promyelocytic leukemia (PML) bodies. However, the function of its nuclear body association remains unclear. Here we demonstrate that murine FLASH is covalently modified by SUMO at Lys residue 1792. Interestingly, ectopic expression of SUMO results in proteasome-dependent degradation of FLASH. A point mutant of FLASH with a mutated SUMO acceptor lysine residue, FLASHK1792R, is resistant to SUMO-induced degradation. Finally, we show that arsenic trioxide, a drug known to potentiate SUMO modification and degradation of PML, triggers recruitment of FLASH to PML bodies and concomitant loss of FLASH protein. Our data suggest that SUMO targets FLASH for proteasome-dependent degradation, which is associated with recruitment of FLASH to PML bodies. PMID:23673342

  7. Isolation of methyl gamma linolenate from Spirulina platensis using flash chromatography and its apoptosis inducing effect.

    PubMed

    Jubie, S; Dhanabal, S P; Chaitanya, M V N L

    2015-08-04

    Isolation of methyl gamma linolenate from Spirulina platensis using flash chromatography and its apoptosis inducing effect against human lung carcinoma A- 549 cell lines. Gamma linolenic acid is an important omega-6 polyunsaturated fatty acid (PUFA) of medicinal interest was isolated from microalgae Spirulina platensis using flash chromatography system (Isolera system) as its methyl ester. The isolated methyl gamma linolenate was characterized by IR, (1)H NMR, (13)C NMR and mass spectral analysis and the data were consistent with the structure. The percentage yield of isolated methyl gamma linolenate is found to be 71% w/w, which is a very good yield in comparison to other conventional methods. It was subjected to in-vitro cytotoxic screening on A-549 lung cancer cell lines using SRB assay and result was compared with standard rutin. It may be concluded that the Flash chromatography system plays a major role in improving the yield for the isolation of methyl gamma linoleate from Spirulina platensis and the isolated molecule is a potent cytotoxic agent towards human lung carcinoma cell lines, however it may be further taken up for an extensive study.

  8. Self-nanoemulsifying drug delivery systems of tamoxifen citrate: design and optimization.

    PubMed

    Elnaggar, Yosra S R; El-Massik, Magda A; Abdallah, Ossama Y

    2009-10-01

    Tamoxifen citrate is an antiestrogen for peroral breast cancer treatment. The drug delivery encounters problems of poor water solubility and vulnerability to enzymatic degradation in both intestine and liver. In the current study, tamoxifen citrate self-nanoemulsifying drug delivery systems (SNEDDS) were prepared in an attempt to circumvent such obstacles. Preliminary screening was carried out to select proper ingredient combinations. All surfactants screened were recognized for their bioactive aspects. Ternary phase diagrams were then constructed and an optimum system was designated. Three tamoxifen SNEDDS were then compared for optimization. The systems were assessed for robustness to dilution, globule size, cloud point, surface morphology and drug release. An optimum system composed of tamoxifen citrate (1.6%), Maisine 35-1 (16.4%), Caproyl 90 (32.8%), Cremophor RH40 (32.8%) and propylene glycol (16.4%) was selected. The system was robust to different dilution volumes and types. It possessed a mean globule size of 150 nm and a cloud point of 80 degrees C. Transmission electron microscopy demonstrated spherical particle morphology. The drug release from the selected formulation was significantly higher than other SNEDDS and drug suspension, as well. Realizing drug incorporation into an optimized nano-sized SNEDD system that encompasses a bioactive surfactant, our results proposed that the prepared system could be promising to improve oral efficacy of the tamoxifen citrate.

  9. The Origin of Hot Subluminous Horizontal-Branch Stars in (omega) Centauri and NGC 2808

    NASA Technical Reports Server (NTRS)

    Sweigart, Allen V.; Brown, Thomas M.; Lanz, Thierry; Landsman, Wayne B.; Hubeny, Ivan

    2001-01-01

    Hot subluminous stars lying up to 0.7 mag below the extreme horizontal branch (EHB) are found in the ultraviolet (UV) color magnitude diagrams of both (omega) Cen and NGC 2808. In order to explore the evolutionary status of these subluminous stars, we have evolved a set of low-mass stars continuously from the main sequence through the helium-core flash to the HB (horizontal branch) for a wide range in the mass loss along the red-giant branch (RGB). Stars with the largest mass loss evolve off the RGB to high effective temperatures before igniting helium in their cores. Our results indicate that the subluminous EHB stars, as well as the gap within the EHB of NGC 2808, can be explained if these stars undergo a late helium-core flash while descending the white-dwarf cooling curve. Under these conditions the convection zone produced by the helium flash will penetrate into the stellar envelope, thereby mixing most, if not all, of the envelope hydrogen into the hot helium-burning interior, where it is rapidly consumed. This phenomenon is analogous to the 'born-again' scenario for producing hydrogen-deficient stars following a very late helium-shell flash. This 'flash mixing' of the stellar envelope greatly enhances the envelope helium and carbon abundances and, as a result, leads to a discontinuous jump in the HB effective temperature. We argue that the EHB gap in NGC 2808 is associated with this theoretically predicted dichotomy in the HB morphology. Using new helium- and carbon-rich stellar atmospheres, we show that these changes in the envelope abundances of the flash-mixed stars will suppress the UV flux by the amount needed to explain the hot subluminous EHB stars in (omega) Cen and NGC 2808. Moreover, we demonstrate that models without flash mixing lie, at most, only approximately 0.1 mag below the EHB, and hence fail to explain the observations. Flash mixing may also provide a new evolutionary channel for producing the high gravity, helium-rich sdO and sdB stars.

  10. Five Years of Tamoxifen Continues to Benefit Women 15 Years after Treatment

    Cancer.gov

    In a large randomized clinical trial, women with early-stage breast cancer who received 5 years of adjuvant treatment with tamoxifen had better outcomes up to 15 years after the start of treatment than those who received 2 years of tamoxifen therapy.

  11. Laser-induced pressure-wave and barocaloric effect during flash diffusivity measurements

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wang, Hsin; Porter, Wallace D.; Dinwiddie, Ralph Barton

    We report laser-induced pressure-wave and barocaloric effect captured by an infrared detector during thermal diffusivity measurements. Very fast (< 1 ms) and negative transients during laser flash measurements were captured by the infrared detector on thin, high thermal conductivity samples. Standard thermal diffusivity analysis only focuses the longer time scale thermal transient measured from the back surface due to thermal conduction. These negative spikes are filtered out and ignored as noise or anomaly from instrument. This study confirmed that the initial negative signal was indeed a temperature drop induced by the laser pulse. The laser pulse induced instantaneous volume expansionmore » and the associated cooling in the specimen can be explained by the barocaloric effect. The initial cooling (< 100 microsecond) is also known as thermoelastic effect in which a negative temperature change is generated when the material is elastically deformed by volume expansion. A subsequent temperature oscillation in the sample was observed and only lasted about one millisecond. The pressure-wave induced thermal signal was systematically studied and analyzed. In conclusion, the underlying physics of photon-mechanical-thermal energy conversions and the potential of using this signal to study barocaloric effects in solids are discussed.« less

  12. Laser-induced pressure-wave and barocaloric effect during flash diffusivity measurements

    DOE PAGES

    Wang, Hsin; Porter, Wallace D.; Dinwiddie, Ralph Barton

    2017-08-01

    We report laser-induced pressure-wave and barocaloric effect captured by an infrared detector during thermal diffusivity measurements. Very fast (< 1 ms) and negative transients during laser flash measurements were captured by the infrared detector on thin, high thermal conductivity samples. Standard thermal diffusivity analysis only focuses the longer time scale thermal transient measured from the back surface due to thermal conduction. These negative spikes are filtered out and ignored as noise or anomaly from instrument. This study confirmed that the initial negative signal was indeed a temperature drop induced by the laser pulse. The laser pulse induced instantaneous volume expansionmore » and the associated cooling in the specimen can be explained by the barocaloric effect. The initial cooling (< 100 microsecond) is also known as thermoelastic effect in which a negative temperature change is generated when the material is elastically deformed by volume expansion. A subsequent temperature oscillation in the sample was observed and only lasted about one millisecond. The pressure-wave induced thermal signal was systematically studied and analyzed. In conclusion, the underlying physics of photon-mechanical-thermal energy conversions and the potential of using this signal to study barocaloric effects in solids are discussed.« less

  13. HRD1 sensitizes breast cancer cells to Tamoxifen by promoting S100A8 degradation

    PubMed Central

    Liang, XiuBin; Li, Min; Shi, Ming; Li, Yan; Jenkins, Gareth; Lin, XiaWen; Wei, XueFei; Jia, ZhiJun; Feng, XueFeng; Su, DongMing; Guo, WanHua

    2017-01-01

    Estrogen receptor alpha positive (ER+) of breast cancer could develop resistance to antiestrogens including Tamoxifen. Our previous study showed that the E3 ubiquitin ligase HRD1 played an important role in anti-breast cancer. However, its role in chemotherapy resistance hasn't been reported. In this study, we found that HRD1 expression was downregulated in Tamoxifen-resistant breast cancer cell line MCF7/Tam compared to the Tamoxifen sensitive cell line MCF7. Moreover, S100A8 is the direct target of HRD1 by proteome analysis. Our data showed that HRD1 decreased the protein level of S100A8 through ubiquitination while HRD1 was regulated by acetylation of histone. More importantly, HRD1 knockdown significantly increased the cell survival of MCF7 cells to the Tamoxifen treatment. HRD1 overexpression sensitized MCF7/Tam cells to the Tamoxifen treatment in vitro and in vivo. In conclusion, the decrease of HRD1 expression contributed to Tamoxifen resistance in breast cancer. PMID:28423597

  14. Thrombosis of digital arteries associated with tamoxifen use: case report.

    PubMed

    Hutchison, Richard L; Rayan, Ghazi M

    2012-02-01

    Arterial thrombosis in the upper extremity occurs often at the wrist. We report a unique case of thrombosis that involved multiple digital arteries, without radial or ulnar artery involvement, which developed only after using tamoxifen despite chronic occupational blunt percussive hand use. Revascularization was achieved after thrombectomy. Multiple digital arterial thromboses may complicate the use of tamoxifen. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  15. A Comprehensive Study on Energy Efficiency and Performance of Flash-based SSD

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Park, Seon-Yeon; Kim, Youngjae; Urgaonkar, Bhuvan

    2011-01-01

    Use of flash memory as a storage medium is becoming popular in diverse computing environments. However, because of differences in interface, flash memory requires a hard-disk-emulation layer, called FTL (flash translation layer). Although the FTL enables flash memory storages to replace conventional hard disks, it induces significant computational and space overhead. Despite the low power consumption of flash memory, this overhead leads to significant power consumption in an overall storage system. In this paper, we analyze the characteristics of flash-based storage devices from the viewpoint of power consumption and energy efficiency by using various methodologies. First, we utilize simulation tomore » investigate the interior operation of flash-based storage of flash-based storages. Subsequently, we measure the performance and energy efficiency of commodity flash-based SSDs by using microbenchmarks to identify the block-device level characteristics and macrobenchmarks to reveal their filesystem level characteristics.« less

  16. Flash Galaxy Cluster Merger, Simulated using the Flash Code, Mass Ratio 1:1

    ScienceCinema

    None

    2018-05-11

    Since structure in the universe forms in a bottom-up fashion, with smaller structures merging to form larger ones, modeling the merging process in detail is crucial to our understanding of cosmology. At the current epoch, we observe clusters of galaxies undergoing mergers. It is seen that the two major components of galaxy clusters, the hot intracluster gas and the dark matter, behave very differently during the course of a merger. Using the N-body and hydrodynamics capabilities in the FLASH code, we have simulated a suite of representative galaxy cluster mergers, including the dynamics of both the dark matter, which is collisionless, and the gas, which has the properties of a fluid. 3-D visualizations such as these demonstrate clearly the different behavior of these two components over time. Credits: Science: John Zuhone (Harvard-Smithsonian Center for Astrophysics Visualization: Jonathan Gallagher (Flash Center, University of Chicago)

 This research used resources of the Argonne Leadership Computing Facility at Argonne National Laboratory, which is supported by the Office of Science of the U.S. Dept. of Energy (DOE) under contract DE-AC02-06CH11357. This research was supported by the National Nuclear Security Administration's (NNSA) Advanced Simulation and Computing (ASC) Academic Strategic Alliance Program (ASAP).

  17. Flash Galaxy Cluster Merger, Simulated using the Flash Code, Mass Ratio 1:1

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    None

    2010-08-09

    Since structure in the universe forms in a bottom-up fashion, with smaller structures merging to form larger ones, modeling the merging process in detail is crucial to our understanding of cosmology. At the current epoch, we observe clusters of galaxies undergoing mergers. It is seen that the two major components of galaxy clusters, the hot intracluster gas and the dark matter, behave very differently during the course of a merger. Using the N-body and hydrodynamics capabilities in the FLASH code, we have simulated a suite of representative galaxy cluster mergers, including the dynamics of both the dark matter, which ismore » collisionless, and the gas, which has the properties of a fluid. 3-D visualizations such as these demonstrate clearly the different behavior of these two components over time. Credits: Science: John Zuhone (Harvard-Smithsonian Center for Astrophysics Visualization: Jonathan Gallagher (Flash Center, University of Chicago)

 This research used resources of the Argonne Leadership Computing Facility at Argonne National Laboratory, which is supported by the Office of Science of the U.S. Dept. of Energy (DOE) under contract DE-AC02-06CH11357. This research was supported by the National Nuclear Security Administration's (NNSA) Advanced Simulation and Computing (ASC) Academic Strategic Alliance Program (ASAP).« less

  18. Estrogenic activity of tamoxifen on normal mammary parenchyma in the luteal phase of the menstrual cycle.

    PubMed

    Facina, G; de Lima, G R; Simões, M J; Novo, N F; Gebrim, L H

    1997-01-01

    Tamoxifen, an anti-estrogenic drug used in the adjuvant treatment of breast cancer, deserves more investigation for the determination of its efficacy as a prophylactic agent against breast cancer in high risk women. Thus, the action of tamoxifen on the human mammary gland was studied by measuring the number of lysosomes in normal mammary epithelium during the administration of tamoxifen. Tamoxifen was administered only during the luteal phase of the menstrual cycle to avoid interference with corpus luteum formation. A fragment of breast tissue adjacent to a fibroadenoma was obtained during surgery from 35 premenopausal women aged 15 to 37 years who had been eumenorrheic for at least 6 months; 18 of these patients were treated with tamoxifen and 17 were used as controls. Lysosome counts were performed under the light microscope on slides submitted to the acid phosphatase cytochemical technique and the data were analyzed statistically by the Mann-Whitney test. The fragments from the group treated with tamoxifen showed a significant decrease in lysosome numbers. Tamoxifen administered after ovulation significantly decreases the number of lysosomes in the cells of normal mammary epithelium, demonstrating the antiestrogenic effect of the drug on this target tissue.

  19. Unrecognized hepatic steatosis and non-alcoholic steatohepatitis in adjuvant tamoxifen for breast cancer patients.

    PubMed

    Murata, Y; Ogawa, Y; Saibara, T; Nishioka, A; Fujiwara, Y; Fukumoto, M; Inomata, T; Enzan, H; Onishi, S; Yoshida, S

    2000-01-01

    Adjuvant tamoxifen has become the treatment of choice against estrogen receptor-positive breast cancer. Adverse effects are rarely observed and since symptoms of hepatic steatosis, non-alcoholic steatohepatitis and cirrhosis are usually negligible, such effects are not well characterized despite large cohort studies of adjuvant tamoxifen. This issue remains to be systematically studied. The present study consisted of 136 breast cancer patients treated with or without tamoxifen. Patients had laboratory tests once each month and underwent abdominal computed tomography (CT) annually for 5 years. The extent of hepatic steatosis was assessed by CT as the liver/spleen ratio. While receiving adjuvant tamoxifen, 40 of 105 patients developed hepatic steatosis (liver/spleen ratio <0.9) without obvious changes in body mass index. Twenty-one had a liver spleen ratio of <0.5, whereas none of the 31 patients treated without tamoxifen had a ratio <0.9 or <0.5 (p<0.0001 and p<0.0001, respectively). Hepatic steatosis was recognized in 35 of the 40 patients within the first 2 years of receiving adjuvant tamoxifen and 21 of the 40 had increased transaminase levels. Liver biopsy revealed NASH in 6 of 7 patients among the 21 with a liver/spleen ratio of <0.5. A subset of individuals given adjuvant tamoxifen developed progressive hepatic steatosis without significant changes in the body mass index. We suggest a liver/spleen ratio of <0.5 as a criterion upon which liver biopsy should be recommended since NASH frequently occurred in such patients.

  20. Quality of life in relation to tamoxifen or exemestane treatment in postmenopausal breast cancer patients: a Tamoxifen Exemestane Adjuvant Multinational (TEAM) Trial side study.

    PubMed

    van Nes, J G H; Fontein, D B Y; Hille, E T M; Voskuil, D W; van Leeuwen, F E; de Haes, J C J M; Putter, H; Seynaeve, C; Nortier, J W R; van de Velde, C J H

    2012-07-01

    Tamoxifen and aromatase inhibitors are associated with side effects which can significantly impact quality of life (QoL). We assessed QoL in the Tamoxifen Exemestane Adjuvant Multinational (TEAM) Trial and compared these data with reported adverse events in the main database. 2,754 Dutch postmenopausal early breast cancer patients were randomized between 5 years of exemestane, or tamoxifen (2.5-3 years) followed by exemestane (2.5-2 years). 742 patients were invited to participate in the QoL side study and complete questionnaires at 1 (T1) and 2 (T2) years after start of endocrine treatment. Questionnaires comprised the EORTC QLQ-C30 and BR23 questionnaires, supplemented with FACT-ES questions. 543 patients completed questionnaires at T1 and 454 patients (84%) at T2. Overall QoL and most functioning scales improved over time. The only clinically relevant and statistically significant difference between treatment types concerned insomnia; exemestane-treated patients reported more insomnia than tamoxifen-treated patients. Discrepancy was observed between QoL issue scores reported by the patients and adverse events reported by physicians. Certain QoL issues are treatment- and/or time-specific and deserve attention by health care providers. There is a need for careful inquiry into QoL issues by those prescribing endocrine treatment to optimize QoL and treatment adherence.

  1. Quantification of tamoxifen and three of its phase-I metabolites in human plasma by liquid chromatography/triple-quadrupole mass spectrometry.

    PubMed

    Binkhorst, Lisette; Mathijssen, Ron H J; Ghobadi Moghaddam-Helmantel, Inge M; de Bruijn, Peter; van Gelder, Teun; Wiemer, Erik A C; Loos, Walter J

    2011-12-15

    In view of future pharmacokinetic studies, a highly sensitive ultra performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method has been developed for the simultaneous quantification of tamoxifen and three of its main phase I metabolites in human lithium heparinized plasma. The analytical method has been thoroughly validated in agreement with FDA recommendations. Plasma samples of 200 μl were purified by liquid-liquid extraction with 1 ml n-hexane/isopropanol, after deproteination through addition of 50 μl acetone and 50 μl deuterated internal standards in acetonitrile. Tamoxifen, N-desmethyl-tamoxifen, 4-hydroxy-tamoxifen and endoxifen were chromatographically separated on an Acquity UPLC(®) BEH C18 1.7 μm 2.1 mm×100 mm column eluted at a flow-rate of 0.300 ml/min on a gradient of 0.2mM ammonium formate and acetonitrile, both acidified with 0.1% formic acid. The overall run time of the method was 10 min, with elution times of 2.9, 3.0, 4.1 and 4.2 min for endoxifen, 4-hydroxy-tamoxifen, N-desmethyl-tamoxifen and tamoxifen, respectively. Tamoxifen and its metabolites were quantified by triple-quadrupole mass spectrometry in the positive ion electrospray ionization mode. The multiple reaction monitoring transitions were set at 372>72 (m/z) for tamoxifen, 358>58 (m/z) for N-desmethyl-tamoxifen, 388>72 (m/z) for 4-hydroxy-tamoxifen and 374>58 (m/z) for endoxifen. The analytical method was highly sensitive with the lower limit of quantification validated at 5.00 nM for tamoxifen and N-desmethyl-tamoxifen and 0.500 nM for 4-hydroxy-tamoxifen and endoxifen, which is equivalent to 1.86, 1.78, 0.194 and 0.187 ng/ml for tamoxifen, N-desmethyl-tamoxifen, 4-hydroxy-tamoxifen and endoxifen, respectively. The method was also precise and accurate, with within-run and between-run precisions within 12.0% and accuracy ranging from 89.5 to 105.3%. The method has been applied to samples from a clinical study and cross-validated with a validated LC

  2. Flash characteristics of plasma induced by hypervelocity impact

    NASA Astrophysics Data System (ADS)

    Zhang, Kai; Long, Renrong; Zhang, Qingming; Xue, Yijiang; Ju, Yuanyuan

    2016-08-01

    Using a two-stage light gas gun, a series of hypervelocity impact experiments was conducted in which 6.4-mm-diameter spherical 2024-aluminum projectiles impact 23-mm-thick targets made of the same material at velocities of 5.0, 5.6, and 6.3 km/s. Both an optical pyrometer composed of six photomultiplier tubes and a spectrograph were used to measure the flash of the plasma during hypervelocity impact. Experimental results show that, at a projectile velocity of 6.3 km/s, the strong flash lasted about 10 μs and reached a temperature of 4300 K. Based on the known emission lines of AL I, spectral methods can provide the plasma electron temperature. An electron-temperature comparison between experiment and theoretical calculation indicates that single ionization and secondary ionization are the two main ionizing modes at velocities 5.0-6.3 km/s.

  3. Optimal flash rate and duty cycle for flashing visual indicators.

    NASA Technical Reports Server (NTRS)

    Markowitz, J.

    1971-01-01

    This experiment examined the ability of observers to determine, as quickly as possible, whether a visual indicator was steadily on or flashing. Six flash rates (periods) were combined factorially with three duty cycles (on-off ratios) to define 18 ?types' of intermittent signals. Experimental sessions were divided into six runs of 100 trials, each run utilizing one of the six flash rates. On any given trial in a run, the probability of a steady signal occurring was 0.5 and the probability of a flashing signal occurring was 0.5. A different duty cycle was employed daily for each experimental session. In all, 400 trials were devoted to each of the flash rates at each duty cycle. Accuracy and latency of response were the dependent variables of interest. The results show that the observers view the light for an interval of time appropriate to the expected flash rate and duty cycle; whether they judge the light to be steady or intermittent depends upon whether the light is extinguished during the predetermined waiting period. Adoption of this temporal criterion delays responding in comparison to those tasks involving responses to light onset. The decision or response criteria held by the observers are also sensitive to the parameters of the flashing light: observers become increasingly willing to call a flashing light ?steady' as flash duration increases.

  4. Tamoxifen therapy benefit for patients with 70-gene signature high and low risk.

    PubMed

    van 't Veer, Laura J; Yau, Christina; Yu, Nancy Y; Benz, Christopher C; Nordenskjöld, Bo; Fornander, Tommy; Stål, Olle; Esserman, Laura J; Lindström, Linda Sofie

    2017-11-01

    Breast cancer molecular prognostic tools that predict recurrence risk have mainly been established on endocrine-treated patients and thus are not optimal for the evaluation of benefit from endocrine therapy. The Stockholm tamoxifen (STO-3) trial which randomized postmenopausal node-negative patients to 2-year tamoxifen (followed by an optional randomization for an additional 3-year tamoxifen vs nil), versus no adjuvant treatment, provides a unique opportunity to evaluate long-term 20-year benefit of endocrine therapy within prognostic risk classes of the 70-gene prognosis signature that was developed on adjuvantly untreated patients. We assessed by Kaplan-Meier analysis 20-year breast cancer-specific survival (BCSS) and 10-year distant metastasis-free survival (DMFS) for 538 estrogen receptor (ER)-positive, STO-3 trial patients with retrospectively ascertained 70-gene prognosis classification. Multivariable analysis of long-term (20 years) BCSS by STO-3 trial arm in the 70-gene high-risk and low-risk subgroups was performed using Cox proportional hazard modeling adjusting for classical patient and tumor characteristics. Tamoxifen-treated, 70-gene low- and high-risk patients had 20-year BCSS of 90 and 83%, as compared to 80 and 65% for untreated patients, respectively (log-rank p < 0.0001). Notably, there is equivalent tamoxifen benefit in both high (HR 0.42 (0.21-0.86), p = 0.018) and low (HR 0.46 (0.25-0.85), p = 0.013) 70-gene risk categories even after adjusting for clinico-pathological factors for BCSS. Limited tamoxifen exposure as given in the STO-3 trial provides persistent benefit for 10-15 years after diagnosis in a time-varying analysis. 10-year DMFS was 93 and 85% for low- and high-risk tamoxifen-treated, versus 83 and 70% for low- and high-risk untreated patients, respectively (log-rank p < 0.0001). Patients with ER-positive breast cancer, regardless of high or low 70-gene risk classification, receive significant survival benefit lasting over

  5. Sliding p21-activated kinase 1 to nucleus impacts tamoxifen sensitivity.

    PubMed

    Rayala, Suresh K; Kumar, Rakesh

    2007-08-01

    The anti-estrogen, tamoxifen is the most commonly used treatment for patients with estrogen receptor (ER)-alpha-positive breast cancer. Recent data suggest that levels of ER coregulatory proteins as well as extra- and intracellular signaling in response to growth factor stimulation of breast cancer cells play an important role in acquiring resistance to anti-estrogen action. P21-activated kinase 1 (PAK1), a major target of the small GTPases, growth factors and lipid signaling, regulates cell motility, hormone action, invasiveness, and survival, all of which are required for both tumor development and normal mammary gland development. Over the years, the PAK1 has been regarded as cytosolic serine-threonine kinase with regulatory function in cytoskeleton reorganization and motility. However, emerging data now provide evidence of PAK1 function in the nucleus of breast cancer cells. Elevated PAK1 expression in premenopausal breast cancer patients correlates well with the lack of tamoxifen response despite the presence of ER-alpha expression, and such relationship was even distinctly stronger in breast tumors with nuclear PAK1. These typical effects of PAK1 are mechanistically linked with the ability of PAK1 to phosphorylate ER-alpha on serine 305, accompanied by secondary activation of serine 118, and such structural modifications may participate in the development of tamoxifen resistance. These findings suggest that the levels, subcellular localization, and activation status of PAK1 are likely to be important determinants of tamoxifen resistance, and that raising the possibility that tamoxifen resistance might be prevented or reversed by PAK1 inhibition.

  6. Breast density measurements using ultrasound tomography for patients undergoing tamoxifen treatment

    NASA Astrophysics Data System (ADS)

    Sak, Mark; Duric, Neb; Littrup, Peter; Li, Cuiping; Bey-Knight, Lisa; Sherman, Mark; Boyd, Norman; Gierach, Gretchen

    2013-03-01

    Women with high breast density have an increased risk of developing breast cancer. Women treated with the selective estrogen receptor modulator tamoxifen for estrogen receptor positive breast cancer experience a 50% reduction in risk of contralateral breast cancer and overall reduction of similar magnitude has been identified among high-risk women receiving the drug for prevention. Tamoxifen has been shown to reduce mammographic density, and in the IBIS-1 chemoprevention trial, risk reduction and decline in density were significantly associated. Ultrasound tomography (UST) is an imaging modality that can create tomographic sound speed images of the breast. These sound speed images are useful because breast density is proportional to sound speed. The aim of this work is to examine the relationship between USTmeasured breast density and the use of tamoxifen. So far, preliminary results for a small number of patients have been observed and are promising. Correlations between the UST-measured density and mammographic density are strong and positive, while relationships between UST density with some patient specific risk factors behave as expected. Initial results of UST examinations of tamoxifen treated patients show that approximately 45% of the patients have a decrease in density in the contralateral breast after only several months of treatment. The true effect of tamoxifen on UST-measured density cannot yet be fully determined until more data are collected. However, these promising results suggest that UST can be used to reliably assess quantitative changes in breast density over short intervals and therefore suggest that UST may enable rapid assessment of density changes associated with therapeutic and preventative interventions.

  7. Anti-tumor effects of retinoids combined with trastuzumab or tamoxifen in breast cancer cells: induction of apoptosis by retinoid/trastuzumab combinations.

    PubMed

    Koay, Debbie C; Zerillo, Cynthia; Narayan, Murli; Harris, Lyndsay N; DiGiovanna, Michael P

    2010-01-01

    HER2 and estrogen receptor (ER) are important in breast cancer and are therapeutic targets of trastuzumab (Herceptin) and tamoxifen, respectively. Retinoids inhibit breast cancer growth, and modulate signaling by HER2 and ER. We hypothesized that treatment with retinoids and simultaneous targeting of HER2 and/or ER may have enhanced anti-tumor effects. The effects of retinoids combined with trastuzumab or tamoxifen were examined in two human breast cancer cell lines in culture, BT474 and SKBR3. Assays of proliferation, apoptosis, differentiation, cell cycle distribution, and receptor signaling were performed. In HER2-overexpressing/ER-positive BT474 cells, combining all-trans retinoic acid (atRA) with tamoxifen or trastuzumab synergistically inhibited cell growth, and altered cell differentiation and cell cycle. Only atRA/trastuzumab-containing combinations induced apoptosis. BT474 and HER2-overexpressing/ER-negative SKBR3 cells were treated with a panel of retinoids (atRA, 9-cis-retinoic acid, 13-cis-retinoic acid, or N-(4-hydroxyphenyl) retinamide (fenretinide) (4-HPR)) combined with trastuzumab. In BT474 cells, none of the single agents except 4-HPR induced apoptosis, but again combinations of each retinoid with trastuzumab did induce apoptosis. In contrast, the single retinoid agents did cause apoptosis in SKBR3 cells; this was only modestly enhanced by addition of trastuzumab. The retinoid drug combinations altered signaling by HER2 and ER. Retinoids were inactive in trastuzumab-resistant BT474 cells. Combining retinoids with trastuzumab maximally inhibits cell growth and induces apoptosis in trastuzumab-sensitive cells. Treatment with such combinations may have benefit for breast cancer patients.

  8. Benefit/Risk Assessment for Breast Cancer Chemoprevention With Raloxifene or Tamoxifen for Women Age 50 Years or Older

    PubMed Central

    Freedman, Andrew N.; Yu, Binbing; Gail, Mitchell H.; Costantino, Joseph P.; Graubard, Barry I.; Vogel, Victor G.; Anderson, Garnet L.; McCaskill-Stevens, Worta

    2011-01-01

    Purpose The Study of Tamoxifen and Raloxifene (STAR) demonstrated that raloxifene was as effective as tamoxifen in reducing the risk of invasive breast cancer (IBC) in postmenopausal women and had lower risks of thromboembolic events, endometrial cancer, and cataracts but had a nonstatistically significant higher risk of noninvasive breast cancer. There is a need to summarize the risks and benefits of these agents. Patients and Methods Baseline incidence rates of IBC and other health outcomes, absent raloxifene and tamoxifen, were estimated from breast cancer chemoprevention trials; the Surveillance, Epidemiology and End Results Program; and the Women's Health Initiative. Effects of raloxifene and tamoxifen were estimated from STAR and the Breast Cancer Prevention Trial. We assigned weights to health outcomes to calculate the net benefit from raloxifene compared with placebo and tamoxifen compared with placebo. Results Risks and benefits of treatment with raloxifene or tamoxifen depend on age, race, breast cancer risk, and history of hysterectomy. Over a 5-year period, postmenopausal women with an intact uterus had a better benefit/risk index for raloxifene than for tamoxifen. For postmenopausal women without a uterus, the benefit/risk ratio was similar. The benefits and risks of raloxifene and tamoxifen are described in tables that can help identify groups of women for whom the benefits outweigh the risks. Conclusion We developed a benefit/risk index to quantify benefits from chemoprevention with tamoxifen or raloxifene. This index can complement clinical evaluation in deciding whether to initiate chemoprevention and in comparing the benefits and risks of raloxifene versus tamoxifen. PMID:21537036

  9. NAND FLASH Radiation Tolerant Intelligent Memory Stack (RTIMS FLASH)

    NASA Astrophysics Data System (ADS)

    Sellier, Charles; Wang, Pierre

    2014-08-01

    The NAND Flash Radiation Tolerant and Intelligent Memory Stack (RTIMS FLASH) is a User's Friendly, Plug-and- Play and Radiation Protected high density NAND Flash Memory. It provides a very high density, radiation hardened by design and non-volatile memory module suitable for all space applications such as commercial or scientific geo-stationary missions, earth observation, navigation, manned space vehicles and deep space scientific exploration. The Intelligent Memory Module embeds a very high density of non-volatile NAND Flash memory and one Intelligent Flash Memory Controller (FMC). The FMC provides the module with a full protection against the radiation effects such as SEL, SEFI and SEU. It's also granting the module with bad block immunity as well as high level service functions that will benefit to the user's applications.

  10. Flash characteristics of plasma induced by hypervelocity impact

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Zhang, Kai; Beijing Automotive Technology Center, Beijing 100021; Long, Renrong, E-mail: longrenrong@bit.edu.cn, E-mail: qmzhang@bit.edu.cn

    2016-08-15

    Using a two-stage light gas gun, a series of hypervelocity impact experiments was conducted in which 6.4-mm-diameter spherical 2024-aluminum projectiles impact 23-mm-thick targets made of the same material at velocities of 5.0, 5.6, and 6.3 km/s. Both an optical pyrometer composed of six photomultiplier tubes and a spectrograph were used to measure the flash of the plasma during hypervelocity impact. Experimental results show that, at a projectile velocity of 6.3 km/s, the strong flash lasted about 10 μs and reached a temperature of 4300 K. Based on the known emission lines of AL I, spectral methods can provide the plasma electron temperature. An electron-temperaturemore » comparison between experiment and theoretical calculation indicates that single ionization and secondary ionization are the two main ionizing modes at velocities 5.0–6.3 km/s.« less

  11. Tamoxifen treatment for pubertal gynecomastia in two siblings with partial androgen insensitivity syndrome.

    PubMed

    Saito, Reiko; Yamamoto, Yukiyo; Goto, Motohide; Araki, Shunsuke; Kubo, Kazuyasu; Kawagoe, Rinko; Kawada, Yasusada; Kusuhara, Koichi; Igarashi, Maki; Fukami, Maki

    2014-01-01

    Although tamoxifen has been shown to be fairly safe and effective for idiopathic pubertal gynecomastia, it remains unknown whether it is also beneficial for gynecomastia associated with endocrine disorders. Here, we report the effect of tamoxifen on pubertal gynecomastia in 2 siblings with partial androgen insensitivity syndrome (PAIS). Cases 1 and 2 presented with persistent pubertal gynecomastia at 13 and 16 years of age, respectively. Physical examinations revealed breast of Tanner stage 3 and normal male-type external genitalia in both cases. Clinical features such as female-type pubic hair and borderline small testis indicated mildly impaired masculinization. Molecular analysis identified a previously reported p.Arg789Ser mutation in the androgen receptor gene (AR) in the 2 cases. Two months of oral administration of tamoxifen ameliorated gynecomastia to Tanner stage 2 with no adverse events. Additional treatment with testosterone enanthate showed negligible effects on body hair and penile length. Hormone values of the 2 cases during tamoxifen treatment remained similar to those in previously reported untreated patients with PAIS. The results indicate that tamoxifen was effective in treating pubertal gynecomastia in these 2 patients with PAIS and may be considered as a therapeutic option in this situation pending further studies.

