| 1. |
- Simões, Bruno M, et al.
(author)
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Anti-estrogen Resistance in Human Breast Tumors Is Driven by JAG1-NOTCH4-Dependent Cancer Stem Cell Activity.
- 2015
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In: Cell Reports. - : Elsevier BV. - 2211-1247. ; 12:12, s. 1968-1977
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Journal article (peer-reviewed)abstract
- Breast cancers (BCs) typically express estrogen receptors (ERs) but frequently exhibit de novo or acquired resistance to hormonal therapies. Here, we show that short-term treatment with the anti-estrogens tamoxifen or fulvestrant decrease cell proliferation but increase BC stem cell (BCSC) activity through JAG1-NOTCH4 receptor activation both in patient-derived samples and xenograft (PDX) tumors. In support of this mechanism, we demonstrate that high ALDH1 predicts resistance in women treated with tamoxifen and that a NOTCH4/HES/HEY gene signature predicts for a poor response/prognosis in 2 ER+ patient cohorts. Targeting of NOTCH4 reverses the increase in Notch and BCSC activity induced by anti-estrogens. Importantly, in PDX tumors with acquired tamoxifen resistance, NOTCH4 inhibition reduced BCSC activity. Thus, we establish that BCSC and NOTCH4 activities predict both de novo and acquired tamoxifen resistance and that combining endocrine therapy with targeting JAG1-NOTCH4 overcomes resistance in human breast cancers.
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| 2. |
- Demir, Ahmet U., et al.
(author)
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Prevalence of sleep disorders in the Turkish adult population epidemiology of sleep study
- 2015
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In: Sleep and Biological Rhythms. - : Springer Science and Business Media LLC. - 1446-9235 .- 1479-8425. ; 13, s. 298-308
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Journal article (peer-reviewed)abstract
- © 2015 Japanese Society of Sleep Research. Sleep disorders constitute an important public health problem. Prevalence of sleep disorders in Turkish adult population was investigated in a nationwide representative sample of 5021 Turkish adults (2598 women and 2423 men, response rate: 91%) by an interviewer-administered questionnaire. Insomnia was defined by the DSM-IV criteria, habitual snoring and risk for sleep-related breathing disorders (SDB) by the Berlin questionnaire, excessive daytime sleepiness (EDS) by the Epworth sleepiness scale score, and restless legs syndrome (RLS) by the complaints according to the International Restless Legs Syndrome Study Group criteria. Mean age of the participants was 40.7 ± 15.1 (range 18 to 90) years. Prevalence rates (men/women) were insomnia 15.3% (10.5%/20.2%; P < 0.001), high probability of SDB 13.7% (11.1%/20.2%; P < 0.001), EDS 5.4% (5.0%/5.7%; P: 0.09), RLS 5.2% (3.0%/7.3%; P < 0.001). Aging and female gender were associated with higher prevalence of sleep disorders except for habitual snoring. Prevalence rates of the sleep disorders among Turkish adults based on the widely used questionnaires were close to the lower end of the previous estimates reported from different parts of the world. These findings would help for the assessment of the health burden of sleep disorders and addressing the risk groups for planning and implementation of health care. Sleep and Biological Rhythms
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| 3. |
- Turkez, Hasan, et al.
(author)
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Boron Compounds Exhibit Protective Effects against Aluminum-Induced Neurotoxicity and Genotoxicity : In Vitro and In Vivo Study
- 2022
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In: Toxics. - : MDPI. - 2305-6304. ; 10:8
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Journal article (peer-reviewed)abstract
- Genetic, neuropathological and biochemical investigations have revealed meaningful relationships between aluminum (Al) exposure and neurotoxic and hematotoxic damage. Hence, intensive efforts are being made to minimize the harmful effects of Al. Moreover, boron compounds are used in a broad mix of industries, from cosmetics and pharmaceuticals to agriculture. They affect critical biological functions in cellular events and enzymatic reactions, as well as endocrinal and mineral metabolisms. There are limited dose-related data about boric acid (BA) and other boron compounds, including colemanite (Col), ulexite (UX) and borax (BX), which have commercial prominence. In this study, we evaluate boron compounds' genetic, cytological, biochemical and pathological effects against aluminum chloride (AlCl3)-induced hematotoxicity and neurotoxicity on different cell and animal model systems. First, we perform genotoxicity studies on in vivo rat bone marrow cells and peripheric human blood cultures. To analyze DNA and chromosome damage, we use single cell gel electrophoresis (SCGE or comet assay) and micronucleus (MN) and chromosome aberration (CA) assays. The nuclear division index (NDI) is used to monitor cytostasis. Second, we examine the biochemical parameters (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), malondialdehyde (MDA), total antioxidant capacity (TAC) and total oxidative status (TOS)) to determine oxidative changes in blood and brain. Next, we assess the histopathological alterations by using light and electron microscopes. Our results show that Al increases oxidative stress and genetic damage in blood and brain in vivo and in vitro studies. Al also led to severe histopathological and ultrastructural alterations in the brain. However, the boron compounds alone did not cause adverse changes based on the above-studied parameters. Moreover, these compounds exhibit different levels of beneficial effects by removing the harmful impact of Al. The antioxidant, antigenotoxic and cytoprotective effects of boron compounds against Al-induced damage indicate that boron may have a high potential for use in medical purposes in humans. In conclusion, our analysis suggests that boron compounds (especially BA, BX and UX) can be administered to subjects to prevent neurodegenerative and hematological disorders at determined doses.
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