Mitotic perturbation is a key mechanism of action of decitabine in myeloid tumor treatment.

Decitabine (DAC) is clinically used to treat myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Our genome-wide CRISPR-dCas9 activation screen using MDS-derived AML cells indicates that mitotic regulation is critical for DAC resistance. DAC strongly induces abnormal mitosis (abscission failure or tripolar mitosis) in human myeloid tumors at clinical concentrations, especially in those with TP53 mutations or antecedent hematological disorders. This DAC-induced mitotic disruption and apoptosis are significantly attenuated in DNMT1-depleted cells. In contrast, overexpression of Dnmt1, but not the catalytically inactive mutant, enhances DAC-induced mitotic defects in myeloid tumors. We also demonstrate that DAC-induced mitotic disruption is enhanced by pharmacological inhibition of the ATR-CLSPN-CHK1 pathway. These data challenge the current assumption that DAC inhibits leukemogenesis through DNMT1 inhibition and subsequent DNA hypomethylation and highlight the potent activity of DAC to disrupt mitosis through aberrant DNMT1-DNA covalent bonds.

GREB1 isoform 4 is specifically transcribed by MITF and required for melanoma proliferation.

Growth regulation by estrogen in breast cancer 1 (GREB1) is involved in hormone-dependent and -independent tumor development (e.g., hepatoblastoma). In this study, we found that a GREB1 splicing variant, isoform 4 (Is4), which encodes C-terminal half of full-length GREB1, is specifically expressed via microphthalmia-associated transcription factor (MITF) in melanocytic melanoma, and that two MITF-binding E-box CANNTG motifs at the 5'-upstream region of GREB1 exon 19 are necessary for GREB1 Is4 transcription. MITF and GREB1 Is4 were strongly co-expressed in approximately 20% of the melanoma specimens evaluated (17/89 cases) and their expression was associated with tumor thickness. GREB1 Is4 silencing reduced melanoma cell proliferation in association with altered expression of cell proliferation-related genes in vitro. In addition, GREB1 Is4 targeting by antisense oligonucleotide (ASO) decreased melanoma xenograft tumor formation and GREB1 Is4 expression in a BRAFV600E; PTENflox melanoma mouse model promoted melanoma formation, demonstrating the crucial role of GREB1 Is4 for melanoma proliferation in vivo. GREB1 Is4 bound to CAD, the rate-limiting enzyme of pyrimidine metabolism, and metabolic flux analysis revealed that GREBI Is4 is necessary for pyrimidine synthesis. These results suggest that MITF-dependent GREB1 Is4 expression leads to melanoma proliferation and GREB1 Is4 represents a new molecular target in melanoma.

The effect of nonrestorative sleep on incident hypertension 1-2 years later among middle-aged Hispanics/Latinos.

BACKGROUND: Insomnia is known to be a major risk factor for incident hypertension. Nonrestorative sleep (NRS), which refers to insufficiently rested sleep, has reported to associate with various diseases. This study aimed to investigate the longitudinal association between insomnia-related symptoms including NRS and incident hypertension 1-2 years later by age group (young, 18-39 years and middle-age, 40-64 years) using existing cohort data involving Hispanics/Latinos. METHODS: This study included 1100 subjects who had participated in both the Hispanic Community Health Study/Study of Latinos and its follow-up study, the Sueño Ancillary Study, and met additional eligibility criteria. Incident hypertension was assessed by self-reported history and/or the use of antihypertensives. The Women's Health Initiative Insomnia Rating Scale (WHIIRS) was used to evaluate insomnia-related symptoms (difficulty initiating sleep, difficulty maintaining sleep, early morning awakening, difficulty returning to sleep, and NRS). Logistic regression analyses were conducted to assess the degree to which insomnia-related symptoms at baseline predicted incident hypertension. RESULTS: Among the participants (64% middle-aged, 36% young adults), 140 (12.7%) developed hypertension during the follow-up period. Among the sleep-related symptoms, only NRS predicted incident hypertension after adjusting for sociodemographic factors and physical condition (odds ratio: 1.88, 95% confidence interval: 1.10-3.21, p = 0.022) in middle-aged adults. None of the insomnia-related symptoms were associated with incident hypertension in the young adults. No association was found between WHIIRS-defined insomnia (total score ≥ 9) and incident hypertension in middle-aged adults or young adults. CONCLUSION: The present findings suggest the importance of focusing on NRS to help prevent the development of hypertension in middle-aged adults.

Transdiagnostic association between subjective insomnia and depressive symptoms in major psychiatric disorders.