  12. Tamoxifen decreases the myofibroblast count in the healing bile duct tissue of pigs

    PubMed Central

    Siqueira, Orlando Hiroshi Kiono; Filho, Benedito Herani; de Paula, Rafael Erthal; Áscoli, Fábio Otero; da Nóbrega, Antonio Cláudio Lucas; Carvalho, Angela Cristina Gouvêa; Pires, Andréa Rodrigues Cordovil; Gaglionone, Nicolle Cavalcante; Cunha, Karin Soares Gonçalves; Granjeiro, José Mauro

    2013-01-01

    OBJECTIVE: The aim of this study was to evaluate the effect of oral tamoxifen treatment on the number of myofibroblasts present during the healing process after experimental bile duct injury. METHODS: The sample consisted of 16 pigs that were divided into two groups (the control and study groups). Incisions and suturing of the bile ducts were performed in the two groups. Tamoxifen (20 mg/day) was administered only to the study group. The animals were sacrificed after 30 days. Quantification of myofibroblasts in the biliary ducts was made through immunohistochemistry analysis using anti-alpha smooth muscle actin of the smooth muscle antibody. Immunohistochemical quantification was performed using a digital image system. RESULTS: In the animals treated with tamoxifen (20 mg/day), there was a significant reduction in immunostaining for alpha smooth muscle actin compared with the control group (0.1155 vs. 0.2021, p = 0.046). CONCLUSION: Tamoxifen reduced the expression of alpha smooth muscle actin in the healing tissue after bile duct injury, suggesting a decrease in myofibroblasts in the scarred area of the pig biliary tract. These data suggest that tamoxifen could be used in the prevention of biliary tract stenosis after bile duct surgeries. PMID:23420165

  13. Phenomenon of hot-cold hemolysis: chelator-induced lysis of sphingomyelinase-treated erythrocytes.

    PubMed Central

    Smyth, C J; Möllby, R; Wadström, T

    1975-01-01

    Staphylococcus aureus produces a phospholipase C specific for sphingomyelin (beta-hemolysin). Erythrocytes with approximately 50% sphingomyelin in their membranes, e.g., from sheep, have been shown to have up to 60% of this phospholipid hydrolyzed by this enzyme at 37 C in isotonic buffered saline without hemolysis. Cooling of sphingomyelinase C-treated erythrocytes to 4 C causes complete lysis of the cells, a phenomenon known as hot-cold hemolysis. The addition of ethylenediaminetetraacetate (EDTA) to sheep erythrocytes preincubated with sphingomyelinase C was found to induce rapid hemolysis at 37 C. The treated cells became susceptible to chelator-induced hemolysis and to hot-cold hemolysis simultaneously, and the degree of lysis of both mechanisms increased equally with prolonged preincubation with sphingomyelinase C. Erythrocytes of species not readily susceptible to hot-cold hemolysis were equally insusceptible to chelator-induced lysis. Chelators of the EDTA series were the most effective, whereas chelators more specific for Ca2+, Zn2+, Fe2+, Cu2+, and Mg2+ were without effect. The rate of chelator-induced lysis was dependent on the preincubation period with beta-hemolysin and on the concentration of chelator added. The optimal concentration of EDTA was found to equal the amount of exogenously added Mg2+, a cation necessary for sphingomyelinase C activity. Hypotonicity increased the rate of chelator-induced hemolysis, whereas increasing the osmotic pressure to twice isotonic completely inhibited chelator-induced lysis. The data suggest that exogenously added and/or membrane-bound divalent cations are important for the stability of sphingomyelin-depleted membranes. The phenomenon of hot-cold hemolysis may be a consequence of the temperature dependence of divalent ion stabilization. Images PMID:333

  14. CYP2D6 genotype in relation to tamoxifen efficacy in a Dutch cohort of the tamoxifen exemestane adjuvant multinational (TEAM) trial.

    PubMed

    Dezentjé, V O; van Schaik, R H N; Vletter-Bogaartz, J M; van der Straaten, T; Wessels, J A M; Kranenbarg, E M-K; Berns, E M; Seynaeve, C; Putter, H; van de Velde, C J H; Nortier, J W R; Gelderblom, H; Guchelaar, H-J

    2013-07-01

    The clinical importance of CYP2D6 genotype as predictor of tamoxifen efficacy is still unclear. Recent genotyping studies on CYP2D6 using DNA derived from tumor blocks have been criticized because loss of heterozygosity (LOH) in tumors may lead to false genotype assignment. Postmenopausal early breast cancer patients who were randomized to receive tamoxifen, followed by exemestane in a large randomized controlled trial were genotyped for five CYP2D6 alleles. CYP2D6 genotypes and phenotypes were related to disease-free survival during tamoxifen use (DFS-t) in 731 patients. By analyzing microsatellites flanking the CYP2D6 gene, patients whose genotyping results were potentially affected by LOH were excluded. In addition, exploratory analyses on 24 genetic variants of other metabolic enzymes and the estrogen receptor were performed. For the CYP2D6 analysis, only 2.3 % of the samples were excluded, because influence of LOH could not be ruled out. No association was found between the CYP2D6 genotype or predicted phenotype and DFS-t (poor vs. extensive metabolizers: unadjusted hazard ratio 1.33, 95 % CI 0.52-3.43; P = 0.55). DFS-t was associated with UGT2B15*2 (Vt/Vt + Wt/Vt vs. Wt/Wt: adjusted hazard ratio 0.47, 95 % CI 0.25-0.89; P = 0.019) and the estrogen receptor-1 polymorphism ESR1 PvuII (gene-dose effect: adjusted hazard ratio 1.63, 95 % CI 1.04-2.54; P = 0.033). In postmenopausal early breast cancer patients treated with adjuvant tamoxifen followed by exemestane neither CYP2D6 genotype nor phenotype did affect DFS-t. This is in accordance with two recent studies in the BIG1-98 and ATAC trials. Our study is the first CYP2D6 association study using DNA from paraffin-embedded tumor tissue in which potentially false interpretation of genotyping results because of LOH was excluded. Polymorphisms in the estrogen receptor-1 and UGT2B15 may be associated with tamoxifen efficacy, but these findings need replication.

  15. Cognitive function in postmenopausal women receiving adjuvant letrozole or tamoxifen for breast cancer in the BIG 1-98 randomized trial

    PubMed Central

    Phillips, Kelly Anne; Ribi, Karin; Sun, Zhuoxin; Stephens, Alisa; Thompson, Alastair; Harvey, Vernon; Thürlimann, Beat; Cardoso, Fatima; Pagani, Olivia; Coates, Alan S.; Goldhirsch, Aron; Price, Karen N.; Gelber, Richard D.; Bernhard, Jürg

    2010-01-01

    Summary Cognitive function in postmenopausal women receiving letrozole or tamoxifen as adjuvant endocrine treatment was compared during the fifth year of treatment in a substudy of the BIG 1-98 trial. In BIG 1-98 patients were randomized to receive adjuvant A) 5-years tamoxifen, B) 5-years letrozole, C) 2-years tamoxifen followed by 3-years letrozole, or D) 2-years letrozole followed by 3-years tamoxifen. The primary comparison was the difference in composite score for patients taking letrozole (B+C; N=65) versus tamoxifen (A+D; N=55). The patients taking letrozole had better overall cognitive function than those taking tamoxifen (difference in mean composite z-scores =0.28, p=0.04, 95% CI:0.02, 0.54, Cohen's D = 0.40 indicating small to moderate effect). In this substudy, breast cancer patients taking adjuvant letrozole during the fifth year of treatment had better cognitive function than those taking tamoxifen, suggesting aromatase inhibitors do not adversely impact cognition compared with tamoxifen. PMID:20385495

  16. ESR1 Promoter Hypermethylation Does Not Predict Atypia in RPFNA nor Persistent Atypia after 12 Months Tamoxifen Chemoprevention

    PubMed Central

    Baker, Joseph C.; Ostrander, Julie H.; Lem, Siya; Broadwater, Gloria; Bean, Gregory R.; D'Amato, Nicholas C.; Goldenberg, Vanessa K.; Rowell, Craig; Ibarra-Drendall, Catherine; Grant, Tracey; Pilie, Patrick G.; Vasilatos, Shauna N.; Troch, Michelle M.; Scott, Victoria; Wilke, Lee G.; Paisie, Carolyn; Rabiner, Sarah M.; Torres-Hernandez, Alejandro; Zalles, Carola M.; Seewaldt, Victoria L.

    2009-01-01

    Purpose Currently, we lack biomarkers to predict whether high-risk women with mammary atypia will respond to tamoxifen chemoprevention. Experimental Design Thirty-four women with cytologic mammary atypia from the Duke University High-Risk clinic were offered tamoxifen chemoprevention. We tested whether ESR1 promoter hypermethylation and/or estrogen receptor (ER) protein expression by immunohistochemistry predicted persistent atypia in 18 women who were treated with tamoxifen for 12 months and in 16 untreated controls. Results We observed a statistically significant decrease in the Masood score of women on tamoxifen chemoprevention for 12 months compared with control women. This was a significant interaction effect of time (0, 6, and 12 months) and treatment group (tamoxifen versus control) P = 0.0007. However, neither ESR1 promoter hypermethylation nor low ER expression predicted persistent atypia in Random Periareolar Fine Needle Aspiration after 12 months tamoxifen prevention. Conclusions Results from this single institution pilot study provide evidence that, unlike for invasive breast cancer, ESR1 promoter hypermethylation and/or low ER expression is not a reliable marker of tamoxifen-resistant atypia. PMID:18708376

  17. Relationship between Genotypes Sult1a2 and Cyp2d6 and Tamoxifen Metabolism in Breast Cancer Patients

    PubMed Central

    Fernández-Santander, Ana; Gaibar, María; Novillo, Apolonia; Romero-Lorca, Alicia; Rubio, Margarita; Chicharro, Luis Miguel; Tejerina, Armando; Bandrés, Fernando

    2013-01-01

    Tamoxifen is a pro-drug widely used in breast cancer patients to prevent tumor recurrence. Prior work has revealed a role of cytochrome and sulfotransferase enzymes in tamoxifen metabolism. In this descriptive study, correlations were examined between concentrations of tamoxifen metabolites and genotypes for CYP2D6, CYP3A4, CYP3A5, SULT1A1, SULT1A2 and SULT1E1 in 135 patients with estrogen receptor-positive breast cancer. Patients were genotyped using the Roche-AmpliChip® CYP450 Test, and Real-Time and conventional PCR-RFLP. Plasma tamoxifen, 4-hydroxy-tamoxifen, N-desmethyl-tamoxifen, endoxifen and tamoxifen-N-oxide were isolated and quantified using a high-pressure liquid chromatography-tandem mass spectrometry system. Significantly higher endoxifen levels were detected in patients with the wt/wt CYP2D6 compared to the v/v CYP2D6 genotype (p<0.001). No differences were detected in the remaining tamoxifen metabolites among CYP2D6 genotypes. Patients featuring the SULT1A2*2 and SULT1A2*3 alleles showed significantly higher plasma levels of 4-hydroxy-tamoxifen and endoxifen (p = 0.025 and p = 0.006, respectively), as likely substrates of the SULT1A2 enzyme. Our observations indicate that besides the CYP2D6 genotype leading to tamoxifen conversion to potent hydroxylated metabolites in a manner consistent with a gene-dose effect, SULT1A2 also seems to play a role in maintaining optimal levels of both 4-hydroxy-tamoxifen and endoxifen. PMID:23922954

  18. Tamoxifen induces the expression of maspin through estrogen receptor-alpha.

    PubMed

    Liu, Zesheng; Shi, Heidi Y; Nawaz, Zafar; Zhang, Ming

    2004-06-08

    Maspin (mammary serine protease inhibitor) is a tumor suppressor gene that plays an important role in inhibiting tumor growth, invasion and metastasis. Maspin expression is down regulated at transcription level in primary and metastatic breast tumor cells. Previous studies on hormonal regulation of maspin prompt us to test whether an estrogen antagonist tamoxifen (TAM) can exert its anti-tumor function by up regulating maspin gene expression. For this purpose, we first tested whether maspin promoter could be activated in normal and several breast tumor cells. We then carried out a series of promoter analysis in which estrogen receptors and TAM were reconstituted in an in vitro cell culture system. Here we report our new finding that tumor suppresser gene maspin is one of the TAM target genes. TAM induces a maspin/luciferase reporter in cell culture and this induction requires the presence of (estrogen receptor alpha) ERalpha but not estrogen receptor-beta (ERbeta). Maspin promoter deletion and mutation analysis showed that the cis element(s) within a region between -90and+87 bp but not the HRE site (-272 bp) was involved in TAM induction of maspin expression. TAM bound ERalpha may directly control maspin gene expression through the interaction with cofactor (s). Analysis using several ERalpha mutants showed that the N-terminal A/B motif (AF-1) was critical for maspin basal level transcription activation. An ERalpha mutant with point mutations at DNA binding domain abolished estrogen induction of an ERE-luciferase reporter but was still active in activating maspin promoter by TAM. LBD-AF2 domain was required for ERalpha-dependent TAM induction. Deletion of LBD-AF2 or a point mutation in the ERalpha LBD-AF2 region (LBDmtL539A) completely abolished the activation of maspin promoter, suggesting that TAM induction of maspin involves the recruitment of cofactor(s) by ERalpha to the maspin promoter region. This finding indicates that one of the pathways for cancer

  19. FLASH Interface; a GUI for managing runtime parameters in FLASH simulations

    NASA Astrophysics Data System (ADS)

    Walker, Christopher; Tzeferacos, Petros; Weide, Klaus; Lamb, Donald; Flocke, Norbert; Feister, Scott

    2017-10-01

    We present FLASH Interface, a novel graphical user interface (GUI) for managing runtime parameters in simulations performed with the FLASH code. FLASH Interface supports full text search of available parameters; provides descriptions of each parameter's role and function; allows for the filtering of parameters based on categories; performs input validation; and maintains all comments and non-parameter information already present in existing parameter files. The GUI can be used to edit existing parameter files or generate new ones. FLASH Interface is open source and was implemented with the Electron framework, making it available on Mac OSX, Windows, and Linux operating systems. The new interface lowers the entry barrier for new FLASH users and provides an easy-to-use tool for experienced FLASH simulators. U.S. Department of Energy (DOE), NNSA ASC/Alliances Center for Astrophysical Thermonuclear Flashes, U.S. DOE NNSA ASC through the Argonne Institute for Computing in Science, U.S. National Science Foundation.

  20. The effect of tamoxifen on pubertal bone development in adolescents with pubertal gynecomastia.

    PubMed

    Akgül, Sinem; Derman, Orhan; Kanbur, Nuray

    2016-01-01

    During puberty, estrogen has a biphasic effect on epiphyses; at low levels, it leads to an increase in height and bone mass, whereas at high levels, it leads to closure of the epiphysis. Tamoxifen is a selective estrogen receptor modulator that has been used in the treatment of pubertal gynecomastia. Although it has not been approved for this indication, studies have shown it to be both successful and safe. In males, the peak of pubertal bone development occurs during Tanner stage 3-4, which is also when pubertal gynecomastia reaches its highest prevalence. Thus tamoxifen treatment could potentially effect pubertal bone development. The aim of this study was to assess the effects of tamoxifen on bone mineral density (BMD) and skeletal maturation when used for pubertal gynecomastia. We evaluated 20 boys with pubertal gynecomastia receiving tamoxifen for at least 4 months. BMD was measured with dual-energy X-ray absorptiometry. Z-score and absolute BMD (g/cm(2)) was determined at baseline and 2 months after completing tamoxifen treatment. Bone age and height was evaluated before treatment and again one year later. Using absolute BMD (g/cm(2)), the mean difference from baseline was significant between the two groups both at spine (p=0.002) and femur (p=0.001), but not with the Z-score. This result was attributed to the expected increase during puberty according to sex and age. No significant effect on skeletal maturation was found (p=1.112). We conclude that when pubertal bone development is concerned, tamoxifen is safe for the treatment of pubertal gynecomastia as neither bone mineralization nor growth potential was affected.

  1. Flash Platform Examination

    DTIC Science & Technology

    2011-03-01

    than would be performed in software”[108]. Uro Tinic, one of the Flash player’s engineers, further clarifies exactly what Flash player 10 hardware...www.adobe.com/products/flashplayer/features/ (Access date: 28 Sep 2009). [109] Uro , T. What Does GPU Acceleration Mean? (online), http...133] Shorten, A. (2009), Design to Development: Flash Catalyst to Flash Builder, In Proceedings of Adobe Max 2009, Los Angeles, CA. 142 DRDC

  2. Flash photolysis of rhodopsin in the cat retina

    PubMed Central

    1981-01-01

    The bleaching of rhodopsin by short-duration flashes of a xenon discharge lamp was studied in vivo in the cat retina with the aid of a rapid, spectral-scan fundus reflectometer. Difference spectra recorded over a broad range of intensities showed that the bleaching efficacy of high-intensity flashes was less than that of longer duration, steady lights delivering the same amount of energy. Both the empirical results and those derived from a theoretical analysis of flash photolysis indicate that, under the conditions of these experiments, the upper limit of the flash bleaching of rhodopsin in cat is approximately 90%. Although the fact that a full bleach could not be attained is attributable to photoreversal, i.e., the photic regeneration of rhodopsin from its light-sensitive intermediates, the 90% limit is considerably higher than the 50% (or lower) value obtained under other experimental circumstances. Thus, it appears that the duration (approximately 1 ms) and spectral composition of the flash, coupled with the kinetic parameters of the thermal and photic reactions in the cat retina, reduce the light-induced regeneration of rhodopsin to approximately 10%. PMID:7252476

  3. Integrative Analysis of Response to Tamoxifen Treatment in ER-Positive Breast Cancer Using GWAS Information and Transcription Profiling.

    PubMed

    Hicks, Chindo; Kumar, Ranjit; Pannuti, Antonio; Miele, Lucio

    2012-01-01

    Variable response and resistance to tamoxifen treatment in breast cancer patients remains a major clinical problem. To determine whether genes and biological pathways containing SNPs associated with risk for breast cancer are dysregulated in response to tamoxifen treatment, we performed analysis combining information from 43 genome-wide association studies with gene expression data from 298 ER(+) breast cancer patients treated with tamoxifen and 125 ER(+) controls. We identified 95 genes which distinguished tamoxifen treated patients from controls. Additionally, we identified 54 genes which stratified tamoxifen treated patients into two distinct groups. We identified biological pathways containing SNPs associated with risk for breast cancer, which were dysregulated in response to tamoxifen treatment. Key pathways identified included the apoptosis, P53, NFkB, DNA repair and cell cycle pathways. Combining GWAS with transcription profiling provides a unified approach for associating GWAS findings with response to drug treatment and identification of potential drug targets.

  4. Tamoxifen Alters the Plasma Concentration of Molecules Associated with Cardiovascular Risk in Women with Breast Cancer Undergoing Chemotherapy

    PubMed Central

    Romero, Walckiria G.; Da Silva, Fabrício B.; Borgo, Mariana V.; Bissoli, Nazaré S.; Gouvêa, Sonia A.

    2012-01-01

    Objectives. The objective of this study was to evaluate the effect of tamoxifen on blood markers that are associated with cardiovascular risk, such as C-reactive protein (CRP), apolipoprotein A-1 (Apo-A), and apolipoprotein B-100 (Apo-B), in women undergoing chemotherapy for breast cancer. Methods. Over a period of 12 months, we followed 60 women with breast cancer. The women were divided into the following groups: a group that received only chemotherapy (n = 23), a group that received chemotherapy plus tamoxifen (n = 21), and a group that received only tamoxifen (n = 16). Plasma CRP levels were assessed at 0, 3, 6, and 12 months, and Apo-A and Apo B levels as well as the Apo-B/Apo-A ratio were assessed at 0 and 12 months. Results. We found increases in the plasma concentration of CRP in the chemotherapy alone and chemotherapy plus tamoxifen groups after 3 and 6 months of treatment (before the introduction of tamoxifen). However, after 12 months of treatment, women who used tamoxifen (the chemotherapy plus tamoxifen and tamoxifen alone groups) showed a significant reduction in CRP and Apo-B levels and a decrease in the Apo-B/Apo-A ratio. A significant increase in serum Apo-A levels was observed in the group receiving chemotherapy alone as a treatment for breast cancer. Conclusion. The use of tamoxifen after chemotherapy for the treatment of breast cancer significantly reduces the levels of cardiovascular disease risk markers (CRP, Apo-B, and the Apo-B/Apo-A ratio). PMID:22491005

  5. Hot days induced by precipitation deficits at the global scale

    PubMed Central

    Mueller, Brigitte; Seneviratne, Sonia I.

    2012-01-01

    Global warming increases the occurrence probability of hot extremes, and improving the predictability of such events is thus becoming of critical importance. Hot extremes have been shown to be induced by surface moisture deficits in some regions. In this study, we assess whether such a relationship holds at the global scale. We find that wide areas of the world display a strong relationship between the number of hot days in the regions’ hottest month and preceding precipitation deficits. The occurrence probability of an above-average number of hot days is over 70% after precipitation deficits in most parts of South America as well as the Iberian Peninsula and Eastern Australia, and over 60% in most of North America and Eastern Europe, while it is below 30–40% after wet conditions in these regions. Using quantile regression analyses, we show that the impact of precipitation deficits on the number of hot days is asymmetric, i.e. extreme high numbers of hot days are most strongly influenced. This relationship also applies to the 2011 extreme event in Texas. These findings suggest that effects of soil moisture-temperature coupling are geographically more widespread than commonly assumed. PMID:22802672

  6. Flashes and Floaters.

    PubMed

    Sharma, Priya; Sridhar, Jayanth; Mehta, Sonia

    2015-09-01

    Flashes and floaters are common ocular complaints. Flashes refer to aberrations of light that are seen in a patient's field of gaze. The flashes can be of varying sizes, colors, frequency, and durations, depending on the cause. Floaters are another common visual phenomenon caused by particles or debris in the vitreous gel of the eye that cause shadows and thus visual changes, especially against bright backgrounds and in brightly lit environments. Flashes and floaters can occur individually or together. This article discusses common causes of flashes and floaters to help with the triaging and management of these patients. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. Automated Studies of Continuing Current in Lightning Flashes

    NASA Astrophysics Data System (ADS)

    Martinez-Claros, Jose

    Continuing current (CC) is a continuous luminosity in the lightning channel that lasts longer than 10 ms following a lightning return stroke to ground. Lightning flashes following CC are associated with direct damage to power lines and are thought to be responsible for causing lightning-induced forest fires. The development of an algorithm that automates continuing current detection by combining NLDN (National Lightning Detection Network) and LEFA (Langmuir Electric Field Array) datasets for CG flashes will be discussed. The algorithm was applied to thousands of cloud-to-ground (CG) flashes within 40 km of Langmuir Lab, New Mexico measured during the 2013 monsoon season. It counts the number of flashes in a single minute of data and the number of return strokes of an individual lightning flash; records the time and location of each return stroke; performs peak analysis on E-field data, and uses the slope of interstroke interval (ISI) E-field data fits to recognize whether continuing current (CC) exists within the interval. Following CC detection, duration and magnitude are measured. The longest observed C in 5588 flashes was 631 ms. The performance of the algorithm (vs. human judgement) was checked on 100 flashes. At best, the reported algorithm is "correct" 80% of the time, where correct means that multiple stations agree with each other and with a human on both the presence and duration of CC. Of the 100 flashes that were validated against human judgement, 62% were hybrid. Automated analysis detects the first but misses the second return stroke in many cases where the second return stroke is followed by long CC. This problem is also present in human interpretation of field change records.

  8. [Ultrahigh dose-rate, "flash" irradiation minimizes the side-effects of radiotherapy].

    PubMed

    Favaudon, V; Fouillade, C; Vozenin, M-C

    2015-10-01

    Pencil beam scanning and filter free techniques may involve dose-rates considerably higher than those used in conventional external-beam radiotherapy. Our purpose was to investigate normal tissue and tumour responses in vivo to short pulses of radiation. C57BL/6J mice were exposed to bilateral thorax irradiation using pulsed (at least 40 Gy/s, flash) or conventional dose-rate irradiation (0.03 Gy/s or less) in single dose. Immunohistochemical and histological methods were used to compare early radio-induced apoptosis and the development of lung fibrosis in the two situations. The response of two human (HBCx-12A, HEp-2) tumour xenografts in nude mice and one syngeneic, orthotopic lung carcinoma in C57BL/6J mice (TC-1 Luc+), was monitored in both radiation modes. A 17 Gy conventional irradiation induced pulmonary fibrosis and activation of the TGF-beta cascade in 100% of the animals 24-36 weeks post-treatment, as expected, whereas no animal developed complications below 23 Gy flash irradiation, and a 30 Gy flash irradiation was required to induce the same extent of fibrosis as 17 Gy conventional irradiation. Cutaneous lesions were also reduced in severity. Flash irradiation protected vascular and bronchial smooth muscle cells as well as epithelial cells of bronchi against acute apoptosis as shown by analysis of caspase-3 activation and TUNEL staining. In contrast, the antitumour effectiveness of flash irradiation was maintained and not different from that of conventional irradiation. Flash irradiation shifted by a large factor the threshold dose required to initiate lung fibrosis without loss of the antitumour efficiency, suggesting that the method might be used to advantage to minimize the complications of radiotherapy. Copyright © 2015 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.

  9. Non-Smad TGF-β signaling components are possible biomarkers of tamoxifen resistance

    NASA Astrophysics Data System (ADS)

    Babyshkina, N.; Zavyalova, M.; Patalyak, S.; Dronova, T.; Slonimskaya, E.; Cherdyntseva, N.

    2017-09-01

    A crosstalk between the estrogen receptor alpha (ERα) and tyrosine kinase receptors contribute to endocrine resistance. We investigated the effect of the four Smad-independent TGF-β signaling components and the distribution pattern of ERα expression on the response to adjuvant tamoxifen treatment in 122 estrogen positive breast cancer patients. We identified a low mRNA expression of TGF-βR1 in tamoxifen resistant group patients (TR) in contrast to tamoxifen sensitive group (TS). Similarly, negative TGF-βR1 expression was significantly higher in TR patients than in TS patients. The expression of TGF-βR1 was strongly correlated with the distribution pattern of ERα expression, level of CD44+/CD24-/low cells and Akt (pS473) expression. The patients with a low mRNA expression of TGF-βR1 as well as with a negative TGF-βR1 expression had an unfavorable prognosis concerning progression-free survival. The expression of TGF-βR1 and the distribution pattern of ERα expression can be considered as additional molecular predictive markers for estrogen positive breast cancer patients treated with adjuvant tamoxifen.

  10. Approaches for predicting effects of unintended environmental exposure to an endocrine active pharmaceutical, tamoxifen

    EPA Science Inventory

    Tamoxifen is an endocrine-active pharmaceutical (EAP) that is used world-wide. Because tamoxifen is a ubiquitous pharmaceutical and interacts with estrogen receptors, a case study was conducted with this compound to (1) determine effects on reproductive endpoints in a nontarget s...

  11. Use of dried blood spots for the determination of serum concentrations of tamoxifen and endoxifen.

    PubMed

    Jager, N G L; Rosing, H; Schellens, J H M; Beijnen, J H; Linn, S C

    2014-07-01

    The anti-estrogenic effect of tamoxifen is suggested to be mainly attributable to its metabolite (Z)-endoxifen, and a minimum therapeutic threshold for (Z)-endoxifen in serum has been proposed. The objective of this research was to establish the relationship between dried blood spot (DBS) and serum concentrations of tamoxifen and (Z)-endoxifen to allow the use of DBS sampling, a simple and patient-friendly alternative to venous sampling, in clinical practice. Paired DBS and serum samples were obtained from 50 patients using tamoxifen and analyzed using HPLC-MS/MS. Serum concentrations were calculated from DBS concentrations using the formula calculated serum concentration = DBS concentration/([1-haematocrit (Hct)] + blood cell-to-serum ratio × Hct). The blood cell-to-serum ratio was determined ex vivo by incubating a batch of whole blood spiked with both analytes. The average Hct for female adults was imputed as a fixed value. Calculated and analyzed serum concentrations were compared using weighted Deming regression. Weighted Deming regression analysis comparing 44 matching pairs of DBS and serum samples showed a proportional bias for both analytes. Serum concentrations were calculated using [Tamoxifen] serum, calculated  = [Tamoxifen] DBS /0.779 and [(Z)-Endoxifen] serum, calculated = [(Z)-Endoxifen] DBS /0.663. Calculated serum concentrations were within 20 % of analyzed serum concentrations in 84 and 100 % of patient samples for tamoxifen and (Z)-endoxifen, respectively. In conclusion, DBS concentrations of tamoxifen and (Z)-endoxifen were equal to serum concentrations after correction for Hct and blood cell-to-serum ratio. DBS sampling can be used in clinical practice.

  12. The impact of tamoxifen brand switch on side effects and patient compliance in hormone receptor positive breast cancer patients.

    PubMed

    Zeidan, B; Anderson, K; Peiris, L; Rainsbury, D; Laws, S

    2016-10-01

    In 2006 Nolvadex was discontinued and replaced by a variety of alternative generic tamoxifen brands for the adjuvant treatment of breast cancer. Anecdotally, patients are switching brands and taking alternative medications to reduce treatment related symptoms. Nevertheless, more severe side effects may equate to better relapse prevention. This study evaluates generic tamoxifen adherence and its correlation with side effects and brand switch. Consecutive disease free ER positive patients (stage I-III) were invited to respond to a questionnaire. 165 of 327 questionnaires were returned (50% response). Pearson's Chi Square test was used for data analysis. 63 patients (38%) reported a switch between generic tamoxifen. 59% of all patients experienced side effects associated with tamoxifen treatment of which 53% were severe. Patients experiencing differential symptoms dependent on tamoxifen brand reported more severe side effects (p = 0.02). Non-prescribed supplements were taken by 42% of all patients with no significant improvement in climacteric symptoms (p = 0.05). The concomitant use of SSRIs appeared to have no effect on symptoms. A significant number of patients considered discontinuing tamoxifen because of the side effects (p = 0.001), yet this did not translate into discontinuation or non-adherence (p = 0.8 and 0.08 respectively). Severe tamoxifen side effects are commonly experienced by breast cancer patients and can be significantly altered by change in tamoxifen brand. Most patients will continue to take tamoxifen, despite side effects to avoid cancer relapse. Supplementation and antidepressants did not improve tamoxifen related side effects in our cohort. Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.

  13. The Relation between Hot Flashes and Ambulatory Blood Pressure: The Hilo Women’s Health Study

    PubMed Central

    Brown, Daniel E.; Sievert, Lynnette L.; Morrison, Lynn A.; Rahberg, Nichole; Reza, Angela

    2011-01-01

    Objectives Hot flashes (HFs) have been associated with elevated blood pressure, but studies have not examined the relationship between objectively measured HFs and blood pressure during normal daily activities. The objectives of this study are to examine ambulatory blood pressure (BP) differences between women who report HFs and those who do not, and to observe whether an objectively measured HF is associated with transient changes in BP. Methods A sample of 202 women in Hilo, Hawaii aged 45–55 years were asked to fill out a questionnaire that included demographic information and an inventory of symptoms. The women underwent simultaneous 24-hour monitoring of ambulatory BP and HFs, while keeping a diary that included mood and HF reports. Results No significant difference was present in mean BP between women who reported having a HF during the past 2 weeks and those who did not. When measurements controlled for negative mood reports and posture, there was a highly significant elevation in Z scores of systolic BP when a measured, objective HF occurred within 10 minutes preceding a BP reading, and a significant elevation of Z scores of diastolic BP when a subjectively reported HF occurred within 10 minutes after a BP reading. Conclusions These results suggest that objectively measured HFs precede transient elevations of systolic BP, but it is unclear if there is a causal relationship. These results also suggest that women experience subjective HFs within 10 minutes after a transient increase in diastolic BP. Again, the causal relationship is not understood. PMID:21183716

  14. Stimulating the GPR30 estrogen receptor with a novel tamoxifen analogue activates SF-1 and promotes endometrial cell proliferation.

    PubMed

    Lin, Benjamin C; Suzawa, Miyuki; Blind, Raymond D; Tobias, Sandra C; Bulun, Serdar E; Scanlan, Thomas S; Ingraham, Holly A

    2009-07-01

    Estrogens and selective estrogen receptor (ER) modulators such as tamoxifen are known to increase uterine cell proliferation. Mounting evidence suggests that estrogen signaling is mediated not only by ERalpha and ERbeta nuclear receptors, but also by GPR30 (GPER), a seven transmembrane (7TM) receptor. Here, we report that primary human endometriotic H-38 cells express high levels of GPR30 with no detectable ERalpha or ERbeta. Using a novel tamoxifen analogue, STX, which activates GPR30 but not ERs, significant stimulation of the phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways was observed in H-38 cells and in Ishikawa endometrial cancer cells expressing GPR30; a similar effect was observed in JEG3 choriocarcinoma cells. STX treatment also increased cellular pools of phosphatidylinositol (3,4,5) triphosphate, a proposed ligand for the nuclear hormone receptor SF-1 (NR5A1). Consistent with these findings, STX, tamoxifen, and the phytoestrogen genistein were able to increase SF-1 transcription, promote Ishikawa cell proliferation, and induce the SF-1 target gene aromatase in a GPR30-dependent manner. Our findings suggest a novel signaling paradigm that is initiated by estrogen activation of the 7TM receptor GPR30, with signal transduction cascades (PI3K and MAPK) converging on nuclear hormone receptors (SF-1/LRH-1) to modulate their transcriptional output. We propose that this novel GPR30/SF-1 pathway increases local concentrations of estrogen, and together with classic ER signaling, mediate the proliferative effects of synthetic estrogens such as tamoxifen, in promoting endometriosis and endometrial cancers.

  15. Structural insights into selective agonist actions of tamoxifen on human estrogen receptor alpha.

    PubMed

    Chakraborty, Sandipan; Biswas, Pradip Kumar

    2014-08-01

    Tamoxifen-an anti-estrogenic ligand in breast tissues used as a first-line treatment in estrogen receptor (ER)-positive breast cancers-is associated with the development of resistance followed by resumption of tumor growth in about 30 % of cases. Whether tamoxifen assists in proliferation in such cases or whether any ligand-independent pathway to transcription exists is not fully understood; also, no ERα mutants have been detected so far that could lead to tamoxifen resistance. Using in silico conformational analysis of the ERα ligand binding domain (LBD), in the absence and presence of selective agonist (diethylstilbestrol; DES), antagonist (Faslodex; ICI), and selective estrogen receptor modulator (SERM; 4-hydroxy tamoxifen; 4-OHT) ligands, we have elucidated ligand-responsive structural modulations of the ERα-LBD dimer in its agonist and antagonist complexes to address the issue of "tamoxifen resistance". DES and ICI were found to stabilize the dimer in their agonist and antagonist conformations, respectively. The ERα-LBD dimer without the presence of any bound ligand also led to a stable structure in agonist conformation. However, binding of 4-OHT to the antagonist structure led to a flexible conformation allowing the protein to visit conformations populated by agonists as was evident from principal component analysis and radius of gyration plots. Further, the relaxed conformations of the 4-OHT bound protein exhibited a diminished size of the co-repressor binding pocket in the LBD, thus signaling a partial blockage of the co-repressor binding motif. Thus, the ability of 4-OHT-bound ERα-LBD to assume flexible conformations visited by agonists and reduced co-repressor binding surface at the LBD provide crucial structural insights into tamoxifen-resistance that complement our existing understanding.

