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BACKGROUND: Pediatric Sleep Questionnaire (PSQ) is a valid, reliable tool for screening for sleep-related breathing disorders (SRBDs) translated into several languages since 2000. The diagnostic accuracy of an Arabic version of the PSQ has never been tested. Our aim was to translate the original version of PSQ into Arabic (Arabic-PSQ), validate it as a reliable screening tool, and compare it to the gold standard diagnostic method for SRBDs. MATERIALS AND METHODS: This was a prospective longitudinal study of 54 children (2-14 years) who were to undergo polysomnography (PSG). SRBD was assessed by administering the Arabic version of PSQ to the parents of these children. The validity and reliability of the Arabic-PSQ were assessed. Data were analyzed using Stata 16. Correlation between with polysomnographic indices and PSQ scores, as well as measurement of the diagnostic accuracy were determined. Receiver operating characteristic analysis between the mean PSQ scores and binary PSG results was done and the area under curve (AUC) value was calculated. RESULTS: Thirty-four (63%) children were diagnosed with obstructive sleep apnea by PSG (Apnea-Hypopnea Index [AHI] ≥1), 26 of whom were accurately identified with the Arabic-PSQ (76.5%). Arabic-PSQ showed comparable validity and reliability. Using a cutoff of 0.33, the score showed a significant correlation with AHI: Rs: 0.30 (P = 0.029). The sensitivity was 76.5%, the specificity was 50%, the positive predictive was 72.2%, the negative predictive value was 55.6%, the positive likelihood ratio was 1.63, and the negative likelihood ratio was 0.37. CONCLUSIONS: The Arabic-PSQ is a valid tool for the screening of Arabic-speaking populations for SRBD. It is valuable for directing the diagnostic approach in a timely and cost-effective manner.

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Previous studies have shown that administration of ferristatin II to rats is associated with decreased serum iron, reduced transferrin saturation, and increased hepatic hepcidin expression. BMP and IL-6 signaling act via Smad and Stat3 transcription factors, respectively, to increase expression of hepcidin, the master regulator of iron metabolism. In this study, we aimed to explore the underlying mechanism of ferristatin II action on hepcidin production. We found that ferristatin II greatly increased hepcidin expression both in vivo and in vitro. In the rat liver, ferristatin II treatment decreased expression of Smad downstream targets Smad7 and Id1 and increased expression of Stat3 downstream targets α-2-macroglobulin, α-1-acid glycoprotein, and C-reactive peptide. Ferristatin II also increased Stat3 phosphorylation in the rat liver without affecting serum or hepatic IL-6 levels. It is unclear whether the Stat3 activation observed in vivo is a cause or a consequence to hepcidin induction. Reporter gene expression studies demonstrated that ferristatin II synergized with BMP6 and IL-6 to enhance hepcidin expression in vitro. However, this synergy was not due to activation of either Smad or Stat3 signaling, raising the possibility that ferristatin II may activate a novel pathway for hepcidin regulation.

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The iron storage protein ferritin has been continuously studied for over 70years and its function as the primary iron storage protein in cells is well established. Although the intracellular functions of ferritin are for the most part well-characterized, the significance of serum (extracellular) ferritin in human biology is poorly understood. Recently, several lines of evidence have demonstrated that ferritin is a multi-functional protein with possible roles in proliferation, angiogenesis, immunosuppression, and iron delivery. In the context of cancer, ferritin is detected at higher levels in the sera of many cancer patients, and the higher levels correlate with aggressive disease and poor clinical outcome. Furthermore, ferritin is highly expressed in tumor-associated macrophages which have been recently recognized as having critical roles in tumor progression and therapy resistance. These characteristics suggest ferritin could be an attractive target for cancer therapy because its down-regulation could disrupt the supportive tumor microenvironment, kill cancer cells, and increase sensitivity to chemotherapy. In this review, we provide an overview of the current knowledge on the function and regulation of ferritin. Moreover, we examine the literature on ferritin's contributions to tumor progression and therapy resistance, in addition to its therapeutic potential.