In psychiatric disorders, comorbid depressive symptoms are associated with clinically important issues such as reduced quality of life, a poor prognosis, and increased suicide risk. Previous studies have found a close relationship between insomnia and depressive symptoms in major depressive disorder (MDD), and that actively improving insomnia heightens the improvement of depressive symptoms. This study aimed to investigate whether the association between insomnia and depressive symptoms is also found in other psychiatric disorders besides MDD. The subjects were 144 patients with MDD (n = 71), schizophrenia (n = 25), bipolar disorder (n = 22), or anxiety disorders (n = 26). Sleep status was assessed subjectively and objectively using the Athens Insomnia Scale (AIS) and sleep electroencephalography (EEG), respectively. Sleep EEG was performed using a portable EEG device. Depressive symptoms were assessed using the Beck Depression Inventory. Subjective insomnia, as defined by the AIS, was associated with depressive symptoms in all disorders. Moreover, in schizophrenia, a relation between depressive symptoms and insomnia was also found by objective sleep assessment methods using sleep EEG. Our findings suggest that the association between subjective insomnia and depressive symptoms is a transdiagnostic feature in major psychiatric disorders. Further studies are needed to clarify whether therapeutic interventions for comorbid insomnia can improve depressive symptoms in major psychiatric disorders, similar to MDD.

Differences in psychosocial factors and sleep study findings between delayed sleep-wake phase disorder and hypersomnia in teenagers.

Central hypersomnia (HS) and delayed sleep-wake phase disorder (DSWPD) appear commonly in adolescents, and they severely reduce quality of life and have an enormous impact on academic performance and other aspects of development. Although these disorders are thought to be considerably different in etiology, it is sometimes difficult to distinguish them because of their similar clinical features. This study aimed to compare psychosocial factors and sleep study findings between HS and DSWPD in teenagers. The clinical data of 89 teenagers who visited the psychiatric section of the Sleep Medicine Center of Nihon University Itabashi Hospital from January 2013 to December 2019 were analyzed. Psychosocial factors were evaluated at the first visit, and polysomnography (PSG) and the multiple sleep latency test (MSLT) were performed for patients deemed to require definitive diagnosis. Compared with patients with HS, those with DSWPD had a higher rate of mother's employment, introversion, adjustment problems, events that triggered the disorder, concurrent mental disorders, habitual lateness, and difficulty attending school or work. PSG did not show any differences in sleep parameters between the two disorders, except for sleep latency. On the MSLT, sleep latency was shorter in those with HS on the second, third, and fourth tests. The present results suggest that focusing on psychosocial factors could be useful for differential diagnosis of the two disorders that appear commonly in adolescents.

The association between subjective-objective discrepancies in sleep duration and mortality in older men.

A discrepancy in subjective and objective estimations of sleep duration, which often diverge, could have long-term adverse effects on health outcomes in older adults. Using data from 2674 older adult men (≥ 65 years of age) of the Osteoporotic Fractures in Men Sleep Study, we assessed the longitudinal association between misperception index (MI), calculated as MI = (objective sleep duration - subjective sleep duration)/objective sleep duration, and all-cause mortality. During the follow-up with a mean (standard deviation) of 10.8 (4.2) years, 1596 deaths were observed. As a continuous variable, MI showed a linear relationship with all-cause mortality after adjusting for multiple covariates, including polysomnography-measured objective sleep duration [fully adjusted hazard ratio (HR), 0.69; 95% confidence interval [CI], 0.56-0.84]. As a categorical variable, the lowest MI quartile (vs. the interquartile MI range) was associated with increased mortality (fully adjusted HR, 1.28; 95% CI, 1.12-1.46), whereas the highest MI quartile was not associated with mortality (fully adjusted HR, 0.97; 95% CI, 0.85-1.11). The subjective overestimation of sleep duration may be a risk factor for all-cause mortality in older men. Future studies should examine why subjective overestimation of sleep duration is associated with all-cause mortality from a physiological perspective.

Relationship between [18F]FDG PET/CT and metabolomics in patients with colorectal cancer.

INTRODUCTION: Advances in metabolomics have significantly improved cancer detection, diagnosis, treatment, and prognosis. OBJECTIVES: To investigate the relationship between metabolic tumor volume (MTV) using 2-deoxy-2-[18F]fluoro-D-glucose (FDG) positron emission tomography (PET)/ computed tomography (CT) and metabolomics data in patients with colorectal cancer (CRC). METHODS: The metabolome in tumor tissues was analyzed using capillary electrophoresis time-of-flight mass spectrometry in 33 patients with newly diagnosed CRC who underwent FDG PET/CT before treatment and had tumor tissue post-surgery. Based on the FDG PET data, MTV was calculated and was dichotomized according to the median value, and tumors were divided into low-MTV and high-MTV tumors. Metabolomics data were compared between the low-MTV and high-MTV tumors. RESULTS: The levels of most glycolysis-related metabolites were not different between low-MTV and high-MTV tumors. The level of component of the initial part of the tricarboxylic acid (TCA) cycle, citrate, was significantly lower in the high-MTV tumor than in the low-MTV tumor. The TCA intermediate succinate level was significantly higher in the high-MTV tumor than in the low-MTV tumor. In contrast, the TCA intermediate fumarate level was significantly lower in the high-MTV tumor than in the low-MTV tumor. The levels of many amino acids were significantly higher in the high-MTV tumor than in the low-MTV tumor. CONCLUSIONS: Although preliminary, these results suggest that tumors with high FDG metabolism in CRC may obtain more energy by using a reverse reaction of the TCA cycle and amino-acid metabolism. However, further research is required to clarify this relationship.