  16. Bioconcentration of (15)N-tamoxifen at environmental concentration in liver, gonad and muscle of Danio rerio.

    PubMed

    Orias, Frédéric; Simon, Laurent; Mialdea, Gladys; Clair, Angéline; Brosselin, Vanessa; Perrodin, Yves

    2015-10-01

    Pharmaceutical compounds (PCs) are ubiquitous in aquatic ecosystems. In addition to the direct ecotoxicological risk presented by certain PCs, others can accumulate inside organisms and along trophic webs, subsequently contaminating whole ecosystems. We studied the bioconcentration of a bioaccumulative PC already found several times in the environment: tamoxifen. To this end, we exposed Danio rerio for 21d to (15)N-tamoxifen concentrations ranging from 0.1 to 10µg/L and used an analytic method based on stable isotopes to evaluate the tamoxifen content in these organisms. The evolution of the (15)N/(14)N ratio was thus measured in liver, muscle and gonads of exposed fish compared to control fish. We succeeded in quantifying (15)N-tamoxifen bioconcentrations at all the exposure concentrations tested. The highest bioconcentration factors of tamoxifen measured were 14,920 in muscle, 73,800 in liver and 85,600 in gonads of fish after 21d exposure at a nominal concentration of 10µg/L. However, these bioconcentration factors have to be considered as maximal values (BCFMAX). Indeed, despite its proven stability, tamoxifen can be potentially partially degraded during experiments. We now need to refine these results by using a direct analytic method (i.e. LC-MS/MS). Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Tamoxifen citrate loaded ethosomes for transdermal drug delivery system: preparation and characterization.

    PubMed

    Sarwa, Khomendra Kumar; Suresh, Preeti K; Debnath, Manabendra; Ahmad, Mohammad Zaki

    2013-08-01

    Long term tamoxifen citrate therapy is imperative to treat several dermatological and hormonal sensitive disorders. Successful oral and parenteral administration of tamoxifen citrate has been challenging since it undergoes enzymatic degradation and has poor aqueous solubility issues. In the present work, tamoxifen citrate loaded ethosomes were prepared and characterized for transdermal applications. The prepared formulations were characterized for morphological features, particle size distribution, calorimetric attributes, zeta potential and drug entrapment. Permeation profile of prepared ethosomes was compared with liposomes and hydroethonalic solution across cellophane membrane and human cadaver skin. Results of the permeation studies indicate that ethosomes were able to deliver >90% drug within 24 hours of application, while liposomes and hydroethanolic solution delivered only 39.04% and 36.55% respectively. Skin deposition and stability studies are also reported.

  18. Investigational study of tamoxifen phase I metabolites using chromatographic and spectroscopic analytical techniques.

    PubMed

    Teunissen, S F; Rosing, H; Seoane, M Dominguez; Brunsveld, L; Schellens, J H M; Schinkel, A H; Beijnen, J H

    2011-06-01

    A comprehensive overview is presented of currently known phase I metabolites of tamoxifen consisting of their systematic name and molecular structure. Reference standards are utilized to elucidate the MS(n) fragmentation patterns of these metabolites using a linear ion trap mass spectrometer. UV-absorption spectra are recorded and absorption maxima are defined. Serum extracts from ten breast cancer patients receiving 40mg tamoxifen once daily were qualitatively analyzed for tamoxifen phase I metabolites using a liquid chromatography-tandem mass spectrometry set-up. In total, 19 metabolites have been identified in these serum samples. Additionally a synthetic method for the preparation of the putative metabolite 3',4'-dihydroxytamoxifen is described. Copyright © 2011 Elsevier B.V. All rights reserved.

  19. Aspirin regulation of c-myc and cyclinD1 proteins to overcome tamoxifen resistance in estrogen receptor-positive breast cancer cells.

    PubMed

    Cheng, Ran; Liu, Ya-Jing; Cui, Jun-Wei; Yang, Man; Liu, Xiao-Ling; Li, Peng; Wang, Zhan; Zhu, Li-Zhang; Lu, Si-Yi; Zou, Li; Wu, Xiao-Qin; Li, Yu-Xia; Zhou, You; Fang, Zheng-Yu; Wei, Wei

    2017-05-02

    Tamoxifen is still the most commonly used endocrine therapy drug for estrogen receptor (ER)-positive breast cancer patients and has an excellent outcome, but tamoxifen resistance remains a great impediment to successful treatment. Recent studies have prompted an anti-tumor effect of aspirin. Here, we demonstrated that aspirin not only inhibits the growth of ER-positive breast cancer cell line MCF-7, especially when combined with tamoxifen, but also has a potential function to overcome tamoxifen resistance in MCF-7/TAM. Aspirin combined with tamoxifen can down regulate cyclinD1 and block cell cycle in G0/G1 phase. Besides, tamoxifen alone represses c-myc, progesterone receptor (PR) and cyclinD1 in MCF-7 cell line but not in MCF-7/TAM, while aspirin combined with tamoxifen can inhibit the expression of these proteins in the resistant cell line. When knocking down c-myc in MCF-7/TAM, cells become more sensitive to tamoxifen, cell cycle is blocked as well, indicating that aspirin can regulate c-myc and cyclinD1 proteins to overcome tamoxifen resistance. Our study discovered a novel role of aspirin based on its anti-tumor effect, and put forward some kinds of possible mechanisms of tamoxifen resistance in ER-positive breast cancer cells, providing a new strategy for the treatment of ER-positive breast carcinoma.

  20. Identification of a putative protein profile associating with tamoxifen therapy resistance in breast cancer

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Umar, Arzu; Kang, Hyuk; Timmermans, A. M.

    2009-06-01

    Tamoxifen-resistance is a major cause of death in patients with recurrent breast cancer. Current clinical factors can correctly predict therapy response in only half of the treated patients. Identification of proteins that associate with tamoxifen-resistance is a first step towards better response prediction and tailored treatment of patients. In the present study we intended to identify putative protein biomarkers indicative of tamoxifen therapy-resistance in breast cancer, using nanoLC coupled with FTICR MS. Comparative proteome analysis was performed on ~5,500 pooled tumor cells (corresponding to ~550 ng protein lysate/analysis) obtained through laser capture microdissection (LCM) from two independently processed data setsmore » (n=24 and n=27) containing both tamoxifen therapy-sensitive and therapy-resistant tumors. Peptides and proteins were identified by matching mass and elution time of newly acquired LC-MS features to information in previously generated accurate mass and time tag (AMT) reference databases.« less

  1. Flash protection controller

    DOEpatents

    Galbraith, L.K.

    1979-12-07

    A controller provides a high voltage to maintain an electro-optic shutter in a transparent condition until a flash of light which would be harmful to personnel is sensed by a phototransistor. The controller then shorts the shutter to ground to minimize light transmission to the user and maintains light transmission at the pre-flash level for a predetermined time to allow the flash to subside. A log converter and differential trigger circuit keep the controller from being triggered by other light flashes which are not dangerous.

  2. Flash protection controller

    DOEpatents

    Galbraith, Lee K.

    1981-01-01

    A controller provides a high voltage to maintain an electro-optic shutter in a transparent condition until a flash of light which would be harmful to personnel is sensed by a phototransistor. The controller then shorts the shutter to ground to minimize light transmission to the user and maintains light transmission at the pre-flash level for a predetermined time to allow the flash to subside. A log converter and differential trigger circuit keep the controller from being triggered by other light flashes which are not dangerous.

  3. Effects of tamoxifen on bone mineral density and metabolism in postmenopausal women with early-stage breast cancer.

    PubMed

    Zidan, Jamal; Keidar, Zohar; Basher, Walid; Israel, Ora

    2004-01-01

    At the present time, tamoxifen is the most widely used anti-estrogen for adjuvant therapy and metastatic disease in postmenopausal women with breast cancer, a population at high risk for osteoporosis. This prospective study was designed to evaluate the effect of adjuvant tamoxifen on bone mineral density and all biochemical markers concomitantly in women with early-stage breast cancer in one study. Using dual-energy X-ray absorptiometry, prior to and 12 mo after tamoxifen treatment, bone mineral density in lumbar spine and femoral neck was measured in 44 women with T1-T2N0M0 estrogen-receptor-positive breast cancer receiving adjuvant treatment with tamoxifen 20 mg/d. Biomarkers that can affect bone mineral metabolism were measured before and after 3 and 12 mo of tamoxifen treatment. Bone mineral density was minimally increased in lumbar spine and femoral neck after 12 mo treatment with tamoxifen (p = 0.79 and 0.55, respectively). No differences were found in serum levels of calcium, phosphate, creatinine, ALAT, albumin, LDH, calcitonin, or estradiol. A significant decrease in osteocalcin levels was found after 3 and 12 mo (p < or = 0.01). TSH and PTH levels were increased (p < or = 0.05) after 3 mo, returning to baseline after 12 mo. In conclusion, tamoxifen has an estrogen-like effect on bone metabolism in postmenopausal women and is associated with preservation of bone mineral density in lumbar spine and femoral neck. Changes in serum concentration of biochemical markers may reflect decreased bone turnover or bone remodeling and add to the understanding of tamoxifen's effect on bone mineral density.

  4. Tamoxifen and vitamin E treatments delay symptoms in the mouse model of Niemann-Pick C.

    PubMed

    Bascuñan-Castillo, Eric C; Erickson, Robert P; Howison, Christy M; Hunter, Robert J; Heidenreich, Randall H; Hicks, Chad; Trouard, Theodore P; Gillies, Robert J

    2004-01-01

    Niemann-Pick C disease (NPC) is an irreversible neurodegenerative disorder without current treatment. It is the result of deficient intracellular cholesterol movement. We investigated the effects of tamoxifen and vitamin E (D-alpha tocopherol) treatment on patterns of weight loss and motor function in the mouse model of Niemann-Pick C disease (Npc1-/- mice). Tamoxifen has multiple metabolic effects, including reducing oxidative damage, while vitamin E primarily has this property. Npc1-/- mice were identified and treatment was initiated at an approximate age of 21 days. Tamoxifen suspended in peanut oil was administered via intraperitoneal injection (weekly, at a dose calculated to deliver 0.023 microg/g/day). Vitamin E (25 IU) was administered orally via gavage once a week. Weight loss and Rota-Rod performance were analyzed by using Kaplan-Meyer survival curves. Tamoxifen treatment by itself significantly delayed weight loss (an endpoint of neurodegeneration) in male and female mice compared to untreated controls. Motor function was evaluated by performance on a Rota-Rod. Tamoxifen maintained Rota-Rod performance for about an extra week. Vitamin E treatment significantly delayed weight loss in females only. Rota-Rod performance was maintained slightly longer in mice treated with vitamin E. Simultaneous use of both treatments did not delay weight loss longer than tamoxifen-only treatment but had a greater effect than either treatment alone on Rota-Rod performance and demonstrated a significant positive effect on the early "learning curve" portion of the Rota-Rod evaluations. We found significant but relatively small improvements in rate of disease progression by treating Npc1-/- mice with tamoxifen and/or vitamin E. Some sex differences in response and an early improvement in Rota-Rod performance suggest areas for further study.

  5. Effect of tamoxifen on cholesterol synthesis in HepG2 cells and cultured rat hepatocytes.

    PubMed

    Holleran, A L; Lindenthal, B; Aldaghlas, T A; Kelleher, J K

    1998-12-01

    The objective of this study was to investigate the mechanisms by which tamoxifen modifies cholesterol metabolism in cellular models of liver metabolism, HepG2 cells and rat hepatocytes. The effect of tamoxifen on cholesterol and triglyceride-palmitate synthesis was measured using isotopomer spectral analysis (ISA) and gas chromatography-mass spectrometry (GC-MS) and compared with the effects of progesterone, estradiol, the antiestrogen ICI 182,780, and an oxysterol, 25-hydroxycholesterol (25OHC). Cholesterol synthesis in cells incubated in the presence of either [1-(13)C]acetate, [U-13C]glucose, or [4,5-(13)C]mevalonate for 48 hours was reduced in the presence of 10 micromol/L tamoxifen and 12.4 micromol/L 25OHC in both HepG2 cells and rat hepatocytes. The ISA methodology allowed a clear distinction between effects on synthesis and effects on precursor enrichment, and indicated that these compounds did not affect enrichment of the precursors of squalene. Progesterone was effective in both cell types at 30 micromol/L and only in HepG2 cells at 10 micromol/L. Estradiol and ICI 182,780 at 10 micromol/L did not inhibit cholesterol synthesis. None of the compounds altered the synthesis of triglyceride-palmitate in either cell type. Treatment of cells with tamoxifen produced accumulation of three sterol precursors of cholesterol, zymosterol, desmosterol, and delta8 cholesterol. This pattern of precursors indicates inhibition of delta24,25 reduction in addition to the previously described inhibition of delta8 isomerase. We conclude that tamoxifen is an effective inhibitor of the conversion of lanosterol to cholesterol in cellular models at concentrations comparable to those present in the plasma of tamoxifen-treated individuals. Our findings indicate that this mechanism may contribute to the effect of tamoxifen in reducing plasma cholesterol in humans.

  6. An Antiestrogenic Activity Score for tamoxifen and its metabolites is associated with breast cancer outcome

    PubMed Central

    Alexi, X.; van Werkhoven, E.; Madlensky, L.; Natarajan, L.; Flatt, S. W.; Zwart, W.; Linn, S. C.; Parker, B. A.; Wu, A. H. B.; Pierce, J. P.; Huitema, A. D. R.; Beijnen, J. H.

    2018-01-01

    Purpose Endoxifen concentrations have been associated with breast cancer recurrence in tamoxifen-treated patients. However, tamoxifen itself and other metabolites also show antiestrogenic anti-tumor activity. Therefore, the aim of this study was to develop a comprehensive Antiestrogenic Activity Score (AAS), which accounts for concentration and antiestrogenic activity of tamoxifen and three metabolites. An association between the AAS and recurrence-free survival was investigated and compared to a previously published threshold for endoxifen concentrations of 5.97 ng/mL. Patients and methods The antiestrogenic activities of tamoxifen, (Z)-endoxifen, (Z)-4-hydroxytamoxifen, and N-desmethyltamoxifen were determined in a cell proliferation assay. The AAS was determined by calculating the sum of each metabolite concentration multiplied by an IC50 ratio, relative to tamoxifen. The AAS was calculated for 1370 patients with estrogen receptor alpha (ERα)-positive breast cancer. An association between AAS and recurrence was investigated using Cox regression and compared with the 5.97 ng/mL endoxifen threshold using concordance indices. Results An AAS threshold of 1798 was associated with recurrence-free survival, hazard ratio (HR) 0.67 (95% confidence interval (CI) 0.47–0.96), bias corrected after bootstrap HR 0.69 (95% CI 0.48–0.99). The concordance indices for AAS and endoxifen did not significantly differ; however, using the AAS threshold instead of endoxifen led to different dose recommendations for 5.2% of the patients. Conclusions Endoxifen concentrations can serve as a proxy for the antiestrogenic effect of tamoxifen and metabolites. However, for the aggregate effect of tamoxifen and three metabolites, defined by an integrative algorithm, a trend towards improving treatment is seen and moreover, is significantly associated with breast cancer recurrence. PMID:28005246

  7. Lunar Impact Flash Locations

    NASA Technical Reports Server (NTRS)

    Moser, D. E.; Suggs, R. M.; Kupferschmidt, L.; Feldman, J.

    2015-01-01

    A bright impact flash detected by the NASA Lunar Impact Monitoring Program in March 2013 brought into focus the importance of determining the impact flash location. A process for locating the impact flash, and presumably its associated crater, was developed using commercially available software tools. The process was successfully applied to the March 2013 impact flash and put into production on an additional 300 impact flashes. The goal today: provide a description of the geolocation technique developed.

  8. Inhibition of Aerobic Glycolysis Represses Akt/mTOR/HIF-1α Axis and Restores Tamoxifen Sensitivity in Antiestrogen-Resistant Breast Cancer Cells

    PubMed Central

    Woo, Yu Mi; Shin, Yubin; Lee, Eun Ji; Lee, Sunyoung; Jeong, Seung Hun; Kong, Hyun Kyung; Park, Eun Young; Kim, Hyoung Kyu; Han, Jin; Chang, Minsun; Park, Jong-Hoon

    2015-01-01

    Tamoxifen resistance is often observed in the majority of estrogen receptor–positive breast cancers and it remains as a serious clinical problem in breast cancer management. Increased aerobic glycolysis has been proposed as one of the mechanisms for acquired resistance to chemotherapeutic agents in breast cancer cells such as adriamycin. Herein, we report that the glycolysis rates in LCC2 and LCC9—tamoxifen-resistant human breast cancer cell lines derived from MCF7— are higher than those in MCF7S, which is the parent MCF7 subline. Inhibition of key glycolytic enzyme such as hexokinase-2 resulted in cell growth retardation at higher degree in LCC2 and LCC9 than that in MCF7S. This implies that increased aerobic glycolysis even under O2-rich conditions, a phenomenon known as the Warburg effect, is closely associated with tamoxifen resistance. We found that HIF-1α is activated via an Akt/mTOR signaling pathway in LCC2 and LCC9 cells without hypoxic condition. Importantly, specific inhibition of hexokinase-2 suppressed the activity of Akt/mTOR/HIF-1α axis in LCC2 and LCC9 cells. In addition, the phosphorylated AMPK which is a negative regulator of mTOR was decreased in LCC2 and LCC9 cells compared to MCF7S. Interestingly, either the inhibition of mTOR activity or increase in AMPK activity induced a reduction in lactate accumulation and cell survival in the LCC2 and LCC9 cells. Taken together, our data provide evidence that development of tamoxifen resistance may be driven by HIF-1α hyperactivation via modulation of Akt/mTOR and/or AMPK signaling pathways. Therefore, we suggest that the HIF-1α hyperactivation is a critical marker of increased aerobic glycolysis in accordance with tamoxifen resistance and thus restoration of aerobic glycolysis may be novel therapeutic target for treatment of tamoxifen-resistant breast cancer. PMID:26158266

  9. Prescribing tamoxifen in primary care for the prevention of breast cancer: a national online survey of GPs' attitudes.

    PubMed

    Smith, Samuel G; Foy, Robbie; McGowan, Jennifer A; Kobayashi, Lindsay C; DeCensi, Andrea; Brown, Karen; Side, Lucy; Cuzick, Jack

    2017-06-01

    The cancer strategy for England (2015-2020) recommends GPs prescribe tamoxifen for breast cancer primary prevention among women at increased risk. To investigate GPs' attitudes towards prescribing tamoxifen. In an online survey, GPs in England, Northern Ireland, and Wales ( n = 928) were randomised using a 2 × 2 between-subjects design to read one of four vignettes describing a healthy patient seeking a tamoxifen prescription. In the vignette, the hypothetical patient's breast cancer risk (moderate versus high) and the clinician initiating the prescription (GP prescriber versus secondary care clinician [SCC] prescriber) were manipulated in a 1:1:1:1 ratio. Outcomes were willingness to prescribe, comfort discussing harms and benefits, comfort managing the patient, factors affecting the prescribing decision, and awareness of tamoxifen and the National Institute for Health and Care Excellence (NICE) guideline CG164. Half (51.7%) of the GPs knew tamoxifen can reduce breast cancer risk, and one-quarter (24.1%) were aware of NICE guideline CG164. Responders asked to initiate prescribing (GP prescriber) were less willing to prescribe tamoxifen than those continuing a prescription initiated in secondary care (SCC prescriber) (68.9% versus 84.6%, P <0.001). The GP prescribers reported less comfort discussing tamoxifen (53.4% versus 62.5%, P = 0.01). GPs willing to prescribe were more likely to be aware of the NICE guideline ( P = 0.039) and to have acknowledged the benefits of tamoxifen ( P <0.001), and were less likely to have considered its off-licence status ( P <0.001). Initiating tamoxifen prescriptions for preventive therapy in secondary care before asking GPs to continue the patient's care may overcome some prescribing barriers. © British Journal of General Practice 2017.

  10. THE INFLUENCE OF MAGNETIC FIELDS ON INHIBITION OF MCF-7 CELL GROWTH BY TAMOXIFEN

    EPA Science Inventory

    THE INFLUENCE OF MAGNETIC FIELDS ON INHIBITION OF MCF-7 CELL GROWTH BY TAMOXIFEN.
    Harland and Liburdy (1) reported that 1.2-uT, 60-Hz magnetic fields could significantly block the inhibitory action of pharmacological levels of tamoxifen (10-7 M) on the growth of MCF-7 human br...

  11. Nuclear p21-activated kinase 1 in breast cancer packs off tamoxifen sensitivity.

    PubMed

    Rayala, Suresh K; Molli, Poonam R; Kumar, Rakesh

    2006-06-15

    There is significant clinical interest in the factors that influence the development of tamoxifen resistance in estrogen receptor-alpha (ER-alpha)-positive breast cancers. Recent studies suggest that in ER-positive breast tumor cells, elevated protein levels, and in particular, nuclear localization of p21-activated kinase 1 (PAK1), is associated with the progressive limitation of tamoxifen sensitivity. These phenotypic effects of PAK1 in model systems are mechanistically linked with the ability of PAK1 to phosphorylate ER-alpha on serine 305 and subsequent secondary activation of serine 118. These findings prompt further investigation of how nuclear signaling by PAK1 may affect estrogen's action and whether tamoxifen resistance might be prevented or reversed by PAK1 inhibition.

  12. Phosphoproteomic Analysis Identifies Focal Adhesion Kinase 2 (FAK2) as a Potential Therapeutic Target for Tamoxifen Resistance in Breast Cancer*

    PubMed Central

    Wu, Xinyan; Zahari, Muhammad Saddiq; Renuse, Santosh; Nirujogi, Raja Sekhar; Kim, Min-Sik; Manda, Srikanth S.; Stearns, Vered; Gabrielson, Edward; Sukumar, Saraswati; Pandey, Akhilesh

    2015-01-01

    Tamoxifen, an estrogen receptor-α (ER) antagonist, is an important agent for the treatment of breast cancer. However, this therapy is complicated by the fact that a substantial number of patients exhibit either de novo or acquired resistance. To characterize the signaling mechanisms underlying this resistance, we treated the MCF7 breast cancer cell line with tamoxifen for over six months and showed that this cell line acquired resistance to tamoxifen in vitro and in vivo. We performed SILAC-based quantitative phosphoproteomic profiling on the tamoxifen resistant and vehicle-treated sensitive cell lines to quantify the phosphorylation alterations associated with tamoxifen resistance. From >5600 unique phosphopeptides identified, 1529 peptides exhibited hyperphosphorylation and 409 peptides showed hypophosphorylation in the tamoxifen resistant cells. Gene set enrichment analysis revealed that focal adhesion pathway was one of the most enriched signaling pathways activated in tamoxifen resistant cells. Significantly, we showed that the focal adhesion kinase FAK2 was not only hyperphosphorylated but also transcriptionally up-regulated in tamoxifen resistant cells. FAK2 suppression by specific siRNA knockdown or a small molecule inhibitor repressed cellular proliferation in vitro and tumor formation in vivo. More importantly, our survival analysis revealed that high expression of FAK2 is significantly associated with shorter metastasis-free survival in estrogen receptor-positive breast cancer patients treated with tamoxifen. Our studies suggest that FAK2 is a potential therapeutic target for the management of hormone-refractory breast cancers. PMID:26330541

  13. Phototoxic effects of commercial photographic flash lamp on rat eyes.

    PubMed

    Inoue, Makoto; Shinoda, Kei; Ohde, Hisao; Tezuka, Keiji; Hida, Tetsuo

    2006-11-01

    To determine whether exposure of the cornea and retina of rats to flashes from a commercial photographic flash lamp is phototoxic. Sprague-Dawley rats were exposed to 10, 100, or 1,000 flashes of the OPTICAM 16M photographic flash lamp (Fujikoeki, Japan) placed 0.1, 1, or 3 m from the eyes. Corneal damage was assessed by a fluorescein staining score, and the retinal damage by eletroretinography (ERG) and histology before and 24 h after exposure. Exposure of the eyes to 1,000 flashes at 0.1 m increased the fluorescein staining score significantly (P = 0.009, the Mann-Whitney test). Scanning electron microscopy (SEM) of the cornea showed a detachment of the epithelial cells from the surface after this exposure. The amplitude of the a-wave was decreased significantly by 23.0% (P = 0.026) of the amplitude before the exposure, and the b-wave by 19.7% (P = 0.0478) following 1,000 flashes at 0.1 m but not by the other exposures. TUNEL-positive cells were present in the outer nuclear layer only after the extreme exposure, but no significant decrease in retinal thickness was seen under any condition. The fluorescein staining score and ERGs recovered to control levels within 1 week. Light exposure to a photographic flash lamp does not induce damage to the cornea and retina except when they are exposed to 1,000 flashes at 0.1 m.

  14. Quantification of tamoxifen DNA adducts using on-line sample preparation and HPLC-electrospray ionization tandem mass spectrometry.

    PubMed

    Gamboa da Costa, Gonçalo; Marques, M Matilde; Beland, Frederick A; Freeman, James P; Churchwell, Mona I; Doerge, Daniel R

    2003-03-01

    The nonsteroidal antiestrogen tamoxifen is used as an adjuvant chemotherapeutic agent for the treatment of all stages of hormone-dependent breast cancer and more recently as a chemopreventive agent in women with elevated risk of developing the disease. While clearly beneficial for the treatment of breast cancer, tamoxifen has been reported to increase the risk of endometrial cancer in women. Furthermore, it has been shown to be hepatocarcinogenic in rats. Tamoxifen is clearly genotoxic in rat liver, as indicated by the formation of DNA adducts; the occurrence of tamoxifen DNA adducts in human endometrial tissue is more controversial. The detection and quantitation of tamoxifen DNA adducts have relied primarily upon (32)P-postlabeling, with other techniques, such as immunoassays and accelerator mass spectrometry, being used to a much lesser extent. To expand the range of available analytical methodologies for quantifying tamoxifen DNA adducts, we have developed an assay using on-line sample preparation, coupled with HPLC and electrospray ionization tandem mass spectrometry (ES-MS/MS). alpha-Acetoxytamoxifen was reacted with salmon testis DNA at ratios between 0.1 ng and 1 mg alpha-acetoxytamoxifen per mg DNA. After enzymatic hydrolysis to nucleosides, the most highly modified DNA samples were analyzed by HPLC-UV, which indicated the presence of two adduct peaks in approximately a 1:4 ratio. The major adduct was isolated, rigorously characterized as (E)-alpha-(deoxyguanosin-N(2)-yl)tamoxifen, and quantified on the basis of its molar extinction coefficient. A similar reaction was conducted with [N(CD(3))(2)]-alpha-acetoxytamoxifen to prepare a deuterated adduct that could serve as an internal standard for ES-MS/MS. The limit of detection for the HPLC-ES-MS/MS method was approximately 5 adducts/10(9) nucleotides, with an intra- and interassay precision of 3% relative standard deviation. The method was validated over the range of 8-1 520,000 adducts/10(8) nucleotides

  15. Nationwide Case-Control Study Examining the Association between Tamoxifen Use and Alzheimer's Disease in Aged Women with Breast Cancer in Taiwan.

    PubMed

    Liao, Kuan-Fu; Lin, Cheng-Li; Lai, Shih-Wei

    2017-01-01

    Background and Objectives: Little is known about the association between tamoxifen use and Alzheimer's disease in women with breast cancer. The study aimed to explore the association between tamoxifen use and Alzheimer's disease in aged women with breast cancer in Taiwan. Methods : We conducted a retrospective nationwide case-control study using the database of the Taiwan National Health Insurance Program. Totally, 173 female subjects with breast cancer aged ≥ 65 years with newly diagnosed Alzheimer's disease from 2000 to 2011 were identified as the cases. Additionally, 684 female subjects with breast cancer aged ≥ 65 years without any type of dementia were selected as the matched controls. The cases and the matched controls were matched with age and comorbidities. Ever use of tamoxifen was defined as subjects who had at least a prescription for tamoxifen before the index date. Never use of tamoxifen was defined as subjects who never had a prescription for tamoxifen before the index date. We used the logistic regression model to calculate the odds ratio (OR) and 95% confidence interval (CI) of Alzheimer's disease associated with tamoxifen use. Results : The OR of Alzheimer's disease was 3.09 for subjects with ever use of tamoxifen (95% CI 2.10, 4.55), compared with never use. The OR of Alzheimer's disease was 1.23 for subjects with increasing cumulative duration of tamoxifen use for every 1 year (95% CI 1.13, 1.34), compared with never use. Conclusion: The increased odds of Alzheimer's disease associated with tamoxifen use may be due to the survival effect, not the toxic effect. That is, the longer the tamoxifen use, the longer the patients survive, and the greater the likelihood that she may have a chance to develop Alzheimer's disease.

  16. The Effect of Tamoxifen on Thin Endometrium in Patients Undergoing Frozen-Thawed Embryo Transfer.

    PubMed

    Ke, Hanni; Jiang, Jingjing; Xia, Mingdi; Tang, Rong; Qin, Yingying; Chen, Zi-Jiang

    2018-06-01

    Tamoxifen has played a vital role in endocrine therapy for the treatment of estrogen receptor-positive breast cancer. We examined the effect of tamoxifen in patients with a thin endometrium in frozen-thawed embryo transfer (FET) cycles and compared the improvement in endometrial thickness (EMT) and pregnancy outcomes stratified by different etiologies of thin endometrium. A total of 226 women were recruited for a new tamoxifen protocol; all had an EMT of less than 7.5 mm in previous cycles, including natural cycle (NC), hormone replacement treatment (HRT), and ovulation induction (OI) cycles. Compared with previous cycles, tamoxifen cycles showed a significantly increased EMT (from 6.11 ± 0.98 mm to 7.87 ± 1.48 mm in the NC group, from 6.24 ± 1.01 mm to 8.22 ± 1.67 mm in the HRT group, and from 6.34 ± 1.03 mm to 8.05 ± 1.58 mm in the OI group; all P < .001). Patients were further divided into 3 groups based on the causes of their thin endometrium: (1) history of intrauterine adhesion (n = 34), (2) history of uterine curettage (n = 141), and (3) polycystic ovary syndrome (PCOS; n = 51). Patients with PCOS obtained the thickest EMT (9.31 ± 1.55 mm), the lowest cycle cancellation rate (11.76%), and the highest rate of clinical pregnancy (60%) and live birth (55.56%) per transfer ( P < .001). Multivariable regression analysis showed that EMT was related to live birth (odds ratio: 1.487; 95% confidence interval: 1.172-1.887). A tamoxifen protocol improves EMT in patients after NC, HRT, and OI cycles during FET. Patients with PCOS show the most benefit from tamoxifen and achieve better pregnancy outcomes.

  17. GPR30 as an initiator of tamoxifen resistance in hormone-dependent breast cancer.

    PubMed

    Mo, Zhiqiang; Liu, Manran; Yang, Fangfang; Luo, Haojun; Li, Zhenhua; Tu, Gang; Yang, Guanglun

    2013-11-29

    Tamoxifen is widely used to treat hormone-dependent breast cancer, but its therapeutic benefit is limited by the development of drug resistance. Here, we investigated the role of estrogen G-protein coupled receptor 30 (GPR30) on Tamoxifen resistance in breast cancer. Primary tumors (PTs) of breast cancer and corresponding metastases (MTs) were used to evaluate the expression of GPR30 and epidermal growth factor receptor (EGFR) immunohistochemically. Tamoxifen-resistant (TAM-R) subclones derived from parent MCF-7 cells were used to investigate the role of GPR30 in the development of tamoxifen resistance, using MTT assay, western blot, RT-PCR, immunofluorescence, ELISA and flow cytometry. TAM-R xenografts were established to assess anti-tumor effects of combination therapy with GPR30 antagonist G15 plus 4-hydroxytamoxifen (Tam), using tumor volume measurement and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). In 53 human breast cancer specimens, GPR30 expression in MTs increased compared to matched PTs; in MTs, the expression patterns of GPR30 and EGFR were closely related. Compared to parent MCF-7 cells, TAM-R cells had greater growth responses to 17β-estradiol (E2), GPR30 agonist G1 and Tam, and significantly higher activation of Mitogen-activated protein (MAP) kinases; but this increased activity was abolished by G15 or AG1478. In TAM-R cells, GPR30 cell-surface translocation facilitated crosstalk with EGFR, and reduced cAMP generation, attenuating inhibition of EGFR signaling. Combination therapy both promoted apoptosis in TAM-R cells and decreased drug-resistant tumor progression. Long-term endocrine treatment facilitates the translocation of GPR30 to cell surfaces, which interferes with the EGFR signaling pathway; GPR30 also attenuates the inhibition of MAP kinases. These factors contribute to tamoxifen resistance development in breast cancer. Combination therapy with GPR30 inhibitors and tamoxifen may provide a new therapeutic option

  18. Flash!

    NASA Astrophysics Data System (ADS)

    Schilling, Govert

    2002-04-01

    About three times a day our sky flashes with a powerful pulse of gamma ray bursts (GRB), invisible to human eyes but not to astronomers' instruments. The sources of this intense radiation are likely to be emitting, within the span of seconds or minutes, more energy than the sun will in its entire 10 billion years of life. Where these bursts originate, and how they come to have such incredible energies, is a mystery scientists have been trying to solve for three decades. The phenomenon has resisted study -- the flashes come from random directions in space and vanish without trace -- until very recently. In what could be called a cinematic conflation of Flash Gordon and The Hunt for Red October, Govert Schilling's Flash!: The Hunt for the Biggest Explosions in the Universe describes the exciting and ever-changing field of GRB research. Based on interviews with leading scientists, Flash! provides an insider's account of the scientific challenges involved in unravelling the enigmatic nature of GRBs. A science writer who has followed the drama from the very start, Schilling describes the ambition and jealousy, collegiality and competition, triumph and tragedy, that exists among those who have embarked on this recherche. Govert Schilling is a Dutch science writer and astronomy publicist. He is a contributing editor of Sky and Telescope magazine, and regularly writes for the news sections of Science and New Scientist. Schilling is the astronomy writer for de Volkskrant, one of the largest national daily newspapers in The Netherlands, and frequently talks about the Universe on Dutch radio broadcasts. He is the author of more than twenty popular astronomy books, and hundreds of newspaper and magazine articles on astronomy.

  19. 4-protein signature predicting tamoxifen treatment outcome in recurrent breast cancer.

    PubMed

    De Marchi, Tommaso; Liu, Ning Qing; Stingl, Cristoph; Timmermans, Mieke A; Smid, Marcel; Look, Maxime P; Tjoa, Mila; Braakman, Rene B H; Opdam, Mark; Linn, Sabine C; Sweep, Fred C G J; Span, Paul N; Kliffen, Mike; Luider, Theo M; Foekens, John A; Martens, John W M; Umar, Arzu

    2016-01-01

    Estrogen receptor (ER) positive tumors represent the majority of breast malignancies, and are effectively treated with hormonal therapies, such as tamoxifen. However, in the recurrent disease resistance to tamoxifen therapy is common and a major cause of death. In recent years, in-depth proteome analyses have enabled identification of clinically useful biomarkers, particularly, when heterogeneity in complex tumor tissue was reduced using laser capture microdissection (LCM). In the current study, we performed high resolution proteomic analysis on two cohorts of ER positive breast tumors derived from patients who either manifested good or poor outcome to tamoxifen treatment upon recurrence. A total of 112 fresh frozen tumors were collected from multiple medical centers and divided into two sets: an in-house training and a multi-center test set. Epithelial tumor cells were enriched with LCM and analyzed by nano-LC Orbitrap mass spectrometry (MS), which yielded >3000 and >4000 quantified proteins in the training and test sets, respectively. Raw data are available via ProteomeXchange with identifiers PXD000484 and PXD000485. Statistical analysis showed differential abundance of 99 proteins, of which a subset of 4 proteins was selected through a multivariate step-down to develop a predictor for tamoxifen treatment outcome. The 4-protein signature significantly predicted poor outcome patients in the test set, independent of predictive histopathological characteristics (hazard ratio [HR] = 2.17; 95% confidence interval [CI] = 1.15 to 4.17; multivariate Cox regression p value = 0.017). Immunohistochemical (IHC) staining of PDCD4, one of the signature proteins, on an independent set of formalin-fixed paraffin-embedded tumor tissues provided and independent technical validation (HR = 0.72; 95% CI = 0.57 to 0.92; multivariate Cox regression p value = 0.009). We hereby report the first validated protein predictor for tamoxifen treatment outcome in recurrent ER-positive breast

  20. The Working Memory and Dorsolateral Prefrontal-Hippocampal Functional Connectivity Changes in Long-Term Survival Breast Cancer Patients Treated with Tamoxifen

    PubMed Central

    Chen, Xingui; Tao, Longxiang; Li, Jingjing; Wu, Jiaonan; Zhu, Chunyan; Yu, Fengqiong; Zhang, Lei; Zhang, Jingjie; Qiu, Bensheng; Yu, Yongqiang; He, Xiaoxuan

    2017-01-01

    Abstract Background: Tamoxifen is the most widely used drug for treating patients with estrogen receptor-sensitive breast cancer. There is evidence that breast cancer patients treated with tamoxifen exhibit cognitive dysfunction. However, the underlying neural mechanism remains unclear. The present study aimed to investigate the neural mechanisms underlying working memory deficits in combination with functional connectivity changes in premenopausal women with breast cancer who received long-term tamoxifen treatment. Methods: A total of 31 premenopausal women with breast cancer who received tamoxifen and 32 matched healthy control participants were included. The participants completed n-back tasks and underwent resting-state functional magnetic resonance imaging, which measure working memory performance and brain functional connectivity, respectively. A seed-based functional connectivity analysis within the whole brain was conducted, for which the dorsolateral prefrontal cortex was chosen as the seed region. Results: Our results indicated that the tamoxifen group had significant deficits in working memory and general executive function performance and significantly lower functional connectivity of the right dorsolateral prefrontal cortex with the right hippocampus compared with the healthy controls. There were no significant changes in functional connectivity in the left dorsolateral prefrontal cortex within the whole brain between the tamoxifen group and healthy controls. Moreover, significant correlations were found in the tamoxifen group between the functional connectivity strength of the dorsolateral prefrontal cortex with the right hippocampus and decreased working memory performance. Conclusion: This study demonstrates that the prefrontal cortex and hippocampus may be affected by tamoxifen treatment, supporting an antagonistic role of tamoxifen in the long-term treatment of breast cancer patients. PMID:28177081

  1. A selective estrogen receptor modulator, tamoxifen, and membrane fluidity of erythrocytes in normotensive and hypertensive postmenopausal women: an electron paramagnetic resonance investigation.