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Tumor-associated macrophages play a critical role in breast tumor progression; however, it is still unclear what effector molecular mechanisms they employ to impact tumorigenesis. Ferritin is the primary intracellular iron storage protein and is also abundant in circulation. In breast cancer patients, ferritin is detected at higher levels in both serum and tumor lysates, and its increase correlates with poor clinical outcome. In this study, we comprehensively examined the distribution of ferritin in normal and malignant breast tissue at different stages in tumor development. Decreased ferritin expression in cancer cells but increased infiltration of ferritin-rich CD68-positive macrophages was observed with increased tumor histological grade. Interestingly, ferritin stained within the stroma surrounding tumors suggesting local release within the breast. In cell culture, macrophages, but not breast cancer cells, were capable of ferritin secretion, and this secretion was further increased in response to pro-inflammatory cytokines. We next examined the possible functional significance of extracellular ferritin in a breast cancer cell culture model. Ferritin stimulated the proliferation of the epithelial breast cancer cell lines MCF7 and T47D. Moreover, this proliferative effect was independent of the iron content of ferritin and did not increase intracellular iron levels in cancer cells indicating a novel iron-independent function for this protein. Together, these findings suggest that the release of ferritin by infiltrating macrophages in breast tumors may represent an inflammatory effector mechanism by which ferritin directly stimulates tumorigenesis.

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Approximately half of all HER2/neu-overexpressing breast cancer patients do not respond to trastuzumab-containing therapy. Therefore, there remains an urgent and unmet clinical need for the development of predictive biomarkers for trastuzumab response. Recently, several lines of evidence have demonstrated that the inflammatory tumor microenvironment is a major contributor to therapy resistance in breast cancer. In order to explore the predictive value of inflammation in breast cancer patients, we measured the inflammatory biomarkers serum ferritin and C-reactive protein (CRP) in 66 patients immediately before undergoing trastuzumab-containing therapy and evaluated their progression-free and overall survival. The elevation in pre-treatment serum ferritin (>250 ng/ml) or CRP (>7.25 mg/l) was a significant predictor of reduced progression-free survival and shorter overall survival. When patients were stratified based on their serum ferritin and CRP levels, patients with elevation in both inflammatory biomarkers had a markedly poorer response to trastuzumab-containing therapy. Therefore, the elevation in inflammatory serum biomarkers may reflect a pathological state that decreases the clinical efficacy of this therapy. Anti-inflammatory drugs and life-style changes to decrease inflammation in cancer patients should be explored as possible strategies to sensitize patients to anti-cancer therapeutics.

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BACKGROUND: Ferritin has been traditionally considered a cytoplasmic iron storage protein. However, several studies over the last two decades have reported the nuclear localization of ferritin, specifically H-ferritin, in developing neurons, hepatocytes, corneal epithelial cells, and some cancer cells. These observations encouraged a new perspective on ferritin beyond iron storage, such as a role in the regulation of iron accessibility to nuclear components, DNA protection from iron-induced oxidative damage, and transcriptional regulation. SCOPE OF REVIEW: This review will address the translocation and functional significance of nuclear ferritin in the context of human development and disease. MAJOR CONCLUSIONS: The nuclear translocation of ferritin is a selective energy-dependent process that does not seem to require a consensus nuclear localization signal. It is still unclear what regulates the nuclear import/export of ferritin. Some reports have implicated the phosphorylation and O-glycosylation of the ferritin protein in nuclear transport; others suggested the existence of a specific nuclear chaperone for ferritin. The data argue strongly for nuclear ferritin as a factor in human development and disease. Ferritin can bind and protect DNA from oxidative damage. It also has the potential of playing a regulatory role in transcription. GENERAL SIGNIFICANCE: Nuclear ferritin represents a novel new outlook on ferritin functionality beyond its classical role as an iron storage molecule.

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