Adiponectin regulates the circadian rhythm of glucose and lipid metabolism.

Adiponectin is a cytokine secreted from adipocytes and regulates metabolism. Although serum adiponectin levels show diurnal variations, it is not clear if the effects of adiponectin are time-dependent. Therefore, this study conducted locomotor activity analyses and various metabolic studies using the adiponectin knockout (APN (-/-)) and the APN (+/+) mice to understand whether adiponectin regulates the circadian rhythm of glucose and lipid metabolism. We observed that the adiponectin gene deficiency does not affect the rhythmicity of core circadian clock genes expression in several peripheral tissues. In contrast, the adiponectin gene deficiency alters the circadian rhythms of liver and serum lipid levels and results in the loss of the time dependency of very-low-density lipoprotein-triglyceride secretion from the liver. In addition, the whole-body glucose tolerance of the APN (-/-) mice was normal at CT10 but reduced at CT22, compared to the APN (+/+) mice. The decreased glucose tolerance at CT22 was associated with insulin hyposecretion in vivo. In contrast, the gluconeogenesis activity was higher in the APN (-/-) mice than in the APN (+/+) mice throughout the day. These results indicate that adiponectin regulates part of the circadian rhythm of metabolism in the liver.

Associations of nonrestorative sleep and insomnia symptoms with incident depressive symptoms over 1-2 years: Longitudinal results from the Hispanic Community Health Study/Study of Latinos and Sueño Ancillary Study.

BACKGROUND: Nonrestorative sleep (NRS), defined as insufficiently rested or refreshed sleep, is considered to play an important role in the development of depression. The aim of this study is to investigate the predictive ability of insomnia-related symptoms, including NRS, for incident depressive symptoms (DEPs) in a longitudinal manner. METHODS: We used data of 1196 samples aged 18-64 years who participated in both the Hispanic Community Health Study/Study of Latinos conducted in 2008-2010 and the follow-up study (Sueño Ancillary Study) conducted in 2010-2013. DEPs and insomnia-related symptoms (difficulty initiating sleep [DIS], difficulty maintaining sleep [DMS], early morning awakening [EMA], difficulty returning to sleep [DRS], and NRS) were evaluated by the 10-item Center for Epidemiologic Studies Depression Scale and the Women's Health Initiative Insomnia Rating Scale, respectively. A logistic regression analysis was used to evaluate the predictive ability of each insomnia-related symptom at baseline for incident DEPs in couple-years. RESULTS: In the univariate logistic regression analysis, all insomnia-related symptoms had significant associations with incident DEPs (DIS, odds ratio [OR] = 1.6; DMS, OR = 1.6; EMA, OR = 1.5; DRS, OR = 1.9; NRS, OR = 2.5). After adjusting for sociodemographic factors and the confounding effects of other insomnia-related symptoms, only NRS (OR = 2.2, 95% confidence interval = 1.4-3.5, p = .001) was significantly associated with incident DEPs. CONCLUSIONS: NRS was a risk factor for incident DEPs, which includes a predictive ability for other insomnia-related symptoms. Our results suggest that focusing on NRS is an effective strategy for preventing depression in public health promotions.

Mortality associated with nonrestorative short sleep or nonrestorative long time-in-bed in middle-aged and older adults.

Associations of sleep duration with human health could differ depending on whether sleep is restorative. Using data from 5804 participants of the Sleep Heart Health Study, we examined the longitudinal association of sleep restfulness combined with polysomnography-measured total sleep time (TST) or time in bed (TIB), representing different sleeping behaviors, with all-cause mortality. Among middle-aged adults, compared with restful intermediate TST quartile, the lowest TST quartile with feeling unrested was associated with higher mortality (hazard ratio [HR], 1.54; 95% confidence interval [CI] 1.01-2.33); the highest TST quartile with feeling rested was associated with lower mortality (HR, 0.55; 95% CI 0.32-0.97). Among older adults, the highest TIB quartile with feeling unrested was associated with higher mortality, compared with restful intermediate TIB quartile (HR, 1.57; 95% CI 1.23-2.01). Results suggest a role of restorative sleep in differentiating the effects of sleep duration on health outcomes in midlife and beyond.