    PubMed

    Tsuda, Kazushi; Nishio, Ichiro

    2005-08-01

    Recent studies have shown that tamoxifen, which belongs to a group called selective estrogen receptor modulators (SERM), may exert protective effects against cardiovascular diseases and stroke in postmenopausal women. On the other hand, abnormalities in physical properties of the cell membranes may underlie the defects that are strongly linked to hypertension, stroke, and other cardiovascular diseases. The present study was performed to investigate the effects of tamoxifen on cell membrane fluidity (a reciprocal value of membrane microviscosity) in normotensive and hypertensive postmenopausal women. We used an electron paramagnetic resonance (EPR) and spin-labeling method. Tamoxifen significantly decreased the order parameter (S) for 5-nitroxide stearate (5-NS) and the peak height ratio (h(o)/h(-1)) for 16-NS obtained from EPR spectra of erythrocyte membranes in normotensive postmenopausal women (mean +/- SEM, order parameter value; control 0.719 +/- 0.002, n = 41; tamoxifen 1 x 10(-7) mol/L 0.704 +/- 0.002, n = 41, P < .0001; tamoxifen 1 x 10(-6) mol/L 0.696 +/- 0.002, n = 41, P < .0001; tamoxifen 1 x 10(-5) mol/L 0.692 +/- 0.002, n = 41, P < .0001). The finding indicated that tamoxifen increased the membrane fluidity and improved the membrane microviscosity of erythrocytes. The membrane action of tamoxifen was antagonized by the estrogen receptor antagonist ICI 182,780. The effect of tamoxifen was significantly potentiated by the nitric oxide (NO) donors, l-arginine and S-nitroso-N-acetylpenicillamine, and a cGMP analog 8-bromo-cGMP. In contrast, the change evoked by tamoxifen was counteracted by the NO synthase inhibitors N(G)-nitro-l-arginine-methyl-ester and asymmetric dimethyl-l-arginine. In hypertensive postmenopausal women, the membrane fluidity of erythrocytes was significantly lower than in normotensive postmenopausal women. The effect of tamoxifen on the membrane fluidity was more pronounced in hypertensive postmenopausal women than in normotensive

  2. A standing posture is associated with increased susceptibility to the sound-induced flash illusion in fall-prone older adults.

    PubMed

    Stapleton, John; Setti, Annalisa; Doheny, Emer P; Kenny, Rose Anne; Newell, Fiona N

    2014-02-01

    Recent research has provided evidence suggesting a link between inefficient processing of multisensory information and incidence of falling in older adults. Specifically, Setti et al. (Exp Brain Res 209:375-384, 2011) reported that older adults with a history of falling were more susceptible than their healthy, age-matched counterparts to the sound-induced flash illusion. Here, we investigated whether balance control in fall-prone older adults was directly associated with multisensory integration by testing susceptibility to the illusion under two postural conditions: sitting and standing. Whilst standing, fall-prone older adults had a greater body sway than the age-matched healthy older adults and their body sway increased when presented with the audio-visual illusory but not the audio-visual congruent conditions. We also found an increase in susceptibility to the sound-induced flash illusion during standing relative to sitting for fall-prone older adults only. Importantly, no performance differences were found across groups in either the unisensory or non-illusory multisensory conditions across the two postures. These results suggest an important link between multisensory integration and balance control in older adults and have important implications for understanding why some older adults are prone to falling.

  3. Flash Mixing of the White Dwarf Cooling Curve Spectroscopic Confirmation in NGC 2808

    NASA Technical Reports Server (NTRS)

    Brown, Thomas M.; Lanz, Thierry; Sweigart, Allen V.; Cracraft, Misty; Hubeny, Ivan; Landsman, Wayne B.

    2009-01-01

    We present new HST far-UV spectroscopy of two dozen hot evolved stars in NGC 2808, a massive globular cluster with a large population of "blue-hook" stars. The blue-hook stars are found in ultraviolet color-magnitude diagrams of the most massive globular clusters, where they fall at luminosities immediately below the hot end of the horizontal branch (HB), in a region of the HR diagram unexplained by canonical stellar evolution theory. Using new theoretical evolutionary and atmospheric models, we have shown that these subluminous HB stars are very likely the progeny of stars that undergo extensive internal mixing during a late He-core flash on the white dwarf cooling curve. This flash mixing leads to hotter temperatures and an enormous enhancement of the surface He and C abundances; the hotter temperatures and associated decrease in the hydrogen opacity shortward of the Lyman limit makes the stars brighter in the extreme UV but appear sub luminous in the UV and optical. Our far-UV spectroscopy demonstrates that, relative to normal HB stars at the same color, the blue-hook stars of NGC 2808 are hotter and greatly enhanced in He and C, thus providing unambiguous evidence of flash mixing in the subluminous population. Although the C abundance in the blue-hook stars is orders of magnitude larger than that in the normal HB stars, the atmospheric C abundance in both the blue-hook and normal HB stars appears to be affected by gravitational settling. The abundance variations seen in C, Si, and the Fe-peak elements indicate that atmospheric diffusion is at play in our sample, with all of our hot subdwarfs at 25,000 K to 50,000 K exhibiting large enhancements of the iron-peak elements. The hottest subdwarfs in our blue-hook sample may be pulsators, given that they fall in the temperature range of newly-discovered pulsating subdwarfs in omega Cen.

  4. Cytochrome P450 Genetic Variation Associated with Tamoxifen Biotransformation in American Indian and Alaska Native People

    PubMed Central

    Khan, Burhan A.; Robinson, Renee; Fohner, Alison E.; Muzquiz, LeeAnna I.; Schilling, Brian D.; Beans, Julie A.; Olnes, Matthew J.; Trawicki, Laura; Frydenlund, Holly; Laukes, Cindi; Beatty, Patrick; Phillips, Brian; Nickerson, Deborah; Howlett, Kevin; Dillard, Denise A.; Thornton, Timothy A.; Thummel, Kenneth E.

    2018-01-01

    Abstract Despite evidence that pharmacogenetics can improve tamoxifen pharmacotherapy, there are few studies with American Indian and Alaska Native (AIAN) people. We examined variation in cytochrome P450 (CYP) genes (CYP2D6, CYP3A4, CYP3A5, and CYP2C9) and tamoxifen biotransformation in AIAN patients with breast cancer (n = 42) from the Southcentral Foundation in Alaska and the Confederated Salish and Kootenai Tribes in Montana. We tested for associations between CYP diplotypes and plasma concentrations of tamoxifen and metabolites. Only the CYP2D6 variation was significantly associated with concentrations of endoxifen (P = 0.0008) and 4‐hydroxytamoxifen (P = 0.0074), tamoxifen's principal active metabolites, as well as key metabolic ratios. The CYP2D6 was also the most significant predictor of active metabolites and metabolic ratios in a multivariate regression model, including all four genes as predictors, with minor roles for other CYP genes. In AIAN populations, CYP2D6 is the largest contributor to tamoxifen bioactivation, illustrating the importance of validating pharmacogenetic testing for therapy optimization in an understudied population. PMID:29436156

  5. Motion streaks do not influence the perceived position of stationary flashed objects.

    PubMed

    Pavan, Andrea; Bellacosa Marotti, Rosilari

    2012-01-01

    In the present study, we investigated whether motion streaks, produced by fast moving dots Geisler 1999, distort the positional map of stationary flashed objects producing the well-known motion-induced position shift illusion (MIPS). The illusion relies on motion-processing mechanisms that induce local distortions in the positional map of the stimulus which is derived by shape-processing mechanisms. To measure the MIPS, two horizontally offset Gaussian blobs, placed above and below a central fixation point, were flashed over two fields of dots moving in opposite directions. Subjects judged the position of the top Gaussian blob relative to the bottom one. The results showed that neither fast (motion streaks) nor slow moving dots influenced the perceived spatial position of the stationary flashed objects, suggesting that background motion does not interact with the shape-processing mechanisms involved in MIPS.

  6. Flash fire propensity of materials

    NASA Technical Reports Server (NTRS)

    Hilado, C. J.; Cumming, H. J.

    1977-01-01

    Flash fire test results on 86 materials, evaluated using the USF flash fire screening test, are presented. The materials which appear least prone to flash fires are PVC, polyphenylene oxide and sulfide, and polyether and polyaryl sulfone; these did not produce flash fires under these particular test conditions. The principal value of these screening tests at the present time is in identifying materials which appear prone to flash fires, and in identifying which formulations of a generic material are more or less prone to flash fires.

  7. A pooled analysis of CYP2D6 genotype in breast cancer prevention trials of low-dose tamoxifen.

    PubMed

    Johansson, Harriet; Gandini, Sara; Serrano, Davide; Gjerde, Jennifer; Lattanzi, Monia; Macis, Debora; Guerrieri-Gonzaga, Aliana; Aristarco, Valentina; Mellgren, Gunnar; Lien, Ernst; DeCensi, Andrea; Bonanni, Bernardo

    2016-08-01

    Decreased CYP2D6 activity is associated with lower levels of active tamoxifen metabolites. We examined the impact of CYP2D6 genotype on tamoxifen pharmacokinetics, biomarker activity, and efficacy in a pooled analysis of low-dose tamoxifen. Four randomized breast cancer prevention trials of very-low-dose (1 mg/day, n = 52 or 10 mg/week, n = 152) or low-dose tamoxifen (5 mg/day, n = 171) were pooled. DNA from 367 subjects was genotyped for CYP2D6 alleles associated with absent (PM allele: *3, *4, *5, *6, *7, *8, *12, and *14), reduced (IM allele: *9, *10, *17, *29, *41), normal (EM allele), or increased (UM: *XN) enzyme activity. Associations of tamoxifen, metabolites, activity biomarkers, and event-free survival with rapid (UM/EM, UM/IM, EM/EM, EM/IM, or EM/PM alleles) versus slow metabolizers (PM/IM or PM/PM) were investigated through random effects models, with 'study' as the random factor, and Cox regression models, adjusting for confounders. Rapid metabolizers had higher endoxifen levels than slow metabolizers: 15.3 versus 12.2 ng/mL (P = 0.018) with 5 mg/day, and 3.8 versus 2.8 ng/mL (P = 0.004) with 1 mg/day or 10 mg/week tamoxifen. The IGF-I decrease correlated with endoxifen (P = 0.002) and 4-hydroxytamoxifen levels, demonstrating steeper decreases at higher metabolite levels (P = 0.001). After a median follow-up of 12 years, rapid metabolizers with prior history of breast neoplasms allocated to tamoxifen 5 mg/day had a 60 % reduction of risk of recurrences (HR = 0.40, 95 % CI: 0.16-0.99) compared to slow metabolizers. CYP2D6 genotype may have an impact on tamoxifen efficacy at low doses. Trials investigating tamoxifen dose adjustments based on the woman's hormonal context and CYP2D6 genotype are warranted.

  8. Extraction of tamoxifen and its metabolites from formalin-fixed, paraffin-embedded tissues: an innovative quantitation method using liquid chromatography and tandem mass spectrometry.

    PubMed

    Ng, Ella S M; Kangarloo, S Bill; Konno, Mie; Paterson, Alexander; Magliocco, Anthony M

    2014-03-01

    Tamoxifen is a key therapeutic option for breast cancer treatment. Understanding its complex metabolism and pharmacokinetics is important for dose optimization. We examined the possibility of utilizing archival formalin-fixed paraffin-embedded (FFPE) tissue as an alternative sample source for quantification since well-annotated retrospective samples were always limited. Six 15 μm sections of FFPE tissues were deparaffinized with xylene and purified using solid-phase extraction. Tamoxifen and its metabolites were separated and detected by liquid chromatography-tandem mass spectrometry using multiple-reaction monitoring. This method was linear between 0.4 and 200 ng/g for 4-hydroxy-tamoxifen and endoxifen, and 4-2,000 ng/g for tamoxifen and N-desmethyl-tamoxifen. Inter- and intra-assay precisions were <9 %, and mean accuracies ranged from 81 to 106 %. Extraction recoveries were between 83 and 88 %. The validated method was applied to FFPE tissues from two groups of patients, who received 20 mg/day of tamoxifen for >6 months, and were classified into breast tumor recurrence and non-recurrence. Our preliminary data show that levels of tamoxifen metabolites were significantly lower in patients with recurrent cancer, suggesting that inter-individual variability in tamoxifen metabolism might partly account for the development of cancer recurrence. Nevertheless, other causes such as non-compliance or stopping therapy of tamoxifen could possibly lead to the concentration differences. The ability to successfully study tamoxifen metabolism in such tissue samples will rapidly increase our knowledge of how tamoxifen's action, metabolism and tissue distribution contribute to breast cancer control. However, larger population studies are required to understand the underlying mechanism of tamoxifen metabolism for optimization of its treatment.

  9. New Observational Evidence of Flash Mixing on the White Dwarf Cooling Curve

    NASA Technical Reports Server (NTRS)

    Brown, T. M.; Lanz, T.; Sweigart, A. V.; Cracraft, Misty; Hubeny, Ivan; Landsman, W. B.

    2011-01-01

    Blue hook stars are a class of subluminous extreme horizontal branch stars that were discovered in UV images of the massive globular clusters w Cen and NGC 2808. These stars occupy a region of the HR diagram that is unexplained by canonical stellar evolution theory. Using new theoretical evolutionary and atmospheric models, we have shown that the blue hook stars are very likely the progeny of stars that undergo extensive internal mixing during a late helium-core flash on the white dwarf cooling curve. This "flash mixing" produces hotter-than-normal EHB stars with atmospheres significantly enhanced in helium and carbon. The larger bolometric correction, combined with the decrease in hydrogen opacity, makes these stars appear sub luminous in the optical and UV. Flash mixing is more likely to occur in stars born with a high helium abundance, due to their lower mass at the main sequence turnoff. For this reason, the phenomenon is more common in those massive globular clusters that show evidence for secondary populations enhanced in helium. However, a high helium abundance does not, by itself, explain the presence of blue hook stars in massive globular clusters. Here, we present new observational evidence for flash mixing, using recent HST observations. These include UV color-magnitude diagrams of six massive globular clusters and far-UV spectroscopy of hot subdwarfs in one of these clusters (NGC 2808).

  10. Mitochondrial “power” drives tamoxifen resistance: NQO1 and GCLC are new therapeutic targets in breast cancer

    PubMed Central

    Fiorillo, Marco; Sotgia, Federica; Sisci, Diego; Cappello, Anna Rita; Lisanti, Michael P.

    2017-01-01

    Here, we identified two new molecular targets, which are functionally sufficient to metabolically confer the tamoxifen-resistance phenotype in human breast cancer cells. Briefly, ~20 proteins were first selected as potential candidates, based on unbiased proteomics analysis, using tamoxifen-resistant cell lines. Then, the cDNAs of the most promising candidates were systematically transduced into MCF-7 cells. Remarkably, NQO1 and GCLC were both functionally sufficient to autonomously confer a tamoxifen-resistant metabolic phenotype, characterized by i) increased mitochondrial biogenesis, ii) increased ATP production and iii) reduced glutathione levels. Thus, we speculate that pharmacological inhibition of NQO1 and GCLC may be new therapeutic strategies for overcoming tamoxifen-resistance in breast cancer patients. In direct support of this notion, we demonstrate that treatment with a known NQO1 inhibitor (dicoumarol) is indeed sufficient to revert the tamoxifen-resistance phenotype. As such, these findings could have important translational significance for the prevention of tumor recurrence in ER(+) breast cancers, which is due to an endocrine resistance phenotype. Importantly, we also show here that NQO1 has significant prognostic value as a biomarker for the prediction of tumor recurrence. More specifically, higher levels of NQO1 mRNA strongly predict patient relapse in high-risk ER(+) breast cancer patients receiving endocrine therapy (mostly tamoxifen; H.R. > 2.15; p = 0.007). PMID:28411284

  11. Risk of skin cancer following tamoxifen treatment in more than 16,000 breast cancer patients: a cohort study.

    PubMed

    Praestegaard, Camilla; Kjaer, Susanne K; Andersson, Michael; Steding-Jensen, Marianne; Frederiksen, Kirsten; Mellemkjaer, Lene

    2016-11-01

    Women with breast cancer are at increased risk of developing skin cancer. Little is known about how tamoxifen affects this risk. We aimed to investigate whether tamoxifen treatment following breast cancer is associated with skin cancer. A cohort consisting of 44,589 women diagnosed with breast cancer during 1977-2007 from the nationwide clinical database of the Danish Breast Cancer Cooperative Group, was followed for a primary skin cancer [basal cell carcinoma (BCC), squamous cell carcinoma (SCC) or melanoma] in the Danish Cancer Registry supplemented by data on BCC and SCC from the Danish Pathology Register. We investigated incidence of skin cancer among 16,214 women treated with tamoxifen compared to 28,375 women not treated with tamoxifen by calculating incidence rate ratios (IRRs) in Cox regression models. Tamoxifen users were followed for a median of 2.9 years. The median duration of tamoxifen treatment increased from around 1 year among women diagnosed before 1999 to nearly 2.5 years among women diagnosed in 1999 or later. Women treated with tamoxifen had an IRR 1.06 (95 % CI 0.72-1.55) for SCC and an IRR 1.40 (95 % CI 0.95-2.08) for melanoma when compared to non-users. The observed number of these types of cancer (37 SCCs and 38 melanomas among users) did not allow stratification on calendar-period. The overall IRR for BCC was 0.96 (95 % CI 0.84-1.09), but the IRR differed by menopausal status and calendar-period at diagnosis of breast cancer. Our overall results indicate that tamoxifen is not associated with skin cancer. However, the inconsistency of results from stratifications prevents a firm conclusion.

  12. Endocrine effects of adjuvant letrozole compared with tamoxifen in hormone-responsive postmenopausal patients with early breast cancer: the HOBOE trial.

    PubMed

    Rossi, Emanuela; Morabito, Alessandro; Di Rella, Francesca; Esposito, Giuseppe; Gravina, Adriano; Labonia, Vincenzo; Landi, Gabriella; Nuzzo, Francesco; Pacilio, Carmen; De Maio, Ermelinda; Di Maio, Massimo; Piccirillo, Maria Carmela; De Feo, Gianfranco; D'Aiuto, Giuseppe; Botti, Gerardo; Chiodini, Paolo; Gallo, Ciro; Perrone, Francesco; de Matteis, Andrea

    2009-07-01

    PURPOSE We compared the endocrine effects of 6 and 12 months of adjuvant letrozole versus tamoxifen in postmenopausal patients with hormone-responsive early breast cancer within an ongoing phase III trial. PATIENTS AND METHODS Patients were randomly assigned to receive tamoxifen, letrozole, or letrozole plus zoledronic acid. Serum values of estradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, dehydroepiandrosterone-sulphate (DHEA-S), progesterone, and cortisol were measured at baseline and after 6 and 12 months of treatment. For each hormone, changes from baseline at 6 and 12 months were compared between treatment groups, and differences over time for each group were analyzed. Results Hormonal data were available for 139 postmenopausal patients with a median age of 62 years, with 43 patients assigned to tamoxifen and 96 patients assigned to letrozole alone or combined with zoledronic acid. Baseline values were similar between the two groups for all hormones. Many significant changes were observed between drugs and for each drug over time. Namely, three hormones seemed significantly affected by one drug only: estradiol that decreased and progesterone that increased with letrozole and cortisol that increased with tamoxifen. Both drugs affected FSH (decreasing with tamoxifen and slightly increasing with letrozole), LH (decreasing more with tamoxifen than with letrozole), testosterone (slightly increasing with letrozole but not enough to differ from tamoxifen), and DHEA-S (increasing with both drugs but not differently between them). Zoledronic acid did not have significant impact on hormonal levels. CONCLUSION Adjuvant letrozole and tamoxifen result in significantly distinct endocrine effects. Such differences can explain the higher efficacy of letrozole as compared with tamoxifen.

  13. Estrogen receptor antagonism uncovers gender-dimorphic suppression of whole body fat oxidation in humans: differential effects of tamoxifen on the GH and gonadal axes.

    PubMed

    Birzniece, Vita; Ho, Ken K Y

    2015-10-01

    Tamoxifen, a selective estrogen receptor modulator, suppresses GH secretion in women but not in men. It increases testosterone levels in men. As GH and testosterone stimulate fat metabolism, the metabolic consequences of tamoxifen may be greater in women than in men. To determine whether tamoxifen suppresses fat oxidation (Fox) to a greater degree in women than in men. An open-label study of ten healthy postmenopausal women and ten healthy men receiving 2-week treatment with tamoxifen (20  mg/day). GH response to arginine stimulation, serum levels of IGF1, testosterone and LH (men only), sex hormone binding globulin (SHBG) and whole body basal and postprandial Fox. In women, tamoxifen significantly reduced the mean GH response to arginine stimulation (Δ -87%, P<0.05) and circulating IGF1 levels (Δ -23.5±5.4%, P<0.01). Tamoxifen reduced postprandial Fox in women (Δ -34.6±10.3%; P<0.05). In men, tamoxifen did not affect the GH response to arginine stimulation but significantly reduced mean IGF1 levels (Δ -24.8±6.1%, P<0.01). Tamoxifen increased mean testosterone levels (Δ 52±14.2%; P<0.01). Fox was not significantly affected by tamoxifen in men. Tamoxifen attenuated the GH response to stimulation and reduced postprandial Fox in women but not in men. We conclude that at a therapeutic dose, the suppressive effect of tamoxifen on fat metabolism is gender-dependent. Higher testosterone levels may mitigate the suppression of GH secretion and Fox during tamoxifen treatment in men. © 2015 European Society of Endocrinology.

  14. Push the flash floating gate memories toward the future low energy application

    NASA Astrophysics Data System (ADS)

    Della Marca, V.; Just, G.; Regnier, A.; Ogier, J.-L.; Simola, R.; Niel, S.; Postel-Pellerin, J.; Lalande, F.; Masoero, L.; Molas, G.

    2013-01-01

    In this paper the energy consumption of flash floating gate cell, during a channel hot electron operation, is investigated. We characterize the device using different ramp and box pulses on control gate, to find the best solution to have low energy consumption and good cell performances. We use a new dynamic method to measure the drain current absorption in order to evaluate the impact of different bias conditions, and to study the cell behavior. The programming window and the energy consumption are considered as fundamental parameters. Using this dynamic technique, three zones of work are found; it is possible to optimize the drain voltage during the programming operation to minimize the energy consumption. Moreover, the cell's performances are improved using the CHISEL effect, with a reverse body bias. After the study concerning the programming pulses adjusting, we show the results obtained by increasing the channel doping dose parameter. Considering a channel hot electron programming operation, it is important to focus our attention on the bitline leakage consumption contribution. We measured it for the unselected bitline cells, and we show the effects of the lightly doped drain implantation energy on the leakage current. In this way the impact of gate induced drain leakage in band-to-band tunneling regime decreases, improving the cell's performances in a memory array.

  15. AIB1 is required for the acquisition of epithelial growth factor receptor-mediated tamoxifen resistance in breast cancer cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Zhao Wenhui; Zhang Qingyuan; Kang Xinmei

    2009-03-13

    Acquired resistance to tamoxifen has become a serious obstacle in breast cancer treatment. The underlying mechanism responsible for this condition has not been completely elucidated. In this study, a tamoxifen-resistant (Tam-R) MCF-7 breast cancer cell line was developed to mimic the occurrence of acquired tamoxifen resistance as seen in clinical practice. Increased expression levels of HER1, HER2 and the estrogen receptor (ER)-AIB1 complex were found in tamoxifen-resistant cells. EGF stimulation and gefitinib inhibition experiments further demonstrated that HER1/HER2 signaling and AIB1 were involved in the proliferation of cells that had acquired Tam resistance. However, when AIB1 was silenced with AIB1-siRNAmore » in Tam-R cells, the cell growth stimulated by the HER1/HER2 signaling pathway was significantly reduced, and the cells were again found to be inhibited by tamoxifen. These results suggest that the AIB1 protein could be a limiting factor in the HER1/HER2-mediated hormone-independent growth of Tam-R cells. Thus, AIB1 may be a new therapeutic target, and the removal of AIB1 may decrease the crosstalk between ER and the HER1/HER2 pathway, resulting in the restoration of tamoxifen sensitivity in tamoxifen-resistant cells.« less

  16. Tamoxifen in the treatment of advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study.

    PubMed

    Thigpen, T; Brady, M F; Homesley, H D; Soper, J T; Bell, J

    2001-01-15

    In two large Gynecologic Oncology Group studies of patients with advanced or recurrent endometrial carcinoma and no previous systemic therapy, progestins have demonstrated activity against advanced or recurrent endometrial carcinoma with response rates between 15% and 25%. Tamoxifen has been reported as variously active or inactive with or without previous systemic therapy. The purpose of this study was to determine whether tamoxifen exhibits enough activity in patients with advanced or recurrent endometrial carcinoma, who have not received systemic therapy, to warrant a phase III trial. Sixty-eight eligible patients with advanced or recurrent endometrial carcinoma received oral tamoxifen 20 mg bid until toxicity was unacceptable or disease progressed. Three complete (4%) and four partial (6%) responses were observed for an overall response rate of 10% (90% confidence interval [CI], 5.7% to 17.9%). Patients with tumors that were more anaplastic tended to respond less frequently. The median progression-free survival for all 68 eligible patients was 1.9 months (90% CI, 1.7 to 3.2 months). The median survival was 8.8 months (90% CI, 7.0 to 10.1 months). Tamoxifen demonstrated modest activity at best against endometrial carcinoma and does not warrant further investigation as a single agent for this disease. Ongoing trials will assess the sequential use of tamoxifen and progestational agents.

  17. Active Flash: Out-of-core Data Analytics on Flash Storage

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Boboila, Simona; Kim, Youngjae; Vazhkudai, Sudharshan S

    2012-01-01

    Next generation science will increasingly come to rely on the ability to perform efficient, on-the-fly analytics of data generated by high-performance computing (HPC) simulations, modeling complex physical phenomena. Scientific computing workflows are stymied by the traditional chaining of simulation and data analysis, creating multiple rounds of redundant reads and writes to the storage system, which grows in cost with the ever-increasing gap between compute and storage speeds in HPC clusters. Recent HPC acquisitions have introduced compute node-local flash storage as a means to alleviate this I/O bottleneck. We propose a novel approach, Active Flash, to expedite data analysis pipelines bymore » migrating to the location of the data, the flash device itself. We argue that Active Flash has the potential to enable true out-of-core data analytics by freeing up both the compute core and the associated main memory. By performing analysis locally, dependence on limited bandwidth to a central storage system is reduced, while allowing this analysis to proceed in parallel with the main application. In addition, offloading work from the host to the more power-efficient controller reduces peak system power usage, which is already in the megawatt range and poses a major barrier to HPC system scalability. We propose an architecture for Active Flash, explore energy and performance trade-offs in moving computation from host to storage, demonstrate the ability of appropriate embedded controllers to perform data analysis and reduction tasks at speeds sufficient for this application, and present a simulation study of Active Flash scheduling policies. These results show the viability of the Active Flash model, and its capability to potentially have a transformative impact on scientific data analysis.« less

  18. Tamoxifen-model membrane interactions: an FT-IR study

    NASA Astrophysics Data System (ADS)

    Boyar, Handan; Severcan, Feride

    1997-06-01

    The temperature- and concentration-induced effects of tamoxifen (TAM) on dipalmitoyl phosphatidylcholine (DPPC) model membranes were investigated by the Fourier transform-infrared (FT-IR) spectroscopic technique. An investigation of the C-H stretching region and the CO mode reveals that the inclusion of TAM changes the physical properties of the DPPC multibilayers by (i) shifting the main phase transition to lower temperatures; (ii) broadening the transition profile slightly; (iii) disordering the system in the gel and in the liquid crystalline phases; (iv) increasing the dynamics in the gel phase and decreasing the dynamics of the acyl chains in the liquid crystalline phase; (v) increasing the mobility of the terminal methyl group region of the bilayer in the gel phase and decreasing it in the liquid crystalline phase; (vi) increasing the frequency of the CO stretching mode both in the gel and in the liquid crystalline phases, i.e. non-bonding with carbonyl groups.

  19. Tamoxifen metabolite isomer separation and quantification by liquid chromatography-tandem mass spectrometry.

    PubMed

    Jaremko, Malgorzata; Kasai, Yumi; Barginear, Myra F; Raptis, George; Desnick, Robert J; Yu, Chunli

    2010-12-15

    Tamoxifen (Tam), the antiestrogen used to treat estrogen receptor-positive breast cancer is a pro-drug that is converted to its major active metabolites, endoxifen and 4-hydroxy-tamoxifen (4-OH-Tam) by various biotransformation enzymes of which cytochrome P450-2D6 (CYP2D6) is key. The usual Tam dose is 20 mg daily; however, the plasma active metabolite concentrations vary due to common genetic variants encoding the biotransformation enzymes and environmental factors (e.g., concomitant drugs) that inhibit these enzymes. Effective treatment depends on adequate Tam conversion to its active isomers. To monitor metabolite plasma levels, a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to separate and quantitate Tam, N-desmethyl-tamoxifen (ND-Tam), and tamoxifen-N-oxide (Tam-N-oxide), and the E, Z, and Z' isomers of endoxifen and 4-OH-Tam. Known standards were used to identify each metabolite/isomer. Quantitation of these metabolites in plasma was linear from 0.6 to 2000 nM. Intra- and inter-assay reproducibilities were 0.2-8.4% and 0.6-6.3%, respectively. Accuracy determined by spike experiments with known standards was 86-103%. Endoxifen, 4-OH-Tam, and their isomers were stable in fresh frozen plasma for ≥6 months. This method provides the first sensitive, specific, accurate, and reproducible quantitation of Tam and its metabolite isomers for monitoring Tam-treated breast cancer patients.

  20. Why Flash Type Matters: A Statistical Analysis

    NASA Astrophysics Data System (ADS)

    Mecikalski, Retha M.; Bitzer, Phillip M.; Carey, Lawrence D.

    2017-09-01

    While the majority of research only differentiates between intracloud (IC) and cloud-to-ground (CG) flashes, there exists a third flash type, known as hybrid flashes. These flashes have extensive IC components as well as return strokes to ground but are misclassified as CG flashes in current flash type analyses due to the presence of a return stroke. In an effort to show that IC, CG, and hybrid flashes should be separately classified, the two-sample Kolmogorov-Smirnov (KS) test was applied to the flash sizes, flash initiation, and flash propagation altitudes for each of the three flash types. The KS test statistically showed that IC, CG, and hybrid flashes do not have the same parent distributions and thus should be separately classified. Separate classification of hybrid flashes will lead to improved lightning-related research, because unambiguously classified hybrid flashes occur on the same order of magnitude as CG flashes for multicellular storms.

  1. Estrogen receptor (ESR1) mRNA expression and benefit from tamoxifen in the treatment and prevention of estrogen receptor-positive breast cancer.

    PubMed

    Kim, Chungyeul; Tang, Gong; Pogue-Geile, Katherine L; Costantino, Joseph P; Baehner, Frederick L; Baker, Joffre; Cronin, Maureen T; Watson, Drew; Shak, Steven; Bohn, Olga L; Fumagalli, Debora; Taniyama, Yusuke; Lee, Ahwon; Reilly, Megan L; Vogel, Victor G; McCaskill-Stevens, Worta; Ford, Leslie G; Geyer, Charles E; Wickerham, D Lawrence; Wolmark, Norman; Paik, Soonmyung

    2011-11-01

    Several mechanisms have been proposed to explain tamoxifen resistance of estrogen receptor (ER) -positive tumors, but a clinically useful explanation for such resistance has not been described. Because the ER is the treatment target for tamoxifen, a linear association between ER expression levels and the degree of benefit from tamoxifen might be expected. However, such an association has never been demonstrated with conventional clinical ER assays, and the ER is currently used clinically as a dichotomous marker. We used gene expression profiling and ER protein assays to help elucidate molecular mechanism(s) responsible for tamoxifen resistance in breast tumors. We performed gene expression profiling of paraffin-embedded tumors from National Surgical Adjuvant Breast and Bowel Project (NSABP) trials that tested the worth of tamoxifen as an adjuvant systemic therapy (B-14) and as a preventive agent (P-1). This was a retrospective subset analysis based on available materials. In B-14, ESR1 was the strongest linear predictor of tamoxifen benefit among 16 genes examined, including PGR and ERBB2. On the basis of these data, we hypothesized that, in the P-1 trial, a lower level of ESR1 mRNA in the tamoxifen arm was the main difference between the two study arms. Only ESR1 was downregulated by more than two-fold in ER-positive cancer events in the tamoxifen arm (P < .001). Tamoxifen did not prevent ER-positive tumors with low levels of ESR1 expression. These data suggest that low-level expression of ESR1 is a determinant of tamoxifen resistance in ER-positive breast cancer. Strategies should be developed to identify, treat, and prevent such tumors.

  2. Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial.

    PubMed

    van de Velde, Cornelis J H; Rea, Daniel; Seynaeve, Caroline; Putter, Hein; Hasenburg, Annette; Vannetzel, Jean-Michel; Paridaens, Robert; Markopoulos, Christos; Hozumi, Yasuo; Hille, Elysee T M; Kieback, Dirk G; Asmar, Lina; Smeets, Jan; Nortier, Johan W R; Hadji, Peyman; Bartlett, John M S; Jones, Stephen E

    2011-01-22

    Aromatase inhibitors improved disease-free survival compared with tamoxifen when given as an initial adjuvant treatment or after 2-3 years of tamoxifen to postmenopausal women with hormone-receptor-positive breast cancer. We therefore compared the long-term effects of exemestane monotherapy with sequential treatment (tamoxifen followed by exemestane). The Tamoxifen Exemestane Adjuvant Multinational (TEAM) phase 3 trial was conducted in hospitals in nine countries. Postmenopausal women (median age 64 years, range 35-96) with hormone-receptor-positive breast cancer were randomly assigned in a 1:1 ratio to open-label exemestane (25 mg once a day, orally) alone or following tamoxifen (20 mg once a day, orally) for 5 years. Randomisation was by use of a computer-generated random permuted block method. The primary endpoint was disease-free survival (DFS) at 5 years. Main analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, NCT00279448, NCT00032136, and NCT00036270; NTR 267; Ethics Commission Trial27/2001; and UMIN, C000000057. 9779 patients were assigned to sequential treatment (n=4875) or exemestane alone (n=4904), and 4868 and 4898 were analysed by intention to treat, respectively. 4154 (85%) patients in the sequential group and 4186 (86%) in the exemestane alone group were disease free at 5 years (hazard ratio 0·97, 95% CI 0·88-1·08; p=0·60). In the safety analysis, sequential treatment was associated with a higher incidence of gynaecological symptoms (942 [20%] of 4814 vs 523 [11%] of 4852), venous thrombosis (99 [2%] vs 47 [1%]), and endometrial abnormalities (191 [4%] vs 19 [<1%]) than was exemestane alone. Musculoskeletal adverse events (2448 [50%] vs 2133 [44%]), hypertension (303 [6%] vs 219 [5%]), and hyperlipidaemia (230 [5%] vs 136 [3%]) were reported more frequently with exemestane alone. Treatment regimens of exemestane alone or after tamoxifen might be judged to be appropriate options for postmenopausal women with

  3. Functional polymorphisms in UDP-glucuronosyltransferases and recurrence in tamoxifen-treated breast cancer survivors

    PubMed Central

    Ahern, Thomas P.; Christensen, Mariann; Cronin-Fenton, Deirdre P.; Lunetta, Kathryn L.; Søiland, Håvard; Gjerde, Jennifer; Garne, Jens Peter; Rosenberg, Carol L.; Silliman, Rebecca A.; Sørensen, Henrik Toft; Lash, Timothy L.; Hamilton-Dutoit, Stephen

    2011-01-01

    Background Tamoxifen is oxidized by cytochrome-P450 enzymes (e.g., CYP2D6) to two active metabolites, which are eliminated via glucuronidation by UDP-glucuronosyltransferases (UGTs). We measured the association between functional polymorphisms in key UGTs (UGT2B15*2, UGT2B7*2, and UGT1A8*3) and the recurrence rate among breast cancer survivors. Methods We used the Danish Breast Cancer Cooperative Group registry to identify 541 cases of recurrent breast cancer among women with estrogen receptor-positive tumors treated with tamoxifen for at least one year (ER+/TAM+), and 300 cases of recurrent breast cancer among women with estrogen receptor-negative tumors who were not treated with tamoxifen (ER−/TAM−). We matched 1 control to each case on ER status, menopausal status, stage, calendar period, and county. UGT polymorphisms were genotyped from archived primary tumors. We estimated the recurrence odds ratio for the UGT polymorphisms using logistic regression models, with and without stratification on CYP2D6*4 genotype. Results No UGT polymorphism was associated with breast cancer recurrence in either the ER+/TAM+ or ER-/TAM- groups [in the ER+TAM+ group, compared with two normal alleles: adjusted OR for two UGT2B15*2 variant alleles = 1.0 (95% CI: 0.70, 1.5); adjusted OR for two for UGT2B7*2 variant alleles = 0.91 (95% CI: 0.65, 1.3); adjusted OR for 1 or 2 UGT1A8*3 variant alleles = 0.75 (0.41, 1.4)]. Associations were similar within strata of CYP2D6*4 genotype. Conclusions Functional polymorphisms in key tamoxifen-metabolizing enzymes were not associated with breast cancer recurrence risk. Impact Our results do not support the genotyping of key metabolic enzyme polymorphisms to predict response to tamoxifen therapy. PMID:21750172

  4. Highly sensitive simultaneous quantification of estrogenic tamoxifen metabolites and steroid hormones by LC-MS/MS.

    PubMed

    Johänning, Janina; Heinkele, Georg; Precht, Jana C; Brauch, Hiltrud; Eichelbaum, Michel; Schwab, Matthias; Schroth, Werner; Mürdter, Thomas E

    2015-09-01

    Tamoxifen is a mainstay in the treatment of estrogen receptor-positive breast cancer and is metabolized to more than 30 different compounds. Little is known about in vivo concentrations of estrogenic metabolites E-metabolite E, Z-metabolite E, and bisphenol and their relevance for tamoxifen efficacy. Therefore, we developed a highly sensitive HPLC-ESI-MS/MS quantification method for tamoxifen metabolites bisphenol, E-metabolite E, and Z-metabolite E as well as for the sex steroid hormones estradiol, estrone, testosterone, androstenedione, and progesterone. Plasma samples were subjected to protein precipitation followed by solid phase extraction. Upon derivatization with 3-[(N-succinimide-1-yl)oxycarbonyl]-1-methylpyridinium iodide, all analytes were separated on a sub-2-μm column with a gradient of acetonitrile in water with 0.1 % of formic acid. Analytes were detected on a triple-quadrupole mass spectrometer with positive electrospray ionization in the multiple reaction monitoring mode. Our method demonstrated high sensitivity, accuracy, and precision. The lower limits of quantification were 12, 8, and 25 pM for bisphenol, E-metabolite E, and Z-metabolite E, respectively, and 4 pM for estradiol and estrogen, 50 pM for testosterone and androstenedione, and 25 pM for progesterone. The method was applied to plasma samples of postmenopausal patients taken at baseline and under tamoxifen therapy. Graphical Abstract Sample preparation and derivatization for highly sensitive quantification of estrogenic tamoxifen metabolites and steroid hormones by HPLC-MS/MS.

  5. The Effect of Undaria pinnatifida Fucoidan on the Pharmacokinetics of Letrozole and Tamoxifen in Patients With Breast Cancer.

    PubMed

    Tocaciu, Shreya; Oliver, Lesley J; Lowenthal, Ray M; Peterson, Gregory M; Patel, Rahul; Shastri, Madhur; McGuinness, Georgia; Olesen, Inger; Fitton, J Helen

    2018-03-01

    Although the use of complementary and alternative medicines is widespread in cancer patients, clinical evidence of their benefits is sparse. Furthermore, while they are often assumed to be safe with regard to concurrent use of anticancer therapies, few studies have been carried out to investigate possible interactions. Fucoidans are a group of sulfated carbohydrates, derived from marine brown algae, which have long been used as dietary supplements due to their reported medicinal properties, including anticancer activity. The aim of this study was to investigate the effect of co-administration of fucoidan, derived from Undaria pinnatifida, on the pharmacokinetics of 2 commonly used hormonal therapies, letrozole and tamoxifen, in patients with breast cancer. This was an open label non-crossover study in patients with active malignancy taking letrozole or tamoxifen (n = 10 for each group). Patients took oral fucoidan, given in the form of Maritech extract, for a 3-week period (500 mg twice daily). Trough plasma concentrations of letrozole, tamoxifen, 4-hydroxytamoxifen, and endoxifen were measured using HPLC-CAD (high-performance liquid chromatography charged aerosol detector), at baseline and after concomitant administration with fucoidan. No significant changes in steady-state plasma concentrations of letrozole, tamoxifen, or tamoxifen metabolites were detected after co-administration with fucoidan. In addition, no adverse effects of fucoidan were reported, and toxicity monitoring showed no significant differences in all parameters measured over the study period. Administration of Undaria pinnatifida fucoidan had no significant effect on the steady-state trough concentrations of letrozole or tamoxifen and was well tolerated. These results suggest that fucoidan in the studied form and dosage could be taken concomitantly with letrozole and tamoxifen without the risk of clinically significant interactions.

  6. Estrogen signaling selectively induces apoptosis of hematopoietic progenitors and myeloid neoplasms without harming steady-state hematopoiesis.

    PubMed

    Sánchez-Aguilera, Abel; Arranz, Lorena; Martín-Pérez, Daniel; García-García, Andrés; Stavropoulou, Vaia; Kubovcakova, Lucia; Isern, Joan; Martín-Salamanca, Sandra; Langa, Xavier; Skoda, Radek C; Schwaller, Jürg; Méndez-Ferrer, Simón

    2014-12-04

    Estrogens are potent regulators of mature hematopoietic cells; however, their effects on primitive and malignant hematopoietic cells remain unclear. Using genetic and pharmacological approaches, we observed differential expression and function of estrogen receptors (ERs) in hematopoietic stem cell (HSC) and progenitor subsets. ERα activation with the selective ER modulator (SERM) tamoxifen induced apoptosis in short-term HSCs and multipotent progenitors. In contrast, tamoxifen induced proliferation of quiescent long-term HSCs, altered the expression of self-renewal genes, and compromised hematopoietic reconstitution after myelotoxic stress, which was reversible. In mice, tamoxifen treatment blocked development of JAK2(V617F)-induced myeloproliferative neoplasm in vivo, induced apoptosis of human JAK2(V617F+) HSPCs in a xenograft model, and sensitized MLL-AF9(+) leukemias to chemotherapy. Apoptosis was selectively observed in mutant cells, and tamoxifen treatment only had a minor impact on steady-state hematopoiesis in disease-free animals. Together, these results uncover specific regulation of hematopoietic progenitors by estrogens and potential antileukemic properties of SERMs. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Mutational analysis of FLASH and PTPN13 genes in colorectal carcinomas.

    PubMed

    Jeong, Eun Goo; Lee, Sung Hak; Yoo, Nam Jin; Lee, Sug Hyung

    2008-01-01

    The Fas-Fas ligand system is considered a major pathway for induction of apoptosis in cells and tissues. FLASH was identified as a pro-apoptotic protein that transmits apoptosis signal during Fas-mediated apoptosis. PTPN13 interacts with Fas and functions as both suppressor and inducer of Fas-mediated apoptosis. There are polyadenine tracts in both FLASH (A8 and A9 in exon 8) and PTPN13 (A8 in exon 7) genes that could be frameshift mutation targets in colorectal carcinomas. Because genes encoding proteins in Fas-mediated apoptosis frequently harbor somatic mutations in cancers, we explored the possibility as to whether mutations of FLASH and PTPN13 are a feature of colorectal carcinomas. We analysed human FLASH in exon 8 and PTPN13 in exon 7 for the detection of somatic mutations in 103 colorectal carcinomas by a polymerase chain reaction (PCR)- based single-strand conformation polymorphism (SSCP). We detected two mutations in FLASH gene, but none in PTPN13 gene. However, the two mutations were not frameshift (deletion or insertion) mutations in the polyadenine tracts of FLASH. The two mutations consisted of a deletion mutation (c.3734-3737delAGAA) and a missense mutation (c.3703A>C). These data indicate that frameshift mutation in the polyadenine tracts in both FLASH and PTPN13 genes is rare in colorectal carcinomas. Also, the data suggest that both FLASH and PTPN13 mutations in the polyadenine tracts may not have a crucial role in the pathogenesis of colorectal carcinomas.

  8. Estrogen Receptor (ESR1) mRNA Expression and Benefit From Tamoxifen in the Treatment and Prevention of Estrogen Receptor–Positive Breast Cancer

    PubMed Central

    Kim, Chungyeul; Tang, Gong; Pogue-Geile, Katherine L.; Costantino, Joseph P.; Baehner, Frederick L.; Baker, Joffre; Cronin, Maureen T.; Watson, Drew; Shak, Steven; Bohn, Olga L.; Fumagalli, Debora; Taniyama, Yusuke; Lee, Ahwon; Reilly, Megan L.; Vogel, Victor G.; McCaskill-Stevens, Worta; Ford, Leslie G.; Geyer, Charles E.; Wickerham, D. Lawrence; Wolmark, Norman; Paik, Soonmyung

    2011-01-01

    Purpose Several mechanisms have been proposed to explain tamoxifen resistance of estrogen receptor (ER) –positive tumors, but a clinically useful explanation for such resistance has not been described. Because the ER is the treatment target for tamoxifen, a linear association between ER expression levels and the degree of benefit from tamoxifen might be expected. However, such an association has never been demonstrated with conventional clinical ER assays, and the ER is currently used clinically as a dichotomous marker. We used gene expression profiling and ER protein assays to help elucidate molecular mechanism(s) responsible for tamoxifen resistance in breast tumors. Patients and Methods We performed gene expression profiling of paraffin-embedded tumors from National Surgical Adjuvant Breast and Bowel Project (NSABP) trials that tested the worth of tamoxifen as an adjuvant systemic therapy (B-14) and as a preventive agent (P-1). This was a retrospective subset analysis based on available materials. Results In B-14, ESR1 was the strongest linear predictor of tamoxifen benefit among 16 genes examined, including PGR and ERBB2. On the basis of these data, we hypothesized that, in the P-1 trial, a lower level of ESR1 mRNA in the tamoxifen arm was the main difference between the two study arms. Only ESR1 was downregulated by more than two-fold in ER-positive cancer events in the tamoxifen arm (P < .001). Tamoxifen did not prevent ER-positive tumors with low levels of ESR1 expression. Conclusion These data suggest that low-level expression of ESR1 is a determinant of tamoxifen resistance in ER-positive breast cancer. Strategies should be developed to identify, treat, and prevent such tumors. PMID:21947828

  9. Effects of Aqueous Extracts of Chicory and Milk Thistle on Serum Concentrations of Copper, Zinc, and Manganese in Tamoxifen-Treated Rats.

    PubMed

    Abbasalipourkabir, Roghayeh; Ziamajidi, Nasrin; Nasiri, Abolfazl; Behrouj, Hamid

    2016-09-01

    Some medications may change trace element levels in the body. Extracts of various plants, due to having the several elements, can have beneficial effects. Consumption of herbal extracts with chemical drugs may reduce adverse effects of medication. The goal of this study was to evaluate copper (Cu), zinc (Zn), and manganese (Mn) concentrations in serum of rats treated with tamoxifen, chicory, and/or milk thistle extracts. Therefore, 36 adult female Wistar rats were divided into six groups: normal control, chicory control, milk thistle control, tamoxifen, tamoxifen-chicory, and tamoxifen-milk thistle. At the end of the study, the blood samples were collected and sera isolated by centrifugation and analyzed by the atomic absorption spectrophotometry for Cu, Zn, and Mn levels. The Zn concentration increased in milk thistle-supplemented groups. The Cu level increased in the chicory control group only. Tamoxifen had no affect on Cu, Zn, and Mn levels, but seed extract of milk thistle increased Zn concentration, and chicory root extract increased Cu concentration. Although elevated levels of Cu in rats receiving tamoxifen-chicory were milder than rats treated only with chicory, it seems that the extract and tamoxifen impact on the Cu are in conflict with each other.

  10. Tamoxifen Downregulates Ets-oncogene Family Members ETV4 and ETV5 in Benign Breast Tissue: Implications for Durable Risk Reduction

    PubMed Central

    Euhus, David; Bu, Dawei; Xie, Xian-Jin; Sarode, Venetia; Ashfaq, Raheela; Hunt, Kelly; Xia, Weiya; O’Shaughnessy, Joyce; Grant, Michael; Arun, Banu; Dooley, William; Miller, Alexander; Flockhart, David; Lewis, Cheryl

    2011-01-01

    Background Five years of tamoxifen reduces breast cancer risk by nearly 50% but is associated with significant side-effects and toxicities. A better understanding of the direct and indirect effects of tamoxifen in benign breast tissue could elucidate new mechanisms of breast carcinogenesis, suggest novel chemoprevention targets, and provide relevant early response biomarkers for Phase II prevention trials. Methods Seventy-three women at increased risk for breast cancer were randomized to tamoxifen (20 mg daily) or placebo for three months. Blood and breast tissue samples were collected at baseline and post-treatment. Sixty-nine women completed all study activities (37 tamoxifen and 32 placebo). The selected biomarkers focused on estradiol and IGFs in the blood, DNA methylation and cytology in random periareolar fine needle aspirates, and tissue morphometry, proliferation, apoptosis, and gene expression (microarray and RT-PCR) in the tissue core samples. Results Tamoxifen downregulated ets-oncogene transcription factor family members ETV4 and ETV5 and reduced breast epithelial cell proliferation independent of CYP2D6 genotypes or effects on estradiol, ESR1 or IGFs. Reduction in proliferation was correlated with downregulation of ETV4 and DNAJC12. Tamoxifen reduced the expression of ETV4- and ETV5-regulated genes implicated in epithelial-stromal interaction and tissue remodeling. Three months of tamoxifen did not affect breast tissue composition, cytological atypia, preneoplasia or apoptosis. Conclusions A plausible mechanism for the chemopreventive effects of tamoxifen is restriction of lobular expansion into stroma through downregulation of ETV4 and ETV5. Multipotential progenitor cap cells of terminal end buds may be the primary target. PMID:21778330

  11. Atypia in random periareolar fine-needle aspiration affects the decision of women at high risk to take tamoxifen for breast cancer chemoprevention.

    PubMed

    Goldenberg, Vanessa K; Seewaldt, Victoria L; Scott, Victoria; Bean, Gregory R; Broadwater, Gloria; Fabian, Carol; Kimler, Bruce; Zalles, Carola; Lipkus, Isaac M

    2007-05-01

    Random periareolar fine-needle aspiration (RPFNA) is a research procedure designed to (a) evaluate short-term breast cancer risk in women at high risk for developing breast cancer, and (b) track response to chemoprevention. Of import, cellular atypia in breast RPFNA is prospectively associated with a 5.6-fold increase in breast cancer risk in women at high risk. Among 99 women attending a clinic for high-risk breast cancer, we explored the effects of RPFNA cytology results on decision making pertaining to the use of tamoxifen for breast cancer chemoprevention. No patient with nonproliferative or hyperplastic cytology subsequently elected to take tamoxifen. Only 7% of subjects with borderline atypia elected to take tamoxifen. In contrast, 50% with atypia elected to take tamoxifen. These results suggest that the provision of a biomarker of short-term risk can affect the motivation to take tamoxifen for chemoprevention. This conclusion is informative given that tamoxifen, due to its side effects, is often underused by women at high risk of developing breast cancer. Further research is needed to determine the mechanisms through which RPFNA results affect the decision to use tamoxifen, or any other breast cancer chemopreventive agent.

  12. Evaluating Letrozole and Tamoxifen Alone and in Sequence for Postmenopausal Women with Steroid Hormone Receptor-Positive Breast Cancer: the BIG 1-98 Randomized Clinical Trial at 8.1 years Median Follow-Up

    PubMed Central

    Regan, Meredith M.; Neven, Patrick; Giobbie-Hurder, Anita; Goldhirsch, Aron; Ejlertsen, Bent; Mauriac, Louis; Forbes, John F.; Smith, Ian; Láng, István; Wardley, Andrew; Rabaglio, Manuela; Price, Karen N.; Gelber, Richard D.; Coates, Alan S.; Thürlimann, Beat

    2011-01-01

    clinicaltrials.gov NCT00004205. Findings At a median follow-up of 8.7 years from randomization (range 0–12.4), letrozole monotherapy is significantly better than tamoxifen, whether using IPCW or intention-to-treat (ITT) analysis [IPCW: DFS HR 0.82 (95% CI 0.74–0.92), OS HR 0.79 (0.69–0.900, DRFI HR 0.79 (0.68–0.92), BCFI HR 0.80 (0.70–0.92); ITT: DFS HR 0.86 (0.78–0.96), OS HR 0.87 (0.77–0.999), DRFI HR 0.86 (0.74–0.998), BCFI HR 0.86 (0.76–0.98)]. At a median follow-up of 8.0 years from randomization (range 0–11.2), there were no statistically significant differences in any of the four endpoints for either sequence compared with letrozole monotherapy. Eight-year ITT estimates [each with SE ≤ 1.1%] for letrozole monotherapy, letrozole followed by tamoxifen, and tamoxifen followed by letrozole were 78.6%, 77.8%, 77.3% for DFS; 87.5%, 87.7%, 85.9% for OS; 89.9%, 88.7%, 88.1% for DRFI; and 86.1%, 85.3%, 84.3% for BCFI. Interpretation For postmenopausal women with endocrine-responsive early breast cancer, a reduction in breast cancer recurrence and mortality is obtained by letrozole monotherapy when compared to tamoxifen. Sequential treatments involving tamoxifen and letrozole do not improve outcome compared with letrozole monotherapy, but may represent useful strategies considering individual patient’s risk of recurrence and treatment tolerability: more thromboembolic events, vaginal bleeding, hot flushes and night sweats with tamoxifen, while more vaginal dryness, bone fractures, osteoporosis, arthralgia/myalgia, and higher grade cardiac events with letrozole. Funding Novartis, United States National Cancer Institute, International Breast Cancer Study Group. PMID:22018631

  13. Tamoxifen for breast cancer risk reduction: impact of alternative approaches to quality-of-life adjustment on cost-effectiveness analysis.

    PubMed

    Melnikow, Joy; Birch, Stephen; Slee, Christina; McCarthy, Theodore J; Helms, L Jay; Kuppermann, Miriam

    2008-09-01

    In cost-effectiveness analysis (CEA), the effects of health-care interventions on multiple health dimensions typically require consideration of both quantity and quality of life. To explore the impact of alternative approaches to quality-of-life adjustment using patient preferences (utilities) on the outcome of a CEA on use of tamoxifen for breast cancer risk reduction. A state transition Markov model tracked hypothetical cohorts of women who did or did not take 5 years of tamoxifen for breast cancer risk reduction. Incremental quality-adjusted effectiveness and cost-effectiveness ratios (ICERs) for models including and excluding a utility adjustment for menopausal symptoms were compared with each other and to a global utility model. Two hundred fifty-five women aged 50 and over with estimated 5-year breast cancer risk >or=1.67% participated in utility assessment interviews. Standard gamble utilities were assessed for specified tamoxifen-related health outcomes, current health, and for a global assessment of possible outcomes of tamoxifen use. Inclusion of a utility for menopausal symptoms in the outcome-specific models substantially increased the ICER; at the threshold 5-year breast cancer risk of 1.67%, tamoxifen was dominated. When a global utility for tamoxifen was used in place of outcome-specific utilities, tamoxifen was dominated under all circumstances. CEAs may be profoundly affected by the types of outcomes considered for quality-of-life adjustment and how these outcomes are grouped for utility assessment. Comparisons of ICERs across analyses must consider effects of different approaches to using utilities for quality-of-life adjustment.

  14. Two-flash thresholds as a function of flash luminance and area.

    DOT National Transportation Integrated Search

    1968-09-01

    The recent use of strobe lights in aviation suggests the possibility of using temporal patterns of short duration flashes as information-carrying signals. Under night flight conditions, two-flash thresholds were obtained using a two-interval, tempora...

  15. Relationship of ZNF423 and CTSO with breast cancer risk in two randomised tamoxifen prevention trials.

    PubMed

    Brentnall, Adam R; Cuzick, Jack; Byers, Helen; Segal, Corrinne; Reuter, Caroline; Detre, Simone; Sestak, Ivana; Howell, Anthony; Powles, Trevor J; Newman, William G; Dowsett, Mitchell

    2016-08-01

    A case-control study from two randomised breast cancer prevention trials of tamoxifen and raloxifene (P-1 and P-2) identified single-nucleotide polymorphisms (SNPs) in or near genes ZNF423 and CTSO as factors which predict which women will derive most anti-cancer benefit from selective oestrogen receptor modulator (SERM) therapy. In this article, we further examine this question using blood samples from two randomised tamoxifen prevention trials: the International Breast Cancer Intervention Study I (IBIS-I) and the Royal Marsden trial (Marsden). A nested case-control study was designed with 2:1 matching in IBIS-I and 1:1 matching in Marsden. The OncoArray was used for genotyping and included two SNPs previously identified (rs8060157 in ZNF423 and rs10030044 near CTSO), and 102 further SNPs within the same regions. Overall, there were 369 cases and 662 controls, with 148 cases and 268 controls from the tamoxifen arms. Odds ratios were estimated by conditional logistic regression, with Wald 95 % confidence intervals. In the tamoxifen arms, the per-allele odds ratio for rs8060157 was 0.99 (95 %CI 0.73-1.34) and 1.00 (95 %CI 0.76-1.33) for rs10030044. In the placebo arm, the odds ratio was 1.10 (95 %CI 0.87-1.40) for rs8060157 and 1.01 (95 %CI 0.79-1.29) for rs10030044. There was no evidence to suggest that other SNPs in the surrounding regions of these SNPs might predict response to tamoxifen. Results from these two prevention trials do not support the earlier findings. rs8060157 in ZNF423 and rs10030044 near CTSO do not appear to predict response to tamoxifen.

  16. No effect on pharmacokinetics of tamoxifen and 4-hydroxytamoxifen by multiple doses of red clover capsule in rats

    PubMed Central

    Raju, Kanumuri Siva Rama; Taneja, Isha; Valicherla, Guru Raghavendra; Challagundla, Murali Krishna; Rashid, Mamunur; Syed, Anees Ahmed; Gayen, Jiaur Rahman; Singh, Sheelendra Pratap; Wahajuddin, Muhammad

    2015-01-01

    Tamoxifen is used in clinical practice for breast cancer patients and to prevent osteoporosis. Red clover (Trifolium pratense) preparations are consumed worldwide as dietary supplements for relieving postmenopausal symptoms. In the present study we investigated the possible herb-drug interaction between red clover and tamoxifen in rats. 15 days pre-treatment with red clover did not alter the tamoxifen and its active metabolite 4-hydroxytamoxifen pharmacokinetics significantly (p > 0.05). Therefore the therapeutic efficacy of the tamoxifen may not be compromised by the co-administration with red clover. Tamoxifen metabolism is primarily mediated by CYP2D6, CYP3A4 with minor contribution from CYP2C9, CYP2E1 and CYP1A2 isoforms. Although, red clover pre-treatment significantly (p < 0.05) decreased the mRNA expression and activity of CYP3a2, no effect on CYP2d4 and increased expression and activity of CYP2c11 could be the plausible reasons for lack of effect on tamoxifen and its metabolite pharmacokinetics in rats. CYP1a1 and CYP2b2 mRNA expression and activity were also significantly reduced by red clover. To extend the clinical utility of the present study, effect of red clover extract on major CYPs using human liver microsomes and HepG2 cell lines were also determined. Similar finding were observed in the human liver preparations as in rats. PMID:26530625

  17. The vibrational spectroscopic studies and molecular property analysis of Estradiol, Tamoxifen and their interaction by density functional theory

    NASA Astrophysics Data System (ADS)

    Borah, Mukunda Madhab; Gomti Devi, Th.

    2018-07-01

    In the present work Tamoxifen, Estradiol and their interaction are studied using the experimental and theoretical methodologies. The spectral characterization was made by using Raman, FTIR, DFT and VEDA calculation. The optimization of the molecules have been studied using basis set B3LYP/6-31 G(d,p). Complete vibrational assignment of Tamoxifen, Estradiol and Estradiol + Tamoxifen have been attempted and the potential energy distribution and normal mode analysis had also been carried out to determine the contributions of bond oscillators in each normal mode. We have optimized several binding modes of Estradiol and Tamoxifen and taken the lowest energy conformer in our interest. The molecular geometry, HOMO-LUMO energy gap, molecular hardness (η), ionization energy (IE), electron affinity (EA), total energy and dipole moment were analyzed. The observed experimental and the scaled theoretical results were found in good agreement.

  18. Development and validation of an UPLC-MS/MS method for the quantification of tamoxifen and its main metabolites in human scalp hair.

    PubMed

    Drooger, Jan C; Jager, Agnes; Lam, Mei-Ho; den Boer, Mathilda D; Sleijfer, Stefan; Mathijssen, Ron H J; de Bruijn, Peter

    2015-10-10

    The aim of this study was to validate an earlier developed high-performance highly sensitive ultra performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method for quantification of tamoxifen and its three main metabolites (N-desmethyl-tamoxifen, 4-hydroxy-tamoxifen and 4-hydroxy-N-desmethyl-tamoxifen) in scalp hair. This non-invasive method might, by segmental analysis of hair, be useful in the determination of the concentration of drugs and its metabolites over time, which can be used to study a wide variety of clinical relevant questions. Hair samples (150-300 hair strands, cut as close to the scalp as possible from the posterior vertex region of the head) were collected from female patients taking tamoxifen 20mg daily (n=19). The analytes were extracted using a liquid-liquid extraction procedure with carbonate buffer at pH 8.8 and a mixture of n-hexane/isopropranol method, followed by UPLC-MS/MS chromatography, based on an earlier validated method. The calibration curves were linear in the range of 1.00-200 pmol for tamoxifen and N-desmethyl-tamoxifen, with lower limit of quantitation of 1.00 pmol and 0.100-20.0 pmol with lower limit of quantitation of 0.100 pmol for endoxifen and 4-hydroxy-tamoxifen. Assay performance was fair with a within-run and between-run variability less than 9.24 at the three quality control samples and less than 15.7 for the lower limit of quantitation. Importantly, a steep linear decline was observed from distal to proximal hair segments. Probably, this is due to UV exposure as we showed degradation of tamoxifen and its metabolites after exposure to UV-light. Furthermore, higher concentrations of tamoxifen were found in black hair samples compared to blond and brown hair samples. We conclude that measurement of the concentration of tamoxifen and its main metabolites in hair is possible, with the selective, sensitive, accurate and precise UPLC-MS/MS method. However, for tamoxifen, it seems not possible to determine

  19. Proteomic analysis of acquired tamoxifen resistance in MCF-7 cells reveals expression signatures associated with enhanced migration

    PubMed Central

    2012-01-01

    Introduction Acquired tamoxifen resistance involves complex signaling events that are not yet fully understood. Successful therapeutic intervention to delay the onset of hormone resistance depends critically on mechanistic elucidation of viable molecular targets associated with hormone resistance. This study was undertaken to investigate the global proteomic alterations in a tamoxifen resistant MCF-7 breast cancer cell line obtained by long term treatment of the wild type MCF-7 cell line with 4-hydroxytamoxifen (4-OH Tam). Methods We cultured MCF-7 cells with 4-OH Tam over a period of 12 months to obtain the resistant cell line. A gel-free, quantitative proteomic method was used to identify and quantify the proteome of the resistant cell line. Nano-flow high-performance liquid chromatography coupled to high resolution Fourier transform mass spectrometry was used to analyze fractionated peptide mixtures that were isobarically labeled from the resistant and control cell lysates. Real time quantitative PCR and Western blots were used to verify selected proteomic changes. Lentiviral vector transduction was used to generate MCF-7 cells stably expressing S100P. Online pathway analysis was performed to assess proteomic signatures in tamoxifen resistance. Survival analysis was done to evaluate clinical relevance of altered proteomic expressions. Results Quantitative proteomic analysis revealed a wide breadth of signaling events during transition to acquired tamoxifen resistance. A total of 629 proteins were found significantly changed with 364 up-regulated and 265 down-regulated. Collectively, these changes demonstrated the suppressed state of estrogen receptor (ER) and ER-regulated genes, activated survival signaling and increased migratory capacity of the resistant cell line. The protein S100P was found to play a critical role in conferring tamoxifen resistance and enhanced cell motility. Conclusions Our data demonstrate that the adaptive changes in the proteome of

  20. Risk of mortality with concomitant use of tamoxifen and selective serotonin reuptake inhibitors: multi-database cohort study.

    PubMed

    Donneyong, Macarius M; Bykov, Katsiaryna; Bosco-Levy, Pauline; Dong, Yaa-Hui; Levin, Raisa; Gagne, Joshua J

    2016-09-30

     To compare differences in mortality between women concomitantly treated with tamoxifen and selective serotonin reuptake inhibitors (SSRIs) that are potent inhibitors of the cytochrome-P450 2D6 enzyme (CYP2D6) versus tamoxifen and other SSRIs.  Population based cohort study.  Five US databases covering individuals enrolled in private and public health insurance programs from 1995 to 2013.  Two cohorts of women who started taking tamoxifen. In cohort 1, women started taking an SSRI during tamoxifen treatment. In cohort 2, women were already taking an SSRI when they started taking tamoxifen.  All cause mortality in each cohort in women taking SSRIs that are potent inhibitors of CYP2D6 (paroxetine, fluoxetine) versus other SSRIs. Propensity scores were used to match exposure groups in a variable ratio fashion. Results were measured separately for each cohort and combined hazard ratios calculated from Cox regression models across the two cohorts with random effects meta-analysis.  There were 6067 and 8465 new users of tamoxifen in cohorts 1 and 2, respectively. Mean age was 55. A total of 991 and 1014 deaths occurred in cohorts 1 and 2 during a median follow-up of 2.2 (interquartile range 0.9-4.5) and 2.0 (0.8-3.9) years, respectively. The pooled hazard ratio for death for potent inhibitors (rate 58.6/1000 person years) compared with other SSRIs (rate 57.9/1000 person years) across cohorts 1 and 2 was 0.96 (95% confidence interval 0.88 to 1.06). Results were consistent across sensitivity analyses.  Concomitant use of tamoxifen and potent CYP2D6 inhibiting SSRIs versus other SSRIs was not associated with an increased risk of death. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  1. Tamoxifen inhibits tumor cell invasion and metastasis in mouse melanoma through suppression of PKC/MEK/ERK and PKC/PI3K/Akt pathways

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Matsuoka, Hiroshi; Department of Pharmacy, Nara Hospital, Kinki University School of Medicine, 1248-1 Ikoma, Nara 630-0293; Tsubaki, Masanobu

    2009-07-15

    In melanoma, several signaling pathways are constitutively activated. Among these, the protein kinase C (PKC) signaling pathways are activated through multiple signal transduction molecules and appear to play major roles in melanoma progression. Recently, it has been reported that tamoxifen, an anti-estrogen reagent, inhibits PKC signaling in estrogen-negative and estrogen-independent cancer cell lines. Thus, we investigated whether tamoxifen inhibited tumor cell invasion and metastasis in mouse melanoma cell line B16BL6. Tamoxifen significantly inhibited lung metastasis, cell migration, and invasion at concentrations that did not show anti-proliferative effects on B16BL6 cells. Tamoxifen also inhibited the mRNA expressions and protein activities ofmore » matrix metalloproteinases (MMPs). Furthermore, tamoxifen suppressed phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt through the inhibition of PKC{alpha} and PKC{delta} phosphorylation. However, other signal transduction factor, such as p38 mitogen-activated protein kinase (p38MAPK) was unaffected. The results indicate that tamoxifen suppresses the PKC/mitogen-activated protein kinase kinase (MEK)/ERK and PKC/phosphatidylinositol-3 kinase (PI3K)/Akt pathways, thereby inhibiting B16BL6 cell migration, invasion, and metastasis. Moreover, tamoxifen markedly inhibited not only developing but also clinically evident metastasis. These findings suggest that tamoxifen has potential clinical applications for the treatment of tumor cell metastasis.« less

  2. Tamoxifen therapy improves overall survival in luminal A subtype of ductal carcinoma in situ: a study based on nationwide Korean Breast Cancer Registry database.

    PubMed

    Hwang, Ki-Tae; Kim, Eun-Kyu; Jung, Sung Hoo; Lee, Eun Sook; Kim, Seung Il; Lee, Seokwon; Park, Heung Kyu; Kim, Jongjin; Oh, Sohee; Kim, Young A

    2018-06-01

    To determine the prognostic role of tamoxifen therapy for patients with ductal carcinoma in situ (DCIS) according to molecular subtypes. Data of 14,944 patients with DCIS were analyzed. Molecular subtypes were classified into four categories based on expression of estrogen receptor (ER)/progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). Kaplan-Meier estimator was used for overall survival analysis while Cox proportional hazards model was used for univariate and multivariate analyses. Luminal A subtype (ER/PR+, HER2-) showed higher (P = .009) survival rate than triple-negative (TN) subtype. Tamoxifen therapy group showed superior (P < .001) survival than no-tamoxifen therapy group. It had survival benefit only for luminal A subtype (P = .001). Tamoxifen therapy resulted in higher survival rate in subgroups with positive ER (P = .006), positive PR (P = .009), and negative HER2 (P < .001). In luminal A subtype, tamoxifen therapy showed lower hazard ratio (HR) compared to no-tamoxifen therapy (HR, 0.420; 95% CI 0.250-0.705; P = .001). Tamoxifen therapy was a significant independent factor by multivariate analysis (HR, 0.538; 95% CI 0.306-0.946; P = .031) as well as univariate analysis. Tamoxifen therapy group showed superior prognosis than the no-tamoxifen therapy group. Its prognostic influence was only effective for luminal A subtype. Patients with luminal A subtype showed higher survival rate than those with TN subtype. Active tamoxifen therapy is recommended for DCIS patients with luminal A subtype, and routine tests for ER, PR, and HER2 should be considered for DCIS.

  3. 4-Hydroxytamoxifen induces slight uncoupling of mitochondrial oxidative phosphorylation system in relation to the deleterious effects of tamoxifen.

    PubMed

    Cardoso, Carla M P; Moreno, António J M; Almeida, Leonor M; Custódio, José B A

    2002-10-15

    The use of tamoxifen (TAM) has been questioned on the chemotherapy and chemoprevention of breast cancer due to several estrogen receptor-independent cytotoxic effects. As an alternative, its more active metabolite 4-hydroxytamoxifen (OHTAM) has been proposed with presumed lower side effects. In this work, the potential OHTAM toxicity on rat liver mitochondrial bioenergetics in relation to the multiple deleterious effects of TAM was evaluated. OHTAM, at concentrations lower than those putatively reached in tissues following the administration of TAM, does not induce significant perturbations on the respiratory control ratio (RCR), ADP/O, transmembrane potential (DeltaPsi), phosphorylative capacity and membrane integrity of mitochondria. However, at high concentrations, OHTAM depresses the DeltaPsi, RCR and ADP/O, affecting the phosphorylation efficiency, as also inferred from the DeltaPsi fluctuations and pH changes associated with ADP phosphorylation. Moreover, OHTAM, at concentrations that stimulate the rate of state 4 respiration in parallel to the decrease in the DeltaPsi and phosphorylation rate, causes mitochondrial swelling and stimulates both ATPase and citrate synthase activities. However, the OHTAM-observed effects, at high concentrations, are not significant relatively to the damaging effects promoted by TAM and suggest alterations to mitochondrial functions due to proton leak across the mitochondrial inner membrane.

  4. Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: Preventing breast cancer.

    PubMed

    Vogel, Victor G; Costantino, Joseph P; Wickerham, D Lawrence; Cronin, Walter M; Cecchini, Reena S; Atkins, James N; Bevers, Therese B; Fehrenbacher, Louis; Pajon, Eduardo R; Wade, James L; Robidoux, André; Margolese, Richard G; James, Joan; Runowicz, Carolyn D; Ganz, Patricia A; Reis, Steven E; McCaskill-Stevens, Worta; Ford, Leslie G; Jordan, V Craig; Wolmark, Norman

    2010-06-01

    The selective estrogen-receptor modulator (SERM) tamoxifen became the first U.S. Food and Drug Administration (FDA)-approved agent for reducing breast cancer risk but did not gain wide acceptance for prevention, largely because it increased endometrial cancer and thromboembolic events. The FDA approved the SERM raloxifene for breast cancer risk reduction following its demonstrated effectiveness in preventing invasive breast cancer in the Study of Tamoxifen and Raloxifene (STAR). Raloxifene caused less toxicity (versus tamoxifen), including reduced thromboembolic events and endometrial cancer. In this report, we present an updated analysis with an 81-month median follow-up. STAR women were randomly assigned to receive either tamoxifen (20 mg/d) or raloxifene (60 mg/d) for 5 years. The risk ratio (RR; raloxifene:tamoxifen) for invasive breast cancer was 1.24 (95% confidence interval [CI], 1.05-1.47) and for noninvasive disease, 1.22 (95% CI, 0.95-1.59). Compared with initial results, the RRs widened for invasive and narrowed for noninvasive breast cancer. Toxicity RRs (raloxifene:tamoxifen) were 0.55 (95% CI, 0.36-0.83; P = 0.003) for endometrial cancer (this difference was not significant in the initial results), 0.19 (95% CI, 0.12-0.29) for uterine hyperplasia, and 0.75 (95% CI, 0.60-0.93) for thromboembolic events. There were no significant mortality differences. Long-term raloxifene retained 76% of the effectiveness of tamoxifen in preventing invasive disease and grew closer over time to tamoxifen in preventing noninvasive disease, with far less toxicity (e.g., highly significantly less endometrial cancer). These results have important public health implications and clarify that both raloxifene and tamoxifen are good preventive choices for postmenopausal women with elevated risk for breast cancer. 2010 AACR.

  5. Effects of In Vivo Exposure to Tamoxifen on a Non-Target Species, the Marine Fish Cunner (Tautogolabrus adspersus)

    EPA Science Inventory

    Tamoxifen is an endocrine-active pharmaceutical that is used world-wide to treat certain breast cancers. Because tamoxifen has been detected in aquatic environments, a study was undertaken to investigate its biological effects in a non-target species, the marine fish cunner (Taut...

  6. Flash-Type Discrimination

    NASA Technical Reports Server (NTRS)

    Koshak, William J.

    2010-01-01

    This viewgraph presentation describes the significant progress made in the flash-type discrimination algorithm development. The contents include: 1) Highlights of Progress for GLM-R3 Flash-Type discrimination Algorithm Development; 2) Maximum Group Area (MGA) Data; 3) Retrieval Errors from Simulations; and 4) Preliminary Global-scale Retrieval.

  7. Tamoxifen enhances therapeutic effects of gemcitabine on cholangiocarcinoma tumorigenesis.

    PubMed

    Jing, Gu; Yuan, Kaiyu; Turk, Amy N; Jhala, Nirag C; Arnoletti, Juan P; Zhang, Kui; McDonald, Jay M; Chen, Yabing

    2011-06-01

    Cholangiocarcinoma is a highly malignant tumor with limited therapeutic options. We have previously reported that tamoxifen (TMX) induces apoptosis of cholangiocarcinoma cells and reduces cholangiocarcinoma tumorigenesis in mice. In the present studies, we determined the effect of combination therapy of TMX and gemcitabine (GMT), another chemotherapeutical reagent for many cancers, on cholangiocarcinoma tumorigenesis and investigated the responsible mechanisms. GMT inhibited cell growth and induced apoptosis of cholangiocarcinoma cells in a concentration-dependent manner. TMX enhanced GMT-induced apoptosis of cholangiocarcinoma cells. Consistently, GMT (15 mg/kg) inhibited cholangiocarcinoma tumorigenesis in nude mice by 50%. TMX (15 mg/kg) enhanced the inhibitory effect of GMT on tumorigenesis by 33%. The inhibition of tumor growth correlated with enhanced apoptosis in tumor tissues. To elucidate the mechanisms underlying the additive effects of TMX on GMT-induced apoptosis, we determined the activation of caspases in cholangiocarcinoma cells exposed to GMT, TMX, or both. Activation of caspases 9 and 3, as well as cytochrome c release to the cytosol, was demonstrated in cells exposed to both reagents. In contrast, TMX activated caspase 2, whereas GMT had no effect. Inhibition of caspase 2 activation decreased TMX-, but not GMT-, induced activation of caspase 3 and apoptosis of cholangiocarcinoma cells. Similarly, activation of caspase 2 was found in tumors from TMX-treated mice, but not GMT-treated mice. Therefore, the enhanced effect of TMX on GMT-induced cholangiocarcinoma cell death is partially mediated by activation of caspase 2. TMX and GMT both induce apoptosis and inhibit cholangiocarcinoma tumorigenesis, which may be attributed to the activation of distinct apoptosis signals by TMX and GMT. Our studies provide in vivo evidence and molecular insight to support the use of TMX and GMT in combination as an effective therapy for cholangiocarcinoma.

  8. Severe Intestinal Inflammation in the Small Intestine of Mice Induced by Controllable Deletion of Claudin-7.

    PubMed

    Li, Wen-Jing; Xu, Chang; Wang, Kun; Li, Teng-Yan; Wang, Xiao-Nan; Yang, Hui; Xing, Tiaosi; Li, Wen-Xia; Chen, Yan-Hua; Gao, Hong; Ding, Lei

    2018-05-01

    As a potential tumor suppressor gene, Claudin-7 (Cldn7), which is a component of tight junctions, may play an important role in colorectal cancer occurrence and development. To generate a knockout mouse model of inducible conditional Cldn7 in the intestine and analyze the phenotype of the mice after induction with tamoxifen. We constructed Cldn7-flox transgenic mice and crossed them with Villin-CreERT2 mice. The Cldn7 inducible conditional knockout mice appeared normal and were well developed at birth. We induced Cldn7 gene deletion by injecting different dosages of tamoxifen into the mice and then conducted a further phenotypic analysis. After induction for 5 days in succession at a dose of 200 µl tamoxifen in sunflower oil at 10 mg/ml per mouse every time, the mice appeared dehydrated, had a lower temperature, and displayed inactivity or death. The results of hematoxylin-eosin staining showed that the intestines of the Cldn7 inducible conditional knockout mice had severe intestinal defects that included epithelial cell sloughing, necrosis, inflammation and hyperplasia. Owing to the death of ICKO mice, we adjusted the dose of tamoxifen to a dose of 100 µl in sunflower oil at 10 mg/ml per mouse (aged more than 8 weeks old) every 4 days. And we could induce atypical hyperplasia and adenoma in the intestine. Immunofluorescent staining indicated that the intestinal epithelial structure was destroyed. Electron microscopy experimental analysis indicated that the intercellular gap along the basolateral membrane of Cldn7 inducible conditional knockout mice in the intestine was increased and that contact between the cells and matrix was loosened. We generated a model of intestinal Cldn7 inducible conditional knockout mice. Intestinal Cldn7 deletion induced by tamoxifen initiated inflammation and hyperplasia in mice.

  9. The October 2014 United States Treasury bond flash crash and the contributory effect of mini flash crashes

    PubMed Central

    Levine, Zachary S.; Floridi, Luciano

    2017-01-01

    We investigate the causal uncertainty surrounding the flash crash in the U.S. Treasury bond market on October 15, 2014, and the unresolved concern that no clear link has been identified between the start of the flash crash at 9:33 and the opening of the U.S. equity market at 9:30. We consider the contributory effect of mini flash crashes in equity markets, and find that the number of equity mini flash crashes in the three-minute window between market open and the Treasury Flash Crash was 2.6 times larger than the number experienced in any other three-minute window in the prior ten weekdays. We argue that (a) this statistically significant finding suggests that mini flash crashes in equity markets both predicted and contributed to the October 2014 U.S. Treasury Bond Flash Crash, and (b) mini-flash crashes are important phenomena with negative externalities that deserve much greater scholarly attention. PMID:29091931

  10. Population pharmacokinetic modelling to assess the impact of CYP2D6 and CYP3A metabolic phenotypes on the pharmacokinetics of tamoxifen and endoxifen

    PubMed Central

    ter Heine, Rob; Binkhorst, Lisette; de Graan, Anne Joy M; de Bruijn, Peter; Beijnen, Jos H; Mathijssen, Ron H J; Huitema, Alwin D R

    2014-01-01

    Aims Tamoxifen is considered a pro-drug of its active metabolite endoxifen. The major metabolic enzymes involved in endoxifen formation are CYP2D6 and CYP3A. There is considerable evidence that variability in activity of these enzymes influences endoxifen exposure and thereby may influence the clinical outcome of tamoxifen treatment. We aimed to quantify the impact of metabolic phenotype on the pharmacokinetics of tamoxifen and endoxifen. Methods We assessed the CYP2D6 and CYP3A metabolic phenotypes in 40 breast cancer patients on tamoxifen treatment with a single dose of dextromethorphan as a dual phenotypic probe for CYP2D6 and CYP3A. The pharmacokinetics of dextromethorphan, tamoxifen and their relevant metabolites were analyzed using non-linear mixed effects modelling. Results Population pharmacokinetic models were developed for dextromethorphan, tamoxifen and their metabolites. In the final model for tamoxifen, the dextromethorphan derived metabolic phenotypes for CYP2D6 as well as CYP3A significantly (P < 0.0001) explained 54% of the observed variability in endoxifen formation (inter-individual variability reduced from 55% to 25%). Conclusions We have shown that not only CYP2D6, but also CYP3A enzyme activity influences the tamoxifen to endoxifen conversion in breast cancer patients. Our developed model may be used to assess separately the impact of CYP2D6 and CYP3A mediated drug–drug interactions with tamoxifen without the necessity of administering this anti-oestrogenic drug and to support Bayesian guided therapeutic drug monitoring of tamoxifen in routine clinical practice. PMID:24697814

  11. Tamoxifen Use Correlates with Increased Risk of the First Episode of Ischemic Cerebrovascular Disease in Older Women with Breast Cancer: A Case-Control Study in Taiwan

    PubMed Central

    Lai, Shih-Wei; Lin, Cheng-Li; Liao, Kuan-Fu

    2017-01-01

    Background and Objectives: There are inconsistent results about the association between ischemic cerebrovascular disease and tamoxifen use in women with breast cancer. The study aimed to evaluate the association between the risk of ischemic cerebrovascular disease and tamoxifen use in older women with breast cancer in Taiwan. Methods: We designed a retrospective, nationwide, case-control study using the database of the Taiwan National Health Insurance Program. A total of 800 female subjects with breast cancer aged ≥65 years with the first episode of ischemic cerebrovascular disease from 2000 to 2011 were identified as the cases. Additionally, 2,876 female subjects with breast cancer aged ≥65 years without any type of cerebrovascular diseases were selected as the control subjects. The cases and the control subjects were matched with age and comorbidities. Ever use of tamoxifen was defined as a subject who had at least a prescription for tamoxifen before the index date. Never use of tamoxifen was defined as a subject who never had a prescription for tamoxifen before the index date. We used the multivariable logistic regression model to calculate the odds ratio (OR) and 95% confidence interval (CI) for ischemic cerebrovascular disease associated with tamoxifen use. Results: After adjusting for confounding variables, the adjusted OR of ischemic cerebrovascular disease was 2.5 for subjects with ever use of tamoxifen (95% CI 2.10, 2.97), compared with never use of tamoxifen. In addition, the adjusted OR of ischemic cerebrovascular disease was 1.15 (95% CI 1.10, 1.21) in subjects with ever use of tamoxifen as increase in use duration per 1 year. The adjusted OR of ischemic cerebrovascular disease was 2.54 (95% CI 2.03, 3.17) in subjects with ever use of tamoxifen as increase in dosage per 1 mg. Conclusions: Tamoxifen use is significantly associated with 2.5-fold increased odds of ischemic cerebrovascular disease among older women with breast cancer in Taiwan. There

  12. Serum-dependent effects of tamoxifen and cannabinoids upon C6 glioma cell viability.

    PubMed

    Jacobsson, S O; Rongård, E; Stridh, M; Tiger, G; Fowler, C J

    2000-12-15

    In the present study, the effects of the combination of tamoxifen ((Z)-2[p-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylamine citrate) and three cannabinoids (Delta(9)-tetrahydrocannabinol [Delta(9)-THC], cannabidiol, and anandamide [AEA]) upon the viability of C6 rat glioma cells was assessed at different incubation times and using different culturing concentrations of foetal bovine serum (FBS). Consistent with previous data for human glioblastoma cells, the tamoxifen sensitivity of the cells was increased as the FBS content of the culture medium was reduced from 10 to 0.4 and 0%. The cells expressed protein kinase C alpha and calmodulin (the concentration of which did not change significantly as the FBS concentration was reduced), but did not express estrogen receptors. Delta(9)-THC and cannabidiol, but not AEA, produced a modest reduction in cell viability after 6 days of incubation in serum-free medium, whereas no effects were seen in 10% FBS-containing medium. There was no observed synergy between the effects of tamoxifen and the cannabinoids upon cell viability.

  13. Ten Years of Tamoxifen Reduces Breast Cancer Recurrences, Improves Survival

    Cancer.gov

    Taking adjuvant tamoxifen for 10 years after primary treatment leads to a greater reduction in breast cancer recurrences and deaths than taking the drug for only 5 years, according to the results of a large international clinical trial.

  14. Mass spectrometric characterization of tamoxifene metabolites in human urine utilizing different scan parameters on liquid chromatography/tandem mass spectrometry.

    PubMed

    Mazzarino, Monica; de la Torre, Xavier; Di Santo, Roberto; Fiacco, Ilaria; Rosi, Federica; Botrè, Francesco

    2010-03-01

    Different liquid chromatographic/tandem mass spectrometric (LC/MS/MS) scanning techniques were considered for the characterization of tamoxifene metabolites in human urine for anti-doping purpose. Five different LC/MS/MS scanning methods based on precursor ion scan (precursor ion scan of m/z 166, 152 and 129) and neutral loss scan (neutral loss of 72 Da and 58 Da) in positive ion mode were assessed to recognize common ions or common losses of tamoxifene metabolites. The applicability of these methods was checked first by infusion and then by the injection of solution of a mixture of reference standards of four tamoxifene metabolites available in our laboratory. The data obtained by the analyses of the mixture of the reference standards showed that the five methods used exhibited satisfactory results for all tamoxifene metabolites considered at a concentration level of 100 ng/mL, whereas the analysis of blank urine samples spiked with the same tamoxifene metabolites at the same concentration showed that the neutral loss scan of 58 Da lacked sufficient specificity and sensitivity. The limit of detection in urine of the compounds studied was in the concentration range 10-100 ng/mL, depending on the compound structure and on the selected product ion. The suitability of these approaches was checked by the analysis of urine samples collected after the administration of a single dose of 20 mg of tamoxifene. Six metabolites were detected: 4-hydroxytamoxifene, 3,4-dihydroxytamoxifene, 3-hydroxy-4-methoxytamoxifene, N-demethyl-4-hydroxytamoxifene, tamoxifene-N-oxide and N-demethyl-3-hydroxy-4-methoxytamoxifene, which is in conformity to our previous work using a time-of-flight (TOF) mass spectrometer in full scan acquisition mode. Copyright (c) 2010 John Wiley & Sons, Ltd.

  15. Role of nuclear stars in the light flashes observed on Skylab 4.

    PubMed

    McNulty, P J; Filz, R C; Rothwell, P L

    1977-01-01

    The astronauts on Skylab 4 observed bursts of intense visual light-flash activity when their spacecraft passed through the portion of the earth's inner trapped radiation belt known as the South Atlantic Anomaly (SAA). Two experimental sessions were carried out on board Skylab 4 under the auspices of Pinsky et al. who compare the flash rates with the measured flux of Z > or = 1 particles that would pass through the astronaut's eyes. They concluded that the flash rates, which became as great as 20/min, were anomalously high. We explored a number of alternative explanations for the anomalous flash rates that would be consistent with the accepted SAA flux values and the laboratory data on particle induced visual sensations and found that when one includes the effect of nuclear interactions in and near the retina which result in star formation (the emission of slow protons, neutrons and alpha particles form the nucleus in an evaporation-like process) the apparent anomaly is removed.

  16. Impact of NICE guidance on tamoxifen prescribing in England 2011-2017: an interrupted time series analysis.

    PubMed

    Curtis, Helen J; Walker, Alex J; Goldacre, Ben

    2018-05-01

    Tamoxifen was recommended by NICE in 2013 for chemoprevention of breast cancer, but a recent survey suggested only a quarter of GPs are aware of this. We set out to measure the uptake of tamoxifen, and the alternative raloxifene, in national prescribing data sets. Tamoxifen and raloxifene data were extracted from England's monthly prescribing data sets, October 2010-October 2017. We used interrupted time series analysis to reveal national and local responses to guidelines. We investigated variation between practices by calculating percentiles for prescribing rates and ratios of change. We found an increase in monthly tamoxifen prescribing following release of the guidelines, with an increase in gradient (p = 0.001) but no step change (p = 0.342). Alongside a small change in raloxifene prescribing we estimate 8450 women took up chemoprevention between 2013 and 2016. We did not find evidence that this was limited to a small group of practices. Our results suggest that the uptake of new guidance on chemoprevention has been slow and has potentially left women exposed to avoidable risk. Improving dissemination of guidance to healthcare professionals and routinely monitoring implementation could help reduce this risk.

  17. Malignant mixed Mullerian tumour of uterus secondary to tamoxifen therapy for hormone responsive breast cancer.

    PubMed

    Gupta, Mayank; Kiruthiga, Kala Gnanasekaran

    2015-06-29

    Tamoxifen is used in the treatment of hormone responsive breast cancer because of its antiestrogenic effect. However, it also has an estrogenic effect on the uterus, thereby increasing the risk of endometrial hyperplasia, endometrial polyp and endometrial neoplasms such as endometrial adenocarcinoma and malignant mixed Mullerian tumour (MMMT). This case describes the possible pathogenesis and risk of developing MMMT due to long-term tamoxifen intake in hormone responsive breast cancer. 2015 BMJ Publishing Group Ltd.

  18. Bioactivation of tamoxifen to metabolite E quinone methide: reaction with glutathione and DNA.

    PubMed

    Fan, P W; Bolton, J L

    2001-06-01

    Despite the beneficial effects of tamoxifen in the treatment and prevention of breast cancer, long-term usage of this popular antiestrogen has been linked to an increased risk of developing endometrial cancer in women. One of the suggested pathways leading to the potential toxicity of tamoxifen involves its oxidative metabolism to 4-hydroxytamoxifen, which may be further oxidized to an electrophilic quinone methide. Alternatively, tamoxifen could undergo O-dealkylation to give cis/trans-1,2-diphenyl-1-(4-hydroxyphenyl)-but-1-ene, which is commonly known as metabolite E. Because of its structural similarity to 4-hydroxytamoxifen, metabolite E could also be biotransformed to a quinone methide, which has the potential to alkylate DNA and may contribute to the genotoxic effects of tamoxifen. To further probe the chemical reactivity/toxicity of such an electrophilic species, we have prepared metabolite E quinone methide chemically and enzymatically and examined its reactivity with glutathione (GSH) and DNA. Like 4-hydroxytamoxifen quinone methide, metabolite E quinone methide is quite stable; its half-life under physiological conditions is around 4 h, and its half-life in the presence of GSH is approximately 4 min. However, unlike the unstable GSH adducts of 4-hydroxytamoxifen quinone methide, metabolite E GSH adducts are stable enough to be isolated and characterized by NMR and liquid chromatography/tandem mass spectrometry (LC/MS/MS). Reaction of metabolite E quinone methide with DNA generated exclusively deoxyguanosine adducts, which were characterized by LC/MS/MS. These data suggest that metabolite E has the potential to cause cytotoxicity/genotoxicity through the formation of a quinone methide.

  19. Evaluation of tamoxifen in persistent or recurrent nonsquamous cell carcinoma of the cervix: a Gynecologic Oncology Group study.

    PubMed

    Bigler, L R; Tate Thigpen, J; Blessing, J A; Fiorica, J; Monk, B J

    2004-01-01

    This study was undertaken to estimate the antitumor activity of tamoxifen in patients with persistent or recurrent nonsquamous cell carcinoma of the cervix. Furthermore, the nature and degree of adverse effects from tamoxifen in this cohort of individuals was examined. Tamoxifen citrate was to be administered at a dose of 10 mg per orally twice a day until disease progression or unacceptable side effects prevented further therapy. A total of 34 patients (median age: 49 years) were registered to this trial; two were declared ineligible. Thirty-two patients were evaluable for adverse effects and 27 were evaluable for response. There were only six grades 3 and 4 adverse effects reported: leukopenia (in one patient), anemia (in two), emesis (in one), gastrointestinal distress (in one), and neuropathy (in one). The objective response rate was 11.1%, with one complete and two partial responses. In conclusion, tamoxifen appears to have minimal activity in nonsquamous cell carcinoma of the cervix.

  20. Clinical evidence on the magnitude of change in growth pathway activity in relation to Tamoxifen resistance is required.

    PubMed

    Mansouri, Sepideh; Farahmand, Leila; Teymourzadeh, Azin; Majidzadeh-A, Keivan

    2017-08-08

    Despite prolonged disease-free survival and overall survival rates in estrogen receptor (ER)-positive patients undergoing adjuvant treatment, Tamoxifen therapy tends to fail due to eventual acquisition of resistance. Although numerous studies have emphasized the role of receptor tyrosine kinases (RTKs) in the development of Tamoxifen resistance, inadequate clinical evidence is available regarding the alteration of biomarker expression during acquired resistance, thus undermining the validity of the findings. Results of two meta-analyses investigating the effect of HER2 status on the prognosis of Tamoxifen-receiving patients have demonstrated that despite HER2-negative patients having longer disease-free survival; there is no difference in overhaul survival between the two groups. Furthermore, due to the intricate molecular interactions among estrogen receptors including ERα36, ERα66, and also RTKs, it is not surprising that RTK suppression does not restore Tamoxifen sensitivity. In considering such a complex network, we speculate that by the time HER2/EGFR is suppressed via targeted therapies, activation of ERα66 and ERα36 initiate molecular signaling pathways downstream of RTKs, thereby enhancing cell proliferation even in the presence of both Tamoxifen and RTK inhibitors. Although clinical findings regarding the molecular pathways downstream of RTKs have been thoroughly discussed in this review, further clinical studies are required in determining a consistency between preclinical and clinical findings. Discovering the best targets in preventing tumor progression requires thorough comprehension of estrogen-dependent and estrogen-independent pathways during Tamoxifen resistance development. Indeed, exploring additional clinically-proven targets would allow for better characterized treatments being available for breast cancer patients. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  1. Statistical Evolution of the Lightning Flash

    NASA Astrophysics Data System (ADS)

    Zoghzoghy, F. G.; Cohen, M.; Said, R.; Inan, U. S.

    2012-12-01

    Natural lightning is one of the most fascinating and powerful electrical processes on Earth. To date, the physics behind this natural phenomenon are not fully understood, due primarily to the difficulty of obtaining measurements inside thunderstorms and to the wide range of timescales involved (from nanoseconds to seconds). Our aim is to use accurate lightning geo-location data from the National Lightning Detection Network (NLDN) to study statistical patterns in lightning, taking advantage of the fact that millions of lightning flashes occur around the globe every day. We present two sets of results, one involving the patterns of flashes in a storm, and a second involving the patterns of strokes in a flash. These patterns can provide a surrogate measure of the timescales and the spatial extents of the underlying physical processes. First, we study the timescales of charge buildup inside thunderstorms. We find that, following a lightning flash, the probability of another neighboring flash decreases and takes tens of seconds to recover. We find that this suppression effect is a function of flash type, stroke peak current, cloud-to-ground (CG) stroke multiplicity, and other lightning and geographical parameters. We find that the probabilities of subsequent flashes are more suppressed following oceanic lightning, or following flashes with higher peak currents and/or higher multiplicities (for CG flashes). Second, we use NLDN data to study the evolution of the strokes within a CG flash. A CG flash typically includes multiple return strokes, which can occur in the same channel or in multiple channels within a few kilometers. We cluster NLDN stroke data into flashes and produce the probability density function of subsequent strokes as a function of distance and time-delays relative to the previous stroke. Using this technique, we investigate processes which occur during the CG lightning flash with nanosecond to millisecond timescales. For instance, our results suggest

  2. Determination of Tamoxifen and its Major Metabolites in Exposed Fish

    EPA Science Inventory

    Tamoxifen (TAM), (Z)-1-(p-dimethylaminoethoxyphenyl)-1, 2-diphenyl-1-butene, is a nonsteroidal agent that has been used in breast cancer treatment for decades. Its major metabolites are 4-hydroxytamoxifen (4-OHT), N-desmethyltamoxifen (DMT), and endoxifen. While TAM and metabolit...

  3. FLASH2: Operation, beamlines, and photon diagnostics

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Plönjes, Elke, E-mail: elke.ploenjes@desy.de; Faatz, Bart; Kuhlmann, Marion

    2016-07-27

    FLASH2, a major extension of the soft X-ray free-electron laser FLASH at DESY, turns FLASH into a multi-user FEL facility. A new undulator line is located in a separate accelerator tunnel and driven additionally by the FLASH linear accelerator. First lasing of FLASH2 was achieved in August 2014 with simultaneous user operation at FLASH1. The new FLASH2 experimental hall offers space for up to six experimental end stations, some of which will be installed permanently. The wide wavelength range spans from 4-60 nm and 0.8 nm in the 5{sup th} harmonic and in the future deep into the water windowmore » in the fundamental. While this is of high interest to users, it is challenging from the beamline instrumentation point of view. Online diagnostics - which are mostly pulse resolved - for beam intensity, position, wavelength, wave front, and pulse length have been to a large extent developed at FLASH(1) and have now been optimized for FLASH2. Pump-probe facilities for XUV-XUV, XUV optical and XUV-THz experiments will complete the FLASH2 user facility.« less

  4. Liquid-phase explosive crystallization of electron-beam-evaporated a-Si films induced by flash lamp annealing

    NASA Astrophysics Data System (ADS)

    Ohdaira, Keisuke; Matsumura, Hideki

    2013-01-01

    We succeed in the formation of micrometer-order-thick polycrystalline silicon (poly-Si) films through the flash-lamp-induced liquid-phase explosive crystallization (EC) of precursor a-Si films prepared by electron-beam (EB) evaporation. The velocity of the explosive crystallization (vEC) is estimated to be ˜14 m/s, which is close to the velocity of the liquid-phase epitaxy (LPE) of Si at a temperature around the melting point of a-Si of 1418 K. Poly-Si films formed have micrometer-order-long grains stretched along a lateral crystallization direction, and X-ray diffraction (XRD) and electron diffraction pattern measurements reveal that grains in poly-Si films tend to have a particular orientation. These features are significantly different from our previous results: the formation of poly-Si films containing randomly-oriented 10-nm-sized fine grains formed from a-Si films prepared by catalytic chemical vapor deposition (Cat-CVD) or sputtering. One possible reason for the emergence of a different EC mode in EB-evaporated a-Si films is the suppression of solid-phase nucleation (SPN) during Flash Lamp Annealing (FLA) due to tensile stress which precursor a-Si films originally hold. Poly-Si films formed from EB-evaporated a-Si films would contribute to the realization of high-efficiency thin-film poly-Si solar cells because of large and oriented grains.

  5. FLASH LIDAR Based Relative Navigation

    NASA Technical Reports Server (NTRS)

    Brazzel, Jack; Clark, Fred; Milenkovic, Zoran

    2014-01-01

    Relative navigation remains the most challenging part of spacecraft rendezvous and docking. In recent years, flash LIDARs, have been increasingly selected as the go-to sensors for proximity operations and docking. Flash LIDARS are generally lighter and require less power that scanning Lidars. Flash LIDARs do not have moving parts, and they are capable of tracking multiple targets as well as generating a 3D map of a given target. However, there are some significant drawbacks of Flash Lidars that must be resolved if their use is to be of long-term significance. Overcoming the challenges of Flash LIDARs for navigation-namely, low technology readiness level, lack of historical performance data, target identification, existence of false positives, and performance of vision processing algorithms as intermediaries between the raw sensor data and the Kalman filter-requires a world-class testing facility, such as the Lockheed Martin Space Operations Simulation Center (SOSC). Ground-based testing is a critical step for maturing the next-generation flash LIDAR-based spacecraft relative navigation. This paper will focus on the tests of an integrated relative navigation system conducted at the SOSC in January 2014. The intent of the tests was to characterize and then improve the performance of relative navigation, while addressing many of the flash LIDAR challenges mentioned above. A section on navigation performance and future recommendation completes the discussion.

  6. Effect of Tamoxifen and Brain-Penetrant Protein Kinase C and c-Jun N-Terminal Kinase Inhibitors on Tolerance to Opioid-Induced Respiratory Depression in Mice.

    PubMed

    Withey, Sarah L; Hill, Rob; Lyndon, Abigail; Dewey, William L; Kelly, Eamonn; Henderson, Graeme

    2017-04-01

    Respiratory depression is the major cause of death in opioid overdose. We have previously shown that prolonged treatment of mice with morphine induces profound tolerance to the respiratory-depressant effects of the drug (Hill et al., 2016). The aim of the present study was to investigate whether tolerance to opioid-induced respiratory depression is mediated by protein kinase C (PKC) and/or c-Jun N-terminal kinase (JNK). We found that although mice treated for up to 6 days with morphine developed tolerance, as measured by the reduced responsiveness to an acute challenge dose of morphine, administration of the brain-penetrant PKC inhibitors tamoxifen and calphostin C restored the ability of acute morphine to produce respiratory depression in morphine-treated mice. Importantly, reversal of opioid tolerance was dependent on the nature of the opioid ligand used to induce tolerance, as these PKC inhibitors did not reverse tolerance induced by prolonged treatment of mice with methadone nor did they reverse the protection to acute morphine-induced respiratory depression afforded by prolonged treatment with buprenorphine. We found no evidence for the involvement of JNK in morphine-induced tolerance to respiratory depression. These results indicate that PKC represents a major mechanism underlying morphine tolerance, that the mechanism of opioid tolerance to respiratory depression is ligand-dependent, and that coadministration of drugs with PKC-inhibitory activity and morphine (as well as heroin, largely metabolized to morphine in the body) may render individuals more susceptible to overdose death by reversing tolerance to the effects of morphine. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  7. Effect of Tamoxifen and Brain-Penetrant Protein Kinase C and c-Jun N-Terminal Kinase Inhibitors on Tolerance to Opioid-Induced Respiratory Depression in Mice

    PubMed Central

    Withey, Sarah L.; Hill, Rob; Lyndon, Abigail; Dewey, William L.; Kelly, Eamonn

    2017-01-01

    Respiratory depression is the major cause of death in opioid overdose. We have previously shown that prolonged treatment of mice with morphine induces profound tolerance to the respiratory-depressant effects of the drug (Hill et al., 2016). The aim of the present study was to investigate whether tolerance to opioid-induced respiratory depression is mediated by protein kinase C (PKC) and/or c-Jun N-terminal kinase (JNK). We found that although mice treated for up to 6 days with morphine developed tolerance, as measured by the reduced responsiveness to an acute challenge dose of morphine, administration of the brain-penetrant PKC inhibitors tamoxifen and calphostin C restored the ability of acute morphine to produce respiratory depression in morphine-treated mice. Importantly, reversal of opioid tolerance was dependent on the nature of the opioid ligand used to induce tolerance, as these PKC inhibitors did not reverse tolerance induced by prolonged treatment of mice with methadone nor did they reverse the protection to acute morphine-induced respiratory depression afforded by prolonged treatment with buprenorphine. We found no evidence for the involvement of JNK in morphine-induced tolerance to respiratory depression. These results indicate that PKC represents a major mechanism underlying morphine tolerance, that the mechanism of opioid tolerance to respiratory depression is ligand-dependent, and that coadministration of drugs with PKC-inhibitory activity and morphine (as well as heroin, largely metabolized to morphine in the body) may render individuals more susceptible to overdose death by reversing tolerance to the effects of morphine. PMID:28130265

  8. Src Drives Growth of Antiestrogen Resistant Breast Cancer Cell Lines and Is a Marker for Reduced Benefit of Tamoxifen Treatment

    PubMed Central

    Larsen, Sarah L.; Laenkholm, Anne-Vibeke; Duun-Henriksen, Anne Katrine; Bak, Martin; Lykkesfeldt, Anne E.; Kirkegaard, Tove

    2015-01-01

    The underlying mechanisms leading to antiestrogen resistance in estrogen-receptor α (ER)-positive breast cancer is still poorly understood. The aim of this study was therefore to identify biomarkers and novel treatments for antiestrogen resistant breast cancer. We performed a kinase inhibitor screen on antiestrogen responsive T47D breast cancer cells and T47D-derived tamoxifen and fulvestrant resistant cell lines. We found that dasatinib, a broad-spectrum kinase inhibitor, inhibited growth of the antiestrogen resistant cells compared to parental T47D cells. Furthermore western blot analysis showed increased expression and phosphorylation of Src in the resistant cells and that dasatinib inhibited phosphorylation of Src and also signaling via Akt and Erk in all cell lines. Immunoprecipitation revealed Src: ER complexes only in the parental T47D cells. In fulvestrant resistant cells, Src formed complexes with the Human Epidermal growth factor Receptor (HER)1 and HER2. Neither HER receptors nor ER were co-precipitated with Src in the tamoxifen resistant cell lines. Compared to treatment with dasatinib alone, combined treatment with dasatinib and fulvestrant had a stronger inhibitory effect on tamoxifen resistant cell growth, whereas dasatinib in combination with tamoxifen had no additive inhibitory effect on fulvestrant resistant growth. When performing immunohistochemical staining on 268 primary tumors from breast cancer patients who had received tamoxifen as first line endocrine treatment, we found that membrane expression of Src in the tumor cells was significant associated with reduced disease-free and overall survival. In conclusion, Src was identified as target for treatment of antiestrogen resistant T47D breast cancer cells. For tamoxifen resistant T47D cells, combined treatment with dasatinib and fulvestrant was superior to treatment with dasatinib alone. Src located at the membrane has potential as a new biomarker for reduced benefit of tamoxifen. PMID

  9. Differences in metabolite-mediated toxicity of tamoxifen in rodents versus humans elucidated with DNA/microsome electro-optical arrays and nanoreactors.

    PubMed

    Zhao, Linlin; Krishnan, Sadagopan; Zhang, Yun; Schenkman, John B; Rusling, James F

    2009-02-01

    Tamoxifen, a therapeutic and chemopreventive breast cancer drug, was chosen as a model compound because of acknowledged species specific toxicity differences. Emerging approaches utilizing electro-optical arrays and nanoreactors based on DNA/microsome films were used to compare metabolite-mediated toxicity differences of tamoxifen in rodents versus humans. Hits triggered by liver enzyme metabolism were first provided by arrays utilizing a DNA damage end point. The arrays feature thin-film spots containing an electrochemiluminescent (ECL) ruthenium polymer ([Ru(bpy)(2)PVP(10)](2+); PVP, polyvinylpyridine), DNA, and liver microsomes. When DNA damage resulted from reactions with tamoxifen metabolites, it was detected by an increase in light from the oxidation of the damaged DNA by the ECL metallopolymer. The slope of ECL generation versus enzyme reaction time correlated with the rate of DNA damage. An approximate 2-fold greater ECL turnover rate was observed for spots with rat liver microsomes compared to that with human liver microsomes. These results were supported by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of reaction products using nanoreactors featuring analogous films on silica nanoparticles, allowing the direct measurement of the relative formation rate for alpha-(N(2)-deoxyguanosinyl)tamoxifen. We observed 2-5-fold more rapid formation rates for three major metabolites, i.e., alpha-hydroxytamoxifen, 4-hydroxytamoxifen, and tamoxifen N-oxide, catalyzed by rat liver microsomes compared to human liver microsomes. Comparable formation rates were observed for N-desmethyl tamoxifen with rat and human liver microsomes. A better detoxifying capacity for human liver microsomes than rat liver microsomes was confirmed utilizing glucuronyltransferase in microsomes together with UDP-glucuronic acid. Taken together, lower genotoxicity and higher detoxication rates presented by human liver microsomes correlate with the lower risk of tamoxifen in

  10. UPLC-MS/MS method for the determination of tobacco-specific biomarker NNAL, tamoxifen and its main metabolites in rat plasma.

    PubMed

    Xiong, Wei; Zhao, Jiajia; Wang, Ling; Jiang, Xuehua

    2017-06-01

    Cigarette smoke is known to interact with tamoxifen-metabolizing enzymes and transporters and potentially affect its treatment outcome. 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanol (NNAL) is an important metabolite of 4-(methylnitro-samino)-1-(3-pyridyl)-1-butanone (NNK) because it is frequently used as a biomarker to assess human smoke exposure. In order to study the potential pharmacokinetic interaction between cigarette smoke and tamoxifen in rats a UPLC-MS/MS method for the simultaneous determination of NNAL and tamoxifen along with its metabolites in rat plasma has been developed and validated. Analytes were extracted with methanol and separated on a HSS T3 column by a gradient elution with the mobile phase consisting of acetonitrile and water. The lower limits of quantitation ranged from 0.05 to 0.62 ng/mL. Precisions showed RSD <15.8% and accuracy in the range 80.6-116.0%. Mean analyte recoveries ranged from 76.9 to 108.4%. The method was successfully applied to study the effects of cigarette smoke condensate (CSC), NNK and benzo(a)pyrene pre-treatment on the pharmacokinetics of tamoxifen and its metabolites in rats. Significant effects of CSC, NNK, benzo(a)pyrene were observed on pharmacokinetics of tamoxifen and its metabolites. We also found that plasma NNAL levels are statistically significant correlated with plasma 4-hydroxy-tamoxifen and endoxifen. Copyright © 2016 John Wiley & Sons, Ltd.

  11. ASA-FTL: An adaptive separation aware flash translation layer for solid state drives

    DOE PAGES

    Xie, Wei; Chen, Yong; Roth, Philip C

    2016-11-03

    Here, the flash-memory based Solid State Drive (SSD) presents a promising storage solution for increasingly critical data-intensive applications due to its low latency (high throughput), high bandwidth, and low power consumption. Within an SSD, its Flash Translation Layer (FTL) is responsible for exposing the SSD’s flash memory storage to the computer system as a simple block device. The FTL design is one of the dominant factors determining an SSD’s lifespan and performance. To reduce the garbage collection overhead and deliver better performance, we propose a new, low-cost, adaptive separation-aware flash translation layer (ASA-FTL) that combines sampling, data clustering and selectivemore » caching of recency information to accurately identify and separate hot/cold data while incurring minimal overhead. We use sampling for light-weight identification of separation criteria, and our dedicated selective caching mechanism is designed to save the limited RAM resource in contemporary SSDs. Using simulations of ASA-FTL with both real-world and synthetic workloads, we have shown that our proposed approach reduces the garbage collection overhead by up to 28% and the overall response time by 15% compared to one of the most advanced existing FTLs. We find that the data clustering using a small sample size provides significant performance benefit while only incurring a very small computation and memory cost. In addition, our evaluation shows that ASA-FTL is able to adapt to the changes in the access pattern of workloads, which is a major advantage comparing to existing fixed data separation methods.« less

  12. NIR small arms muzzle flash

    NASA Astrophysics Data System (ADS)

    Montoya, Joseph; Kennerly, Stephen; Rede, Edward

    2010-04-01

    Utilization of Near-Infrared (NIR) spectral features in a muzzle flash will allow for small arms detection using low cost silicon (Si)-based imagers. Detection of a small arms muzzle flash in a particular wavelength region is dependent on the intensity of that emission, the efficiency of source emission transmission through the atmosphere, and the relative intensity of the background scene. The NIR muzzle flash signature exists in the relatively large Si spectral response wavelength region of 300 nm-1100 nm, which allows for use of commercial-off-the-shelf (COTS) Si-based detectors. The alkali metal origin of the NIR spectral features in the 7.62 × 39-mm round muzzle flash is discussed, and the basis for the spectral bandwidth is examined, using a calculated Voigt profile. This report will introduce a model of the 7.62 × 39-mm NIR muzzle flash signature based on predicted source characteristics. Atmospheric limitations based on NIR spectral regions are investigated in relation to the NIR muzzle flash signature. A simple signal-to-clutter ratio (SCR) metric is used to predict sensor performance based on a model of radiance for the source and solar background and pixel registered image subtraction.

  13. Study Confirms Letrozole Prevents More Breast Cancer Recurrences than Tamoxifen

    Cancer.gov

    After a median of 8 years of follow-up, women with estrogen-receptor positive breast cancer who received 5 years of letrozole were less likely to have their cancer recur or to die during follow-up than women who received 5 years of tamoxifen.

  14. Reductive amination-assisted quantitation of tamoxifen and its metabolites by liquid phase chromatography tandem mass spectrometry.

    PubMed

    Liang, Shih-Shin; Wang, Tsu-Nai; Chiu, Chien-Chih; Kuo, Po-Lin; Huang, Mei-Fang; Liu, Meng-Chieh; Tsai, Eing-Mei

    2016-02-19

    Tamoxifen, a hormonal therapy drug against estrogen receptor-positive breast cancer, can be metabolized by cytochrome P450 enzymes such as CYP3A4 and CYP3A5, and converted to N-desmethyltamoxifen, which is subsequently, metabolized by CYP2D6 and inverted to form 4-hydroxy-N-desmethyltamoxifen (endoxifen). Conventional mass spectrometry (MS) analyses of tamoxifen and its metabolites require isotopic internal standards (ISs). In this study, endoxifen and N-desmethyltamoxifen amine groups were modified by reductive amination with formaldehyde-D2 to produce new metabolite molecules. Both endoxifen and N-desmethyltamoxifen generated their corresponding D2-methyl modified analogs. This method is expected to simplify MS detection and overcome the difficulty in selecting adequate ISs when tamoxifen metabolites are analyzed by absolute quantification. It identified tamoxifen, D2-methyl modified endoxifen, and D2-methyl modified N-desmethyltamoxifen with a linearity ranging from 2 to 5000 ng/mL with correlation coefficient (R(2)) values of 0.9868, 0.9849, and 0.9880, respectively. Furthermore, this reductive amination-based method may enhance the signal intensities of D2-methyl modified N-desmethyltamoxifen and endoxifen, thus facilitating the MS detection. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. Targeted conjugation of breast anticancer drug tamoxifen and its metabolites with synthetic polymers.

    PubMed

    Sanyakamdhorn, S; Agudelo, D; Bekale, L; Tajmir-Riahi, H A

    2016-09-01

    Conjugation of antitumor drug tamoxifen and its metabolites, 4-hydroxytamxifen and ednoxifen with synthetic polymers poly(ethylene glycol) (PEG), methoxypoly (ethylene glycol) polyamidoamine (mPEG-PAMAM-G3) and polyamidoamine (PAMAM-G4) dendrimers was studied in aqueous solution at pH 7.4. Multiple spectroscopic methods, transmission electron microscopy (TEM) and molecular modeling were used to characterize the drug binding process to synthetic polymers. Structural analysis showed that drug-polymer binding occurs via both H-bonding and hydrophobic contacts. The order of binding is PAMAM-G4>mPEG-PAMAM-G3>PEG-6000 with 4-hydroxttamoxifen forming more stable conjugate than tamoxifen and endoxifen. Transmission electron microscopy showed significant changes in carrier morphology with major changes in the shape of the polymer aggregate as drug encapsulation occurred. Modeling also showed that drug is located in the surface and in the internal cavities of PAMAM with the free binding energy of -3.79 for tamoxifen, -3.70 for 4-hydroxytamoxifen and -3.69kcal/mol for endoxifen, indicating of spontaneous drug-polymer interaction at room temperature. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. Aggressive fibromatosis response to tamoxifen: lack of correlation between MRI and symptomatic response.

    PubMed

    Libertini, M; Mitra, I; van der Graaf, W T A; Miah, A B; Judson, I; Jones, R L; Thomas, K; Moskovic, E; Szucs, Z; Benson, C; Messiou, C

    2018-01-01

    One of the commonly used systemic agents for the treatment of aggressive fibromatosis is the anti-oestrogen drug tamoxifen. However, data on efficacy and optimum methods of response assessment are limited, consisting mainly of small case series and reports. A retrospective database was used to identify consecutive patients diagnosed with aggressive fibromatosis (AF) and treated with tamoxifen plus/minus non-steroidal anti-inflammatory drugs at our tertiary referral centre between 2007 and 2014. MRI and symptom changes were recorded. Thirty-two patients (13 male 19 female, median age 41 years) were included. Median duration of treatment with tamoxifen was 316 days. Of 9 patients with progressive disease by RECIST 1.1 (28%): 4 patients experienced worsening symptoms; 3 patients had improved symptoms and 2 had no change in symptoms. Of 22 patients with stable disease (69%): 11 had no change in symptoms; 6 had improved symptoms and 5 patients had worsening symptoms. One patient achieved a partial response with improved symptoms. No relationship was identified between symptomatic benefit and response by RECIST 1.1 on MRI. Prospective studies in AF should incorporate endpoints focusing on patient symptoms.

  17. Gun muzzle blast and flash

    NASA Astrophysics Data System (ADS)

    Klingenberg, Guenter; Heimerl, Joseph M.

    A repository of fundamental experimental and analytical data concerning the complex phenomena associated with gun-muzzle blast and flash effects is presented, proceeding from gun muzzle signatures to modern gun-propulsion concepts, interior and transitional ballistics, and characterizations of blast-wave research and muzzle flash. Data are presented in support of a novel hypothesis which explains the ignition of secondary flash and elucidates the means for its suppression. Both chemical and mechanical (often competing) methods of flash suppression are treated. The historical work of Kesslau and Ladenburg is noted, together with French, British, Japanese and American research efforts and current techniques of experimental characterization for gun muzzle phenomena.

  18. Motivators and barriers of tamoxifen use as risk-reducing medication amongst women at increased breast cancer risk: a systematic literature review.

    PubMed

    Meiser, B; Wong, W K T; Peate, M; Julian-Reynier, C; Kirk, J; Mitchell, G

    2017-01-01

    Selective estrogen receptor modulators, such as tamoxifen, reduce breast cancer risk by up to 50% in women at increased risk for breast cancer. Despite tamoxifen's well-established efficacy, many studies show that most women are not taking up tamoxifen. This systematic literature review aimed to identify the motivators and barriers to tamoxifen use 's amongst high-risk women. Using MEDLINE, PsycINFO, and Embase plus reviewing reference lists of relevant articles published between 1995 and 2016, 31 studies (published in 35 articles) were identified, which addressed high-risk women's decisions about risk-reducing medication to prevent breast cancer and were peer-reviewed primary clinical studies. A range of factors were identified as motivators of, and barriers to, tamoxifen uptake including: perceived risk, breast-cancer-related anxiety, health professional recommendation, perceived drug effectiveness, concerns about side-effects, knowledge and access to information about side-effects, beliefs about the role of risk-reducing medication, provision of a biomarker, preference for other forms of breast cancer risk reduction, previous treatment experience, concerns about randomization in clinical trial protocols and finally altruism. Results indicate that the decision for high-risk women regarding tamoxifen use or non-use as a risk-reducing medication is not straightforward. Support of women making this decision is essential and needs to encompass the full range of factors, both informational and psychological.

  19. Radiation Tests on 2Gb NAND Flash Memories

    NASA Technical Reports Server (NTRS)

    Nguyen, Duc N.; Guertin, Steven M.; Patterson, J. D.

    2006-01-01

    We report on SEE and TID tests of highly scaled Samsung 2Gbits flash memories. Both in-situ and biased interval irradiations were used to characterize the response of the total accumulated dose failures. The radiation-induced failures can be categorized as followings: single event upset (SEU) read errors in biased and unbiased modes, write errors, and single-event-functional-interrupt (SEFI) failures.

  20. Hold-up power supply for flash memory

    NASA Technical Reports Server (NTRS)

    Ott, William E. (Inventor)

    2004-01-01

    A hold-up power supply for flash memory systems is provided. The hold-up power supply provides the flash memory with the power needed to temporarily operate when a power loss exists. This allows the flash memory system to complete any erasures and writes, and thus allows it to shut down gracefully. The hold-up power supply detects when a power loss on a power supply bus is occurring and supplies the power needed for the flash memory system to temporally operate. The hold-up power supply stores power in at least one capacitor. During normal operation, power from a high voltage supply bus is used to charge the storage capacitors. When a power supply loss is detected, the power supply bus is disconnected from the flash memory system. A hold-up controller controls the power flow from the storage capacitors to the flash memory system. The hold-up controller uses feedback to assure that the proper voltage is provided from the storage capacitors to the flash memory system. This power supplied by the storage capacitors allows the flash memory system to complete any erasures and writes, and thus allows the flash memory system to shut down gracefully.

  1. Functional study of hot pepper 26S proteasome subunit RPN7 induced by Tobacco mosaic virus from nuclear proteome analysis

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lee, Boo-Ja; Kwon, Sun Jae; Kim, Sung-Kyu

    Two-dimensional gel electrophoresis (2-DE) was applied for the screening of Tobacco mosaic virus (TMV)-induced hot pepper (Capsicum annuum cv. Bugang) nuclear proteins. From differentially expressed protein spots, we acquired the matched peptide mass fingerprint (PMF) data, analyzed by MALDI-TOF MS, from the non-redundant hot pepper EST protein FASTA database using the VEMS 2.0 software. Among six identified nuclear proteins, the hot pepper 26S proteasome subunit RPN7 (CaRPN7) was subjected to further study. The level of CaRPN7 mRNA was specifically increased during incompatible TMV-P{sub 0} interaction, but not during compatible TMV-P{sub 1.2} interaction. When CaRPN7::GFP fusion protein was targeted in onionmore » cells, the nuclei had been broken into pieces. In the hot pepper leaves, cell death was exacerbated and genomic DNA laddering was induced by Agrobacterium-mediated transient overexpression of CaPRN7. Thus, this report presents that the TMV-induced CaRPN7 may be involved in programmed cell death (PCD) in the hot pepper plant.« less

  2. Phase I Clinical Trial Assessing Temozolomide and Tamoxifen With Concomitant Radiotherapy for Treatment of High-Grade Glioma

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Patel, Shilpen, E-mail: Shilpenp@uw.edu; DiBiase, Steven; Meisenberg, Barry

    2012-02-01

    Purpose: The new standard treatment of glioblastoma multiforme is concurrent radiotherapy (RT) and temozolomide. The proliferation of high-grade gliomas might be partly dependent on protein kinase C-mediated pathways. Tamoxifen has been shown in vitro to inhibit protein kinase C through estrogen receptor-independent antineoplastic effects. This Phase I trial was designed to determine the maximal tolerated dose (MTD) of tamoxifen when given with temozolomide and concurrent RT to patients with high-grade gliomas. Methods and Materials: A total of 17 consecutive patients in four cohorts with World Health Organization Grade 3 (n = 2) and 4 (n = 15) gliomas were givenmore » tamoxifen twice daily during 6 weeks of concurrent RT and temozolomide. Eligibility included histologic diagnosis, age >18 years old, Karnofsky performance status {>=}60, and no previous brain RT or chemotherapy. The starting dose was 50 mg/m{sup 2} divided twice daily. If no dose-limiting toxicities (DLTs) occurred in 3 patients, the dose was escalated in 25-mg/m{sup 2} increments until the MTD was reached. When {>=}2 patients within a cohort experienced a DLT, the MTD had been exceeded. Temozolomide was given with RT at 75 mg/m{sup 2}. A dose of 60 Gy in 2 Gy/d fractions to a partial brain field was delivered. Results: A total of 6 patients in Cohort 4 had received tamoxifen at 125 mg/m{sup 2}. One patient was excluded, and the fourth patient developed Grade 4 thrombocytopenia (DLT). Thus, 3 more patients needed to be enrolled. A deep venous thrombosis (DLT) occurred in the sixth patient. Thus, the MTD was 100 mg/m{sup 2}. Conclusions: The MTD of tamoxifen was 100 mg/m{sup 2} when given concurrently with temozolomide 75 mg/m{sup 2} and RT. Tamoxifen might have a role in the initial treatment of high-grade gliomas and should be studied in future Phase II trials building on the newly established platform of concurrent chemoradiotherapy.« less

  3. The role of hormonal therapy in patients with relapsed high-grade ovarian carcinoma: a retrospective series of tamoxifen and letrozole.

    PubMed

    George, Angela; McLachlan, Jennifer; Tunariu, Nina; Della Pepa, Chiara; Migali, Cristina; Gore, Martin; Kaye, Stan; Banerjee, Susana

    2017-06-30

    Hormonal therapy is used as a treatment option in high-grade ovarian carcinoma (HGOC), but the role and choice of treatment remains unclear. Agents used include tamoxifen and aromatase inhibitors. Our aim was to evaluate the efficacy of tamoxifen (T) and letrozole (L) in HGOC in clinical practice and investigate factors influencing clinical outcome. A retrospective review of patients with relapsed HGOC treated with either tamoxifen or letrozole at the Royal Marsden Hospital between 2007 and 2012 was performed. The primary endpoint of the study was objective response rate (ORR). Secondary endpoints included CA125 response, clinical benefit rate (CBR) and duration of response. Platinum-sensitivity and ER-status were evaluated as predictors of treatment response. 97 patients were included (43 T, 54 L); median age 63 years (20-92); 91% high-grade serous; median number of lines of prior chemotherapy 3 (1-8); 60% platinum-resistant, 40% platinum-sensitive; 52% ER + ve, 1% ER-ve, 47% unknown. 14 patients (6 T, 8 L) achieved a partial response, with ORR (RECIST) of 14% (T) and 15% (L). The CBR for ≥3 months was 65% (22/43) for tamoxifen and 56% (22/54) for letrozole. There was no significant difference in ORR (p = 0.99) or CBR (p = 0.14) between tamoxifen and letrozole. 22 patients (23%) had a CA-125 response with hormonal therapy (10 T - 23% and 12 L - 22%). ORR did not differ by platinum sensitivity (p = 0.42); or ER-status (positive vs unknown, p = 0.12). Responders to letrozole had longer durations of response than responders to tamoxifen (26 vs 11.5 months, p = 0.03), but equivalent disease stability duration (9.6 vs 7.2 months respectively, p = 0.11). Within the constraints of a retrospective study, we identified that patients treated with letrozole had a significantly longer duration of response than those treated with tamoxifen. Treatment with either tamoxifen or letrozole is a rational treatment option for patients with ER + ve HGOC

  4. 49 CFR 234.217 - Flashing light units.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Flashing light units. 234.217 Section 234.217..., Inspection, and Testing Maintenance Standards § 234.217 Flashing light units. (a) Each flashing light unit.... (b) Each flashing light unit shall be maintained to prevent dust and moisture from entering the...

  5. 49 CFR 234.217 - Flashing light units.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 4 2011-10-01 2011-10-01 false Flashing light units. 234.217 Section 234.217..., Inspection, and Testing Maintenance Standards § 234.217 Flashing light units. (a) Each flashing light unit.... (b) Each flashing light unit shall be maintained to prevent dust and moisture from entering the...

  6. Intraepithelial G3 adenocarcinoma of the endometrium after tamoxifen treatment.

    PubMed

    Marchesoni, Diego; Driul, L; Mozzanega, B; Nardelli, G B; Parenti, A

    2005-01-01

    In this paper we describe a case of endometrial carcinoma observed in a post-menopausal patient who was treated with tamoxifen for 5 years after a mastectomy for cancer. She came to our department because of vaginal bleeding 2 years after the end of tamoxifen treatment. She underwent hysteroscopy and a D and C. A polypoid endometrium completely filled the uterine cavity and was carefully removed by curettage; histology showed a highly undifferentiated neoplasia with a component of serous adenocarcinoma, which was likely to originate from endometrial polyps. The patient underwent radical hysterectomy, but no residual tumor was found in the uterus or in the tubes, ovary, or pelvic nodes, in spite of its low differentiation grade and high potential aggressiveness, and even though the patient was already symptomatic. Two years after surgery the patient is disease free, which is consistent with the evaluation of the surgical specimen, but unusual in poorly differentiated neoplasms.

  7. Novel Carbonyl Analogues of Tamoxifen: Design, Synthesis, and Biological Evaluation

    NASA Astrophysics Data System (ADS)

    Kasiotis, Konstantinos M.; Lambrinidis, George; Fokialakis, Nikolas; Tzanetou, Evangelia N.; Mikros, Emmanuel; Haroutounian, Serkos A.

    2017-09-01

    Aim of this work was to provide tamoxifen analogues with enhanced estrogen receptor binding affinity. Hence, several derivatives were prepared using an efficient triarylethylenes synthetic protocol. The novel compounds bioactivity was evaluated through the determination of their receptor binding affinity and their agonist/antagonist activity against breast cancer tissue using a MCF-7 cell-based assay. Phenyl esters 6a,b and 8a,b exhibited binding affinity to both ERα and ERβ higher than 4-hydroxytamoxifen while compounds 13 and 14 have shown cellular antiestrogenic activity similar to 4-hydroxytamoxifen and the known estrogen receptor inhibitor ICI182,780. Theoretical calculations and molecular modelling were applied to investigate, support and explain the biological profile of the new compounds. The relevant data indicated an agreement between calculations and demonstrated biological activity allowing to extract useful structure-activity relationships. Results herein underline that modifications of tamoxifen structure still provide molecules with substantial activity, as portrayed in the inhibition of MCF-7 cells proliferation.

  8. The regulation of progesterone receptor by 17 beta estradiol and tamoxifen in the Zr-75-1 human breast cancer cell line in defined medium.

    PubMed

    Allegra, J C; Korat, O; Do, H M; Lippman, M

    1981-01-01

    The regulation of progesterone receptor by 17 beta estradiol and tamoxifen in the ZR-75-1 human breast cancer cell line in defined medium is described. ZR-75-1 cells maintained in serum free hormone supplemented medium minus estradiol lack progesterone receptor activity. Readdition of estradiol to these cells leads to a marked stimulation of progesterone receptor activity (0 to greater than 100 fmols of specifically bound progesterone per million cells). Tamoxifen (10(-6)M-10(-8)M) does not stimulate progesterone receptor activity in this cell line. The presence of progesterone receptor activity is not directly related to growth. Withdrawal of insulin in the continued presence of estradiol has no effect on progesterone receptor concentration although net cell growth ceases. Conversely, withdrawal of estradiol in the continued presence of insulin induces a cessation of net cell growth accompanied by a loss of all progesterone receptor activity within 3-5 days.

  9. Simultaneous determination of centchroman and tamoxifen along with their metabolites in rat plasma using LC-MS/MS.

    PubMed

    Rama Raju, Kanumuri Siva; Taneja, Isha; Singh, Sheelendra Pratap; Tripathi, Amit; Mishra, Durga Prasad; Hussain, K Mahaboob; Gayen, Jiaur Rahman; Singh, Shio Kumar; Wahajuddin, Muhammad

    2015-01-01

    Tamoxifen and centchroman are two non-steroidal, selective estrogen receptors modulators, intended for long term therapy in the woman. Because of their wide spread use, there is a possibility of co-prescription of these agents. We studied the probable pharmacokinetic interaction between these agents in breast cancer model rats. A simple, sensitive and rapid LC-ESI-MS/MS method was developed and validated for the simultaneous determination of tamoxifen, centchroman and their active metabolites. The method was linear over a range of 0.2-200 ng/ml. All validation parameters met the acceptance criteria according to regulatory guidelines. LC-MS/MS method for determination of tamoxifen, centchroman and their metabolites was developed and validated. Results show the potential of drug-drug interaction upon co-administration these two marketed drugs.

  10. Tool Weighs Benefits, Risks of Raloxifene or Tamoxifen to Prevent Breast Cancer

    Cancer.gov

    Researchers have developed a benefit-risk index to help guide decisions on whether postmenopausal women at increased risk of developing breast cancer should take raloxifene or tamoxifen to reduce that risk.

  11. Interactions of the anticancer drug tamoxifen with lipid membranes

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Khadka, Nawal K.; Cheng, Xiaolin; Ho, Chian Sing

    Interactions of the hydrophobic anticancer drug tamoxifen (TAM) with lipid model membranes were studied using calcein-encapsulated vesicle leakage, attenuated total reflection Fourier transform infrared (FTIR) spectroscopy, small-angle neutron scattering (SANS), atomic force microscopy (AFM) based force spectroscopy, and all-atom molecular dynamics (MD) simulations. The addition of TAM enhances membrane permeability, inducing calcein to translocate from the interior to the exterior of lipid vesicles. A large decrease in the FTIR absorption band’s magnitude was observed in the hydrocarbon chain region, suggesting suppressed bond vibrational dynamics. Bilayer thickening was determined from SANS data. Force spectroscopy measurements indicate that the lipid bilayer areamore » compressibility modulus KA is increased by a large amount after the incorporation of TAM. MD simulations show that TAM decreases the lipid area and increases chain order parameters. Moreover, orientational and positional analyses show that TAM exhibits a highly dynamic conformation within the lipid bilayer. Lastly, our detailed experimental and computational studies of TAM interacting with model lipid membranes shed new light on membrane modulation by TAM.« less

  12. Interactions of the anticancer drug tamoxifen with lipid membranes

    DOE PAGES

    Khadka, Nawal K.; Cheng, Xiaolin; Ho, Chian Sing; ...

    2015-05-19

    Interactions of the hydrophobic anticancer drug tamoxifen (TAM) with lipid model membranes were studied using calcein-encapsulated vesicle leakage, attenuated total reflection Fourier transform infrared (FTIR) spectroscopy, small-angle neutron scattering (SANS), atomic force microscopy (AFM) based force spectroscopy, and all-atom molecular dynamics (MD) simulations. The addition of TAM enhances membrane permeability, inducing calcein to translocate from the interior to the exterior of lipid vesicles. A large decrease in the FTIR absorption band’s magnitude was observed in the hydrocarbon chain region, suggesting suppressed bond vibrational dynamics. Bilayer thickening was determined from SANS data. Force spectroscopy measurements indicate that the lipid bilayer areamore » compressibility modulus KA is increased by a large amount after the incorporation of TAM. MD simulations show that TAM decreases the lipid area and increases chain order parameters. Moreover, orientational and positional analyses show that TAM exhibits a highly dynamic conformation within the lipid bilayer. Lastly, our detailed experimental and computational studies of TAM interacting with model lipid membranes shed new light on membrane modulation by TAM.« less

  13. In Vitro Metabolism of Tamoxifen in Human, Rat, and Fish Microsomes

    EPA Science Inventory

    Results from an in vivo study comparing biologically-active metabolites in the plasma of Wistar rats and cunner fish (Tautogolabrus adspersus) treated with tamoxifen indicate notable differences in circulating metabolite concentrations between these two species. After a single or...

  14. Importance of highly selective LC-MS/MS analysis for the accurate quantification of tamoxifen and its metabolites: focus on endoxifen and 4-hydroxytamoxifen.

    PubMed

    Jager, N G L; Rosing, H; Linn, S C; Schellens, J H M; Beijnen, J H

    2012-06-01

    The antiestrogenic effect of tamoxifen is mainly attributable to the active metabolites endoxifen and 4-hydroxytamoxifen. This effect is assumed to be concentration-dependent and therefore quantitative analysis of tamoxifen and metabolites for clinical studies and therapeutic drug monitoring is increasing. We investigated the large discrepancies in reported mean endoxifen and 4-hydroxytamoxifen concentrations. Two published LC-MS/MS methods are used to analyse a set of 75 serum samples from patients treated with tamoxifen. The method from Teunissen et al. (J Chrom B, 879:1677-1685, 2011) separates endoxifen and 4-hydroxytamoxifen from other tamoxifen metabolites with similar masses and fragmentation patterns. The second method, published by Gjerde et al. (J Chrom A, 1082:6-14, 2005) however lacks selectivity, resulting in a factor 2-3 overestimation of the endoxifen and 4-hydroxytamoxifen levels, respectively. We emphasize the use of highly selective LC-MS/MS methods for the quantification of tamoxifen and its metabolites in biological samples.

  15. Acyl chain length and charge effect on Tamoxifen-lipid model membrane interactions

    NASA Astrophysics Data System (ADS)

    Bilge, Duygu; Kazanci, Nadide; Severcan, Feride

    2013-05-01

    Tamoxifen (TAM), which is an antiestrogenic agent, is widely used during chemotherapy of breast, pancreas, brain and liver cancers. In this study, TAM and model membrane interactions in the form of multilamellar vesicles (MLVs) were studied for lipids containing different acyl chain length and different charge status as a function of different TAM (1, 6, 9 and 15 mol%) concentrations. Zwitterionic lipids namely dipalmitoyl phosphatidylcholine (DPPC), and dimyristoylphosphatidylcholine (DMPC) lipids were used to see the acyl chain length effect and anionic dipalmitoyl phosphtidylglycerol (DPPG) lipid was used to see the charge effect. For this purpose Fourier transform-infrared (FTIR) spectroscopic and differential scanning calorimetric (DSC) techniques have been conducted. For zwitterionic lipid, concentration dependent different action of TAM was observed both in the gel and liquid crystalline phases by significantly increasing the lipid order and decreasing the dynamics for 1 mol% TAM, while decreasing the lipid order and increasing the dynamics of the lipids for higher concentrations (6, 9 and 15 mol%). However, different than neutral lipids, the dynamics and disorder of DPPG liposome increased for all TAM concentrations. The interactions between TAM and head group of multilamellar liposomes was monitored by analyzing the Cdbnd O stretching and PO2- antisymmetric double bond stretching bands. Increasing Tamoxifen concentrations led to a dehydration around these functional groups in the polar part of the lipids. DSC studies showed that for all types of lipids, TAM eliminates the pre-transition, shifts the main phase transition to lower temperatures and broadened the phase transition curve. The results indicate that not the acyl chain length but the charge status of the polar head group induces different effects on lipid membranes order and dynamics.

  16. [Effect of Evn-50 on cell growth and apoptosis in tamoxifen-resistance human breast cancer cell line MCF-7/TAM-R].

    PubMed

    Hu, Hui-yong; Zhou, Jun; Wan, Fang; Dong, Li-feng; Zhang, Feng; Wang, Yi-ke; Chen, Fang-fang; Chen, Yi-ding

    2012-09-01

    To investigate the effect of Evn-50 extracted from Vitex negundo on human breast cancer cell line MCF-7 and MCF-7/TAM-R cells in vitro. MCF-7 and tamoxifen-resistant MCF-7/TAM-R cells were treated with Evn-50,tamoxifen or combination of Evn-50 and tamoxifen. Cell proliferation inhibition rates were determined by MTT assay. The apoptosis rate and the change of cell cycle were detected by PI staining flow cytometry. Protein expression of phospho-MAPK 44/42 (Thr202/Tyr204),MAPK P44/42, phospho-AKT (Ser473) and AKT were detected with Western blotting. The viability of MCF-7 cells was decreased in combination group [(28.65 ±11.43)%] and Evn-50 group [(53.02 ±15.14)%] compared with TAM group (P<0.01). The cell viability of MCF-7/TAM-R in combination group [(42.11 ±14.30)%] was significantly lower than that in TAM group [(92.18 ±13.16)%] (P<0.01). The cell apoptosis rate was dependent on the time of treatment in all groups,the effects on apoptosis and G2/M phase cells were most prominent at 72 h (P<0.01). Western blotting revealed that protein levels of phosphorylated AKT and p-MAPK44/42 decreased,while the expression of total AKT and MAPK44/42 was stable. In MCF-7/TAM-R cells,the expression of phosphorylation of AKT and MAPK44/42 protein was not changed in Evn-50 or TAM alone group,but significantly inhibited in the combination group at 72 h. Evn-50 can inhibit cell growth and induce apoptosis in MCF-7 and MCF-7/TAM-R cells,it can reverse tamoxifen-resistance of MCF-7/TAM-R cells.The mechanisms may be related to the down-regulation of phosphorylated ERK1/2 in MAPK signal pathway and phosphorylated AKT in AKT signal pathway.

  17. Formation of tamoxifen-DNA adducts in multiple organs of adult female cynomolgus monkeys dosed with tamoxifen for 30 days.

    PubMed

    Schild, Laura J; Divi, Rao L; Beland, Frederick A; Churchwell, Mona I; Doerge, Daniel R; Gamboa da Costa, Gonçalo; Marques, M Matilde; Poirier, Miriam C

    2003-09-15

    The use of the antiestrogen tamoxifen (TAM) is associated with an increase in endometrial cancer. TAM-induced endometrial carcinogenesis may proceed through a genotoxin-mediated pathway, although the detection of endometrial TAM-DNA adducts in exposed women is still controversial. In this study, a monkey model has been used to investigate the question of TAM-DNA adduct formation in primates. Two methods have been used to determine TAM-DNA adducts: a TAM-DNA chemiluminescence immunoassay (TAM-DNA CIA), using an antiserum that has specificity for (E)-alpha-(deoxyguanosin-N(2)-yl)-tamoxifen (dG-TAM) and (E)-alpha-(deoxyguanosin-N(2)-yl)-N-desmethyltamoxifen (dG-desmethyl-TAM) and electrospray ionization tandem mass spectrometry (ES-MS/MS) coupled with on-line sample preparation and high-performance liquid chromatography (HPLC). Mature (19 year old) cynomolgus monkeys were given either vehicle control (n = 1) or TAM (n = 3) twice daily for a total dose of 2 mg of TAM/kg body weight (bw)/day for 30 days by naso-gastric intubation. Tissues were harvested, and DNA was isolated from uterus, ovary, liver, brain cortex, and kidney. By TAM-DNA CIA, values for uterine TAM-DNA adducts in two monkeys were 0.9 and 1.7 adducts/10(8) nucleotides, whereas values for ovarian TAM-DNA adducts in the same animals were 0.4 and 0.5 adducts/10(8) nucleotides. Liver, brain cortex, and kidney DNA samples from the three exposed monkeys had TAM-DNA levels of 2.1-4.2 adducts/10(8) nucleotides, 0.4-5.0 adducts/10(8) nucleotides, and 0.7-2.1 adducts/10(8) nucleotides, respectively. By HPLC-ES-MS/MS, the levels of TAM-DNA adducts detected in all tissues were comparable with those observed by TAM-DNA CIA. Thus, values for uterine TAM-DNA adducts ranged from 0.5 to 1.4 adducts/10(8) nucleotides, whereas values for ovarian TAM-DNA adducts, measurable in two monkeys, were 0.2 and 0.3 adducts/10(8) nucleotides. Liver DNA contained the highest TAM-DNA adduct levels (7.0-11.1 adducts/10(8) nucleotides

  18. The selective estrogen receptor modulators (SERMs) raloxifene and tamoxifen improve ANP levels and decrease nuclear translocation of NF-kB in estrogen-deficient rats.

    PubMed

    Lamas, Aline Z; Nascimento, Andrews M; Medeiros, Ana Raquel S; Caliman, Izabela F; Dalpiaz, Polyana L M; Firmes, Luciana B; Sousa, Glauciene J; Oliveira, Phablo Wendell C; Andrade, Tadeu U; Reis, Adelina M; Gouvea, Sônia A; Bissoli, Nazaré S

    2017-08-01

    The selective estrogen receptor modulators (SERMs) raloxifene and tamoxifen are used for the treatment of osteoporosis and cancer, respectively, in women. The impairment of both the Atrial Natriuretic Peptide (ANP) cell signaling system and the translocation of nuclear factor-kappa B (NF-kB) to the cell nucleus are associated with detrimental cardiovascular effects and inflammation. The effects of SERMs on these parameters in the cardiac tissue of estrogen-deficient rats has not been reported. We investigated the effects of raloxifene and tamoxifen on ANP signaling, p65 NF-kB nuclear translocation, cardiac histology and contractility. Female rats were divided into five groups: control (SHAM), ovariectomized (OVX), OVX-treated 17-β-estradiol (E), OVX-treated raloxifene (RLX) and OVX-treated tamoxifen (TAM). The treatments started 21days after ovariectomy and continued for 14days. Ovariectomy reduced ANP mRNA in the left atrium (LA), decreased the content of ANP protein in the LA and in plasma, and increased the level of p65 NF-kB nuclear translocation in the left ventricle. Both 17-β-estradiol and SERMs were able to reverse these alterations, which were induced by the estrogen deficient state. The hemodynamic and cardiac structural parameters analyzed in the present work were not modified by the interventions. Our study demonstrates, for the first time, the additional benefits of raloxifene and tamoxifen in an estrogen-deficient state. These include the normalization of plasmatic and cardiac ANP levels and cardiac p65 NF-kB translocation. Therefore, these treatments promote cardiovascular protection and may contribute to the prevention of cardiac dysfunction observed long-term in postmenopausal women. Copyright © 2017. Published by Elsevier Urban & Partner Sp. z o.o.

  19. Tamoxifen and Risk of Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers

    PubMed Central

    Phillips, Kelly-Anne; Milne, Roger L.; Rookus, Matti A.; Daly, Mary B.; Antoniou, Antonis C.; Peock, Susan; Frost, Debra; Easton, Douglas F.; Ellis, Steve; Friedlander, Michael L.; Buys, Saundra S.; Andrieu, Nadine; Noguès, Catherine; Stoppa-Lyonnet, Dominique; Bonadona, Valérie; Pujol, Pascal; McLachlan, Sue Anne; John, Esther M.; Hooning, Maartje J.; Seynaeve, Caroline; Tollenaar, Rob A.E.M.; Goldgar, David E.; Beth Terry, Mary; Caldes, Trinidad; Weideman, Prue C.; Andrulis, Irene L.; Singer, Christian F.; Birch, Kate; Simard, Jacques; Southey, Melissa C.; Olsson, Håkan L.; Jakubowska, Anna; Olah, Edith; Gerdes, Anne-Marie; Foretova, Lenka; Hopper, John L.

    2013-01-01

    Purpose To determine whether adjuvant tamoxifen treatment for breast cancer (BC) is associated with reduced contralateral breast cancer (CBC) risk for BRCA1 and/or BRCA2 mutation carriers. Methods Analysis of pooled observational cohort data, self-reported at enrollment and at follow-up from the International BRCA1, and BRCA2 Carrier Cohort Study, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, and Breast Cancer Family Registry. Eligible women were BRCA1 and BRCA2 mutation carriers diagnosed with unilateral BC since 1970 and no other invasive cancer or tamoxifen use before first BC. Hazard ratios (HRs) for CBC associated with tamoxifen use were estimated using Cox regression, adjusting for year and age of diagnosis, country, and bilateral oophorectomy and censoring at contralateral mastectomy, death, or loss to follow-up. Results Of 1,583 BRCA1 and 881 BRCA2 mutation carriers, 383 (24%) and 454 (52%), respectively, took tamoxifen after first BC diagnosis. There were 520 CBCs over 20,104 person-years of observation. The adjusted HR estimates were 0.38 (95% CI, 0.27 to 0.55) and 0.33 (95% CI, 0.22 to 0.50) for BRCA1 and BRCA2 mutation carriers, respectively. After left truncating at recruitment to the cohort, adjusted HR estimates were 0.58 (95% CI, 0.29 to 1.13) and 0.48 (95% CI, 0.22 to 1.05) based on 657 BRCA1 and 426 BRCA2 mutation carriers with 100 CBCs over 4,392 person-years of prospective follow-up. HRs did not differ by estrogen receptor status of the first BC (missing for 56% of cases). Conclusion This study provides evidence that tamoxifen use is associated with a reduction in CBC risk for BRCA1 and BRCA2 mutation carriers. Further follow-up of these cohorts will provide increased statistical power for future prospective analyses. PMID:23918944

  20. Bilateral macular edema in a patient treated with tamoxifen: a case report and review of the literature.

    PubMed

    Zafeiropoulos, Paraskevas; Nanos, Panagiotis; Tsigkoulis, Evangelos; Stefaniotou, Maria

    2014-01-01

    We present a case of a 41-year-old female patient with progressive bilateral visual loss. On examination, her best corrected visual acuity (BCVA) in her right eye was 3/10 and her BCVA in her left eye was 2/10. Fundus and optical coherence tomography examination revealed severe bilateral macular edema. She had been diagnosed with breast cancer 6 years ago and was receiving tamoxifen at a dosage of 20 mg/day ever since. Tamoxifen therapy was discontinued, and the patient received 250 mg of acetazolamide three times a day for a period of 1 month. Both foveae regained their normal contour within 2 months, and her vision was restored to 10/10 BCVA 3 months later. To our knowledge, this is the first case reported where bilateral intraretinal macular edema is the only retinal manifestation in a patient on oral tamoxifen.

  1. Electronic Flash In Data Acquisition

    NASA Astrophysics Data System (ADS)

    Miller, C. E.

    1982-02-01

    Photographic acquisition of data often may be simplified, or the data quality improved upon by employing electronic flash sources with traditional equipment or techniques. The relatively short flash duration compared to movie camera shutters, or to the long integration time of video camera provides improved spatial resolution through blur reduction, particularly important as image movement becomes a significant fraction of film format dimension. Greater accuracy typically is achieved in velocity and acceleration determinations by using a stroboscopic light source rather than a movie camera frame-rate control as a time standard. Electrical efficiency often is an important advantage of electronic flash sources since almost any necessary light level for exposure may be produced, yet the source typically is "off" most of the time. Various synchronization techniques greatly expand the precise control of exposure. Biomechanical and sports equipment studies may involve velocities up to 200 feet-per-second, and often will have associated very rapid actions of interest. The need for brief exposures increases H.s one "ZOOMS in on the action." In golf, for example, the swing may be examined using 100 microsecond (Us) flashes at rates of 60 or 120 flashes-per-second (FPS). Accurate determination of linear and rotational velocity of the ball requires 10 Us flashes at 500-1,000 FPS, while sub-Us flashes at 20,000-50,000 FPS are required to resolve the interaction of the ball and the club, head. Some seldom. used techniques involving streak photography are described, with enhanced results obtained by combining strobe with the usual continuous light source. The combination of strobe and a fast electro-mechanical shutter is considered for Us photography under daylight conditions.

  2. Endoxifen and Other Metabolites of Tamoxifen Inhibit Human Hydroxysteroid Sulfotransferase 2A1 (hSULT2A1)

    PubMed Central

    Squirewell, Edwin J.; Qin, Xiaoyan

    2014-01-01

    Although tamoxifen is a successful agent for treatment and prevention of estrogen-dependent breast cancer, its use has been limited by the low incidence of endometrial cancer. Human hydroxysteroid sulfotransferase 2A1 (hSULT2A1) catalyzes the formation of an α-sulfooxy metabolite of tamoxifen that is reactive toward DNA, and this has been implicated in its carcinogenicity. Also, hSULT2A1 functions in the metabolism of steroid hormones such as dehydroepiandrosterone (DHEA) and pregnenolone (PREG). These roles of hSULT2A1 in steroid hormone metabolism and in generating a reactive metabolite of tamoxifen led us to examine its interactions with tamoxifen and several of its major metabolites. We hypothesized that metabolites of tamoxifen may regulate the catalytic activity of hSULT2A1, either through direct inhibition or through serving as alternate substrates for the enzyme. We found that 4-hydroxy-N-desmethyltamoxifen (endoxifen) is a potent inhibitor of hSULT2A1-catalyzed sulfation of PREG and DHEA, with Ki values of 3.5 and 2.8 μM, respectively. In the hSULT2A1-catalyzed sulfation of PREG, 4-hydroxytamoxifen (4-OHTAM) and N-desmethyltamoxifen (N-desTAM) exhibited Ki values of 12.7 and 9.8 μM, respectively, whereas corresponding Ki values of 19.4 and 17.2 μM were observed with DHEA as substrate. A Ki value of 9.1 μM was observed for tamoxifen-N-oxide with DHEA as substrate, and this increased to 16.9 μM for the hSULT2A1-catalyzed sulfation of PREG. Three metabolites were substrates for hSULT2A1, with relative sulfation rates of 4-OHTAM > N-desTAM > > endoxifen. These results may be useful in interpreting ongoing clinical trials of endoxifen and in improving the design of related molecules. PMID:25157097

  3. Enlarged temporal integration window in schizophrenia indicated by the double-flash illusion.

    PubMed

    Haß, Katharina; Sinke, Christopher; Reese, Tanya; Roy, Mandy; Wiswede, Daniel; Dillo, Wolfgang; Oranje, Bob; Szycik, Gregor R

    2017-03-01

    In the present study we were interested in the processing of audio-visual integration in schizophrenia compared to healthy controls. The amount of sound-induced double-flash illusions served as an indicator of audio-visual integration. We expected an altered integration as well as a different window of temporal integration for patients. Fifteen schizophrenia patients and 15 healthy volunteers matched for age and gender were included in this study. We used stimuli with eight different temporal delays (stimulus onset asynchronys (SOAs) 25, 50, 75, 100, 125, 150, 200 and 300 ms) to induce a double-flash illusion. Group differences and the widths of temporal integration windows were calculated on percentages of reported double-flash illusions. Patients showed significantly more illusions (ca. 36-44% vs. 9-16% in control subjects) for SOAs 150-300. The temporal integration window for control participants went from SOAs 25 to 200 whereas for patients integration was found across all included temporal delays. We found no significant relationship between the amount of illusions and either illness severity, chlorpromazine equivalent doses or duration of illness in patients. Our results are interpreted in favour of an enlarged temporal integration window for audio-visual stimuli in schizophrenia patients, which is consistent with previous research.

  4. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials.

    PubMed

    Davies, C; Godwin, J; Gray, R; Clarke, M; Cutter, D; Darby, S; McGale, P; Pan, H C; Taylor, C; Wang, Y C; Dowsett, M; Ingle, J; Peto, R

    2011-08-27

    As trials of 5 years of tamoxifen in early breast cancer mature, the relevance of hormone receptor measurements (and other patient characteristics) to long-term outcome can be assessed increasingly reliably. We report updated meta-analyses of the trials of 5 years of adjuvant tamoxifen. We undertook a collaborative meta-analysis of individual patient data from 20 trials (n=21,457) in early breast cancer of about 5 years of tamoxifen versus no adjuvant tamoxifen, with about 80% compliance. Recurrence and death rate ratios (RRs) were from log-rank analyses by allocated treatment. In oestrogen receptor (ER)-positive disease (n=10,645), allocation to about 5 years of tamoxifen substantially reduced recurrence rates throughout the first 10 years (RR 0·53 [SE 0·03] during years 0-4 and RR 0·68 [0·06] during years 5-9 [both 2p<0·00001]; but RR 0·97 [0·10] during years 10-14, suggesting no further gain or loss after year 10). Even in marginally ER-positive disease (10-19 fmol/mg cytosol protein) the recurrence reduction was substantial (RR 0·67 [0·08]). In ER-positive disease, the RR was approximately independent of progesterone receptor status (or level), age, nodal status, or use of chemotherapy. Breast cancer mortality was reduced by about a third throughout the first 15 years (RR 0·71 [0·05] during years 0-4, 0·66 [0·05] during years 5-9, and 0·68 [0·08] during years 10-14; p<0·0001 for extra mortality reduction during each separate time period). Overall non-breast-cancer mortality was little affected, despite small absolute increases in thromboembolic and uterine cancer mortality (both only in women older than 55 years), so all-cause mortality was substantially reduced. In ER-negative disease, tamoxifen had little or no effect on breast cancer recurrence or mortality. 5 years of adjuvant tamoxifen safely reduces 15-year risks of breast cancer recurrence and death. ER status was the only recorded factor importantly predictive of the proportional

  5. An Analysis of Total Lightning Flash Rates Over Florida

    NASA Astrophysics Data System (ADS)

    Mazzetti, Thomas O.; Fuelberg, Henry E.

    2017-12-01

    Although Florida is known as the "Sunshine State", it also contains the greatest lightning flash densities in the United States. Flash density has received considerable attention in the literature, but lightning flash rate has received much less attention. We use data from the Earth Networks Total Lightning Network (ENTLN) to produce a 5 year (2010-2014) set of statistics regarding total flash rates over Florida and adjacent regions. Instead of tracking individual storms, we superimpose a 0.2° × 0.2° grid over the study region and count both cloud-to-ground (CG) and in-cloud (IC) flashes over 5 min intervals. Results show that the distribution of total flash rates is highly skewed toward small values, whereas the greatest rate is 185 flashes min-1. Greatest average annual flash rates ( 3 flashes min-1) are located near Orlando. The southernmost peninsula, North Florida, and the Florida Panhandle exhibit smaller average annual flash rates ( 1.5 flashes min-1). Large flash rates > 100 flashes min-1 can occur during any season, at any time during the 24 h period, and at any location within the domain. However, they are most likely during the afternoon and early evening in East Central Florida during the spring and summer months.

  6. A global flash flood forecasting system

    NASA Astrophysics Data System (ADS)

    Baugh, Calum; Pappenberger, Florian; Wetterhall, Fredrik; Hewson, Tim; Zsoter, Ervin

    2016-04-01

    The sudden and devastating nature of flash flood events means it is imperative to provide early warnings such as those derived from Numerical Weather Prediction (NWP) forecasts. Currently such systems exist on basin, national and continental scales in Europe, North America and Australia but rely on high resolution NWP forecasts or rainfall-radar nowcasting, neither of which have global coverage. To produce global flash flood forecasts this work investigates the possibility of using forecasts from a global NWP system. In particular we: (i) discuss how global NWP can be used for flash flood forecasting and discuss strengths and weaknesses; (ii) demonstrate how a robust evaluation can be performed given the rarity of the event; (iii) highlight the challenges and opportunities in communicating flash flood uncertainty to decision makers; and (iv) explore future developments which would significantly improve global flash flood forecasting. The proposed forecast system uses ensemble surface runoff forecasts from the ECMWF H-TESSEL land surface scheme. A flash flood index is generated using the ERIC (Enhanced Runoff Index based on Climatology) methodology [Raynaud et al., 2014]. This global methodology is applied to a series of flash floods across southern Europe. Results from the system are compared against warnings produced using the higher resolution COSMO-LEPS limited area model. The global system is evaluated by comparing forecasted warning locations against a flash flood database of media reports created in partnership with floodlist.com. To deal with the lack of objectivity in media reports we carefully assess the suitability of different skill scores and apply spatial uncertainty thresholds to the observations. To communicate the uncertainties of the flash flood system output we experiment with a dynamic region-growing algorithm. This automatically clusters regions of similar return period exceedence probabilities, thus presenting the at-risk areas at a spatial

  7. Development of biodegradable polymer based tamoxifen citrate loaded nanoparticles and effect of some manufacturing process parameters on them: a physicochemical and in-vitro evaluation.

    PubMed

    Sahana, Basudev; Santra, Kousik; Basu, Sumit; Mukherjee, Biswajit

    2010-09-07

    The aim of the present study was to develop nanoparticles of tamoxifen citrate, a non-steroidal antiestrogenic drug used for the treatment of breast cancer. Biodegradable poly (D, L- lactide-co-glycolide)-85:15 (PLGA) was used to develop nanoparticles of tamoxifen citrate by multiple emulsification (w/o/w) and solvent evaporation technique. Drug-polymer ratio, polyvinyl alcohol concentrations, and homogenizing speeds were varied at different stages of preparation to optimize the desired size and release profile of drug. The characterization of particle morphology and shape was performed by field emission scanning electron microscope (FE-SEM) and particle size distribution patterns were studied by direct light scattering method using zeta sizer. In vitro drug release study showed that release profile of tamoxifen from biodegradable nanoparticles varied due to the change in speed of centrifugation for separation. Drug loading efficiency varied from 18.60% to 71.98%. The FE-SEM study showed that biodegradable nanoparticles were smooth and spherical in shape. The stability studies of tamoxifen citrate in the experimental nanoparticles showed the structural integrity of tamoxifen citrate in PLGA nanoparticles up to 60°C in the tested temperatures. Nanoparticles containing tamoxifen citrate could be useful for the controlled delivery of the drug for a prolonged period.

  8. Simulation of flashing signal operations.

    DOT National Transportation Integrated Search

    1982-01-01

    Various guidelines that have been proposed for the operation of traffic signals in the flashing mode were reviewed. The use of existing traffic simulation procedures to evaluate flashing signals was examined and a study methodology for simulating and...

  9. Effect of aerobic exercises versus laser acupuncture in treatment of postmenopausal hot flushes: a randomized controlled trial.

    PubMed

    Elhosary, Eman Abdelfatah Mohamed; Ewidea, Mahmoud Mohamed; Ahmed, Hamada Ahmed Hamada; El Khatib, Ayman

    2018-02-01

    [Purpose] To compare the effect of aerobic exercises versus laser acupuncture in treatment of postmenopausal hot flushes. [Subjects and Methods] This study was designed as single blind randomized controlled trial. A total of 48 postmenopausal women complained of hot flushes. Their ages ranged between 45 to 55 years and were randomly assigned into 2 equal groups: group (A), which received an aerobic exercises, and group (B), which received laser acupuncture. Both groups recieved 3 sessions per week for two months. The level of follicular stimulating hormone, lutelizing hormone, and hot flushes dairy card were assessed the severity of hot flahes before and after treatment program. [Results] There were Significant reduction in FSH, LH, and menopausal daily hot flush scale in group A compared with group B at the post treatment. [Conclusion] Eight week program of an aerobic exercises yields improvement in FSH, LH, and decrease in severity of hot flushes assessed by hot flush dairy card than laser acupuncture in the treatment of postmenopausal hot flashes.

  10. Experimental observation of the luminescence flash at the collapse phase of a bubble produced by pulsed discharge in water

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Huang, Yifan; Zhang, Liancheng; Zhu, Xinlei

    2015-11-02

    This letter presents an experimental observation of luminescence flash at the collapse phase of an oscillating bubble produced by a pulsed discharge in water. According to the high speed records, the flash lasts around tens of microseconds, which is much longer than the lifetime of laser and ultrasound induced luminescence flashes in nanoseconds and picoseconds, respectively. The pulse width of temperature waveform and minimum radius calculated at the collapse phase also show that the thermodynamic and dynamic signatures of the bubbles in this work are much larger than those of ultrasound and laser induced bubbles both in time and spacemore » scales. However, the peak temperature at the point of collapse is close to the results of ultrasound and laser induced bubbles. This result provides another possibility for accurate emission spectrum measurement other than amplification of the emitted light, such as increasing laser energy or sound energy or substituting water with sulphuric acid.« less

  11. 4-Hydroxylated metabolites of the antiestrogens tamoxifen and toremifene are metabolized to unusually stable quinone methides.

    PubMed

    Fan, P W; Zhang, F; Bolton, J L

    2000-01-01

    Tamoxifen is widely prescribed for the treatment of hormone-dependent breast cancer, and it has recently been approved by the Food and Drug Administration for the chemoprevention of this disease. However, long-term usage of tamoxifen has been linked to increased risk of developing endometrial cancer in women. One of the suggested pathways leading to the potential toxicity of tamoxifen involves its oxidative metabolism to 4-hydroxytamoxifen, which may be further oxidized to an electrophilic quinone methide. The resulting quinone methide has the potential to alkylate DNA and may initiate the carcinogenic process. To further probe the chemical reactivity and toxicity of such an electrophilic species, we have prepared the 4-hydroxytamoxifen quinone methide chemically and enzymatically, examined its reactivity under physiological conditions, and quantified its reactivity with GSH. Interestingly, this quinone methide is unusually stable; its half-life under physiological conditions is approximately 3 h, and its half-life in the presence of GSH is approximately 4 min. The reaction between 4-hydroxytamoxifen quinone methide and GSH appears to be a reversible process because the quinone methide GSH conjugates slowly decompose over time, regenerating the quinone methide as indicated by LC/MS/MS data. The tamoxifen GSH conjugates were detected in microsomal incubations with 4-hydroxytamoxifen; however, none were observed in breast cancer cell lines (MCF-7) perhaps because very little quinone methides is formed. Toremifene, which is a chlorinated analogue of tamoxifen, undergoes similar oxidative metabolism to give 4-hydroxytoremifene, which is further oxidized to the corresponding quinone methide. The toremifene quinone methide has a half-life of approximately 1 h under physiological conditions, and its rate of reaction in the presence of excess GSH is approximately 6 min. More detailed analyses have indicated that the 4-hydroxytoremifene quinone methide reacts with two

  12. Tamoxifen from Failed Contraceptive Pill to Best-Selling Breast Cancer Medicine: A Case-Study in Pharmaceutical Innovation

    PubMed Central

    Quirke, Viviane M.

    2017-01-01

    Today, tamoxifen is one of the world's best-selling hormonal breast cancer drugs. However, it was not always so. Compound ICI 46,474 (as it was first known) was synthesized in 1962 within a project to develop a contraceptive pill in the pharmaceutical laboratories of ICI (now part of AstraZeneca). Although designed to act as an anti-estrogen, the compound stimulated, rather than suppressed ovulation in women. This, and the fact that it could not be patented in the USA, its largest potential market, meant that ICI nearly stopped the project. It was saved partly because the team's leader, Arthur Walpole, threatened to resign, and pressed on with another project: to develop tamoxifen as a treatment for breast cancer. Even then, its market appeared small, because at first it was mainly used as a palliative treatment for advanced breast cancer. An important turning point in tamoxifen's journey from orphan drug to best-selling medicine occurred in the 1980s, when clinical trials showed that it was also useful as an adjuvant to surgery and chemotherapy in the early stages of the disease. Later, trials demonstrated that it could prevent its occurrence or re-occurrence in women at high risk of breast cancer. Thus, it became the first preventive for any cancer, helping to establish the broader principles of chemoprevention, and extending the market for tamoxifen and similar drugs further still. Using tamoxifen as a case study, this paper discusses the limits of the rational approach to drug design, the role of human actors, and the series of feedback loops between bench and bedside that underpins pharmaceutical innovation. The paper also highlights the complex evaluation and management of risk that are involved in all therapies, but more especially perhaps in life-threatening and emotion-laden diseases like cancer. PMID:28955226

  13. Tamoxifen from Failed Contraceptive Pill to Best-Selling Breast Cancer Medicine: A Case-Study in Pharmaceutical Innovation.

    PubMed

    Quirke, Viviane M

    2017-01-01

    Today, tamoxifen is one of the world's best-selling hormonal breast cancer drugs. However, it was not always so. Compound ICI 46,474 (as it was first known) was synthesized in 1962 within a project to develop a contraceptive pill in the pharmaceutical laboratories of ICI (now part of AstraZeneca). Although designed to act as an anti-estrogen, the compound stimulated, rather than suppressed ovulation in women. This, and the fact that it could not be patented in the USA, its largest potential market, meant that ICI nearly stopped the project. It was saved partly because the team's leader, Arthur Walpole, threatened to resign, and pressed on with another project: to develop tamoxifen as a treatment for breast cancer. Even then, its market appeared small, because at first it was mainly used as a palliative treatment for advanced breast cancer. An important turning point in tamoxifen's journey from orphan drug to best-selling medicine occurred in the 1980s, when clinical trials showed that it was also useful as an adjuvant to surgery and chemotherapy in the early stages of the disease. Later, trials demonstrated that it could prevent its occurrence or re-occurrence in women at high risk of breast cancer. Thus, it became the first preventive for any cancer, helping to establish the broader principles of chemoprevention, and extending the market for tamoxifen and similar drugs further still. Using tamoxifen as a case study, this paper discusses the limits of the rational approach to drug design, the role of human actors, and the series of feedback loops between bench and bedside that underpins pharmaceutical innovation. The paper also highlights the complex evaluation and management of risk that are involved in all therapies, but more especially perhaps in life-threatening and emotion-laden diseases like cancer.

  14. Topical thermal therapy with hot packs suppresses physical inactivity-induced mechanical hyperalgesia and up-regulation of NGF.

    PubMed

    Nakagawa, Tatsuki; Hiraga, Shin-Ichiro; Mizumura, Kazue; Hori, Kiyomi; Ozaki, Noriyuki; Koeda, Tomoko

    2017-10-12

    We focused on the analgesic effect of hot packs for mechanical hyperalgesia in physically inactive rats. Male Wistar rats were randomly divided into four groups: control, physical inactivity (PI), PI + sham treatment (PI + sham), and PI + hot pack treatment (PI + hot pack) groups. Physical inactivity rats wore casts on both hind limbs in full plantar flexed position for 4 weeks. Hot pack treatment was performed for 20 min a day, 5 days a week. Although mechanical hyperalgesia and the up-regulation of NGF in the plantar skin and gastrocnemius muscle were observed in the PI and the PI + sham groups, these changes were significantly suppressed in the PI + hot pack group. The present results clearly demonstrated that hot pack treatment was effective in reducing physical inactivity-induced mechanical hyperalgesia and up-regulation of NGF in plantar skin and gastrocnemius muscle.

  15. Microarray analysis on gene regulation by estrogen, progesterone and tamoxifen in human endometrial stromal cells.

    PubMed

    Ren, Chun-E; Zhu, Xueqiong; Li, Jinping; Lyle, Christian; Dowdy, Sean; Podratz, Karl C; Byck, David; Chen, Hai-Bin; Jiang, Shi-Wen

    2015-03-13

    Epithelial stromal cells represent a major cellular component of human uterine endometrium that is subject to tight hormonal regulation. Through cell-cell contacts and/or paracrine mechanisms, stromal cells play a significant role in the malignant transformation of epithelial cells. We isolated stromal cells from normal human endometrium and investigated the morphological and transcriptional changes induced by estrogen, progesterone and tamoxifen. We demonstrated that stromal cells express appreciable levels of estrogen and progesterone receptors and undergo different morphological changes upon hormonal stimulation. Microarray analysis indicated that both estrogen and progesterone induced dramatic alterations in a variety of genes associated with cell structure, transcription, cell cycle, and signaling. However, divergent patterns of changes, and in some genes opposite effects, were observed for the two hormones. A large number of genes are identified as novel targets for hormonal regulation. These hormone-responsive genes may be involved in normal uterine function and the development of endometrial malignancies.

  16. Space Shuttle Main Engine Low Pressure Oxidizer Turbo-Pump Inducer Dynamic Environment Characterization through Water Model and Hot-Fire Testing

    NASA Technical Reports Server (NTRS)

    Arellano, Patrick; Patton, Marc; Schwartz, Alan; Stanton, David

    2006-01-01

    The Low Pressure Oxidizer Turbopump (LPOTP) inducer on the Block II configuration Space Shuttle Main Engine (SSME) experienced blade leading edge ripples during hot firing. This undesirable condition led to a minor redesign of the inducer blades. This resulted in the need to evaluate the performance and the dynamic environment of the redesign, relative to the current configuration, as part of the design acceptance process. Sub-scale water model tests of the two inducer configurations were performed, with emphasis on the dynamic environment due to cavitation induced vibrations. Water model tests were performed over a wide range of inlet flow coefficient and pressure conditions, representative of the scaled operating envelope of the Block II SSME, both in flight and in ground hot-fire tests, including all power levels. The water test hardware, facility set-up, type and placement of instrumentation, the scope of the test program, specific test objectives, data evaluation process and water test results that characterize and compare the two SSME LPOTP inducers are discussed. In addition, dynamic characteristics of the two water models were compared to hot fire data from specially instrumented ground tests. In general, good agreement between the water model and hot fire data was found, which confirms the value of water model testing for dynamic characterization of rocket engine turbomachinery.

  17. Proceedings of the Workshop on the Chemical Suppression of Rocket Afterburning and of Gun Muzzle Flash

    DTIC Science & Technology

    1987-03-01

    We report here the first results of this gun simulator used in the study of muzzle flash. The test setup used is shown in Figure 18. Pressure ports...experiments. For the first tests , the exploding wires mentioned above ignited the gas mixture. Later, "soft" ignition by means of a single tungsten...wire, placed axially in the chamber, was also tested . The voltage pulse applied across this hot wire is shown in Figure 19. This "soft" ignition

  18. Comparison of the effects of the antiestrogens EM-800 and tamoxifen on the growth of human breast ZR-75-1 cancer xenografts in nude mice.

    PubMed

    Couillard, S; Gutman, M; Labrie, C; Bélanger, A; Candas, B; Labrie, F

    1998-01-01

    Although estrone supplementation in ovariectomized (OVX) nude mice bearing ZR-75-1 xenografts caused a 365% increase in average tumor size during the 4-month treatment period, administration of the antiestrogen EM-800 at the daily oral doses of 50, 150, or 400 microg completely prevented estrogen-stimulated tumor growth. At the same doses of tamoxifen, tumor size was inhibited to 189, 117, and 120% above pretreatment values. However, when EM-800 (150 microg/day) was added to the daily 150- and 400-microg doses of tamoxifen, final tumor size was decreased further to 12 and 38% above pretreatment values, respectively. EM-800 (400 microg daily) administered to estrone-supplemented OVX mice caused complete, partial, and stable responses in 11, 22, and 49% of estrone-stimulated tumors, respectively, whereas 19% (7 of 37) progressed. At the same dose of tamoxifen, the corresponding responses were 3% (complete response), 3% (partial response), and 25% (no change), whereas 69% (22 of 32) of tumors progressed. In the absence of estrone supplementation, tamoxifen (400 microg) alone administered to OVX mice stimulated tumor growth to 161% compared with initial size whereas the same dose of EM-800 reduced tumor size by 55%, a value superimposable to that observed in OVX control animals. The agonistic effect of tamoxifen is thus illustrated by the observation that 73% of tumors progressed when tamoxifen was administered alone to OVX animals whereas no tumor progressed with EM-800. The present data strongly suggest that at least part of the initial lack of response and resistance to tamoxifen during tamoxifen treatment in women is due to the estrogenic activity of this compound, whereas the new antiestrogen EM-800 exerts pure antagonistic action.

  19. Minimal impact of adjuvant exemestane or tamoxifen treatment on mammographic breast density in postmenopausal breast cancer patients: a Dutch TEAM trial analysis.

    PubMed

    van Nes, Johanna G H; Beex, Louk V A M; Seynaeve, Caroline; Putter, Hein; Sramek, Alexandr; Lardenoije, Susanne; Duijm-de Carpentier, Marjolijn; Van Rongen, Inge; Nortier, Johan W R; Zonderland, Harmien M; van de Velde, Cornelis J H

    2015-03-01

    Mammographic breast density is one of the strongest independent risk factors for developing breast cancer. We examined the effect of exemestane and tamoxifen on breast density in Dutch postmenopausal early breast cancer patients participating in the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. Analogue mammograms of selected TEAM participants before start, and after one and two (and if available after three) years of adjuvant endocrine therapy were collected centrally and reviewed. Study endpoints were change in breast density over time, and correlations between breast density and locoregional recurrence (LRR), distance recurrence (DR), and contralateral breast cancer (CBC). Mammograms of 378 patients (181 tamoxifen, 197 exemestane) were included in the current per protocol analyses. Baseline breast density was low (breast density score<50% in 75% of patients) and not different between patients randomised to exemestane or tamoxifen (coefficient 0.16, standard error 0.17). Breast density did not change during treatment in exemestane (p=0.25) or tamoxifen users (p=0.59). No relation was observed between breast density and the occurrence of a LRR [hazards ratio (HR) 0.87, 95% CI 0.45-1.68, p=0.67], a DR (HR 1.02, 95% CI 0.77-1.35, p=0.90), or CBC (HR 1.31, 95% CI 0.63-2.72, p=0.48). The in general low breast density score in early postmenopausal breast cancer patients did not substantially change over time, and this pattern was not different between tamoxifen and exemestane users. Breast density was not a predictive marker for efficacy of adjuvant endocrine therapy.

  20. Bipolar cloud-to-ground lightning flash observations

    NASA Astrophysics Data System (ADS)

    Saba, Marcelo M. F.; Schumann, Carina; Warner, Tom A.; Helsdon, John H.; Schulz, Wolfgang; Orville, Richard E.

    2013-10-01

    lightning is usually defined as a lightning flash where the current waveform exhibits a polarity reversal. There are very few reported cases of cloud-to-ground (CG) bipolar flashes using only one channel in the literature. Reports on this type of bipolar flashes are not common due to the fact that in order to confirm that currents of both polarities follow the same channel to the ground, one necessarily needs video records. This study presents five clear observations of single-channel bipolar CG flashes. High-speed video and electric field measurement observations are used and analyzed. Based on the video images obtained and based on previous observations of positive CG flashes with high-speed cameras, we suggest that positive leader branches which do not participate in the initial return stroke of a positive cloud-to-ground flash later generate recoil leaders whose negative ends, upon reaching the branch point, traverse the return stroke channel path to the ground resulting in a subsequent return stroke of opposite polarity.