Association of insomnia symptoms and non-restorative sleep with Typus melancholicus: a Japanese general population survey.

This study aimed to investigate the association between insomnia symptoms and non-restorative sleep (NRS) in individuals with Typus melancholicus, a personality trait linked to depression, in the general population. We analyzed data from a Japanese cross-sectional survey of 2519 randomly sampled adults. Typus melancholicus was evaluated using a modified version of Kasahara's Typus melancholicus inventory (modified-KTM). Logistic regression analysis was used to examine the associations of insomnia symptoms and NRS with modified-KTM scores. We demonstrated that insomnia symptoms and NRS were both positively associated with modified-KTM scores. Our results provide evidence for an association between Typus melancholicus and insomnia.

Association of Subjective Quality and Quantity of Sleep with Quality of Life among a General Population.

This study aimed to determine whether both subjective sleep quality and sleep duration are directly associated with quality of life (QOL), as well as indirectly associated with QOL through insomnia symptoms. Individuals aged 20-69 years without mental illness (n = 9305) were enrolled in this web-based cross-sectional survey. The Short Form-8 was used to assess physical and mental QOL. We used the Pittsburgh Sleep Quality Index (PSQI) and extracted items related to subjective sleep quality and sleep duration. Insomnia symptoms were also extracted from the PSQI. The hypothesized models were tested using structural equation modeling. Worse sleep quality, but not shorter sleep duration, was related to worse physical QOL. Both worse sleep quality and shorter sleep duration were related to worse mental QOL. Insomnia symptoms mediated these relationships. Subgroup analyses revealed a U-shaped relationship between sleep duration and physical/mental QOL. However, the relationship between sleep quality and physical/mental QOL was consistent regardless of sleep duration. The results suggest that subjective sleep quality has a more coherent association with QOL than subjective sleep duration. Because of its high feasibility, a questionnaire on overall sleep quality could be a useful indicator in future epidemiological studies of strategies for improving QOL.

MEK inhibition preferentially suppresses anchorage-independent growth in osteosarcoma cells and decreases tumors in vivo.

Osteosarcoma is the most common high-grade malignancy of bone, and novel therapeutic options are urgently required. Previously, we developed mouse osteosarcoma AXT cells that can proliferate both under adherent and nonadherent conditions. Based on metabolite levels, nonadherent conditions were more similar to the in vivo environment than adherent conditions. A drug screen identified MEK inhibitors, including trametinib, that preferentially decreased the viability of nonadherent AXT cells. Trametinib inhibited the cell cycle and induced apoptosis in AXT cells, and both effects were stronger under nonadherent conditions. Trametinib also potently decreased viability in U2OS cells, but its effects were less prominent in MG63 or Saos2 cells. By contrast, MG63 and Saos2 cells were more sensitive to PI3K inhibition than AXT or U2OS cells. Notably, the combination of MAPK/ERK kinase (MEK) and PI3K inhibition synergistically decreased viability in U2OS and AXT cells, but this effect was less pronounced in MG63 or Saos2 cells. Therefore, signal dependence for cell survival and crosstalk between MEK-ERK and PI3K-AKT pathways in osteosarcoma are cell context-dependent. The activation status of other kinases including CREB varied in a cell context-dependent manner, which might determine the response to MEK inhibition. A single dose of trametinib was sufficient to decrease the size of the primary tumor and circulating tumor cells in vivo. Moreover, combined administration of trametinib and rapamycin or conventional anticancer drugs further increased antitumor activity. Thus, given optimal biomarkers for predicting its effects, trametinib holds therapeutic potential for the treatment of osteosarcoma.

Association between reduced serum BDNF levels and insomnia with short sleep duration among female hospital nurses.

OBJECTIVE: Previous studies have suggested that brain-derived neurotrophic factor (BDNF) is associated with sleep regulation in humans. However, its relationship with self-reported sleep problems has not been clarified. The aim of the present study was to examine the association between serum BDNF levels and sleep problems among hospital nurses. METHODS: Participants were enrolled from among nurses working at a general hospital in Tokyo, Japan. Data from 577 women (age: 35.45 ± 10.90 years) were analyzed. This cross-sectional survey was conducted from November to December 2015. Serum BDNF concentrations were evaluated. Participants completed a self-reported questionnaire on sleep including the presence or absence of insomnia symptoms (ie, difficulty initiating sleep (DIS), difficulty maintaining sleep (DMS), and early morning awakening [EMA]), and sleep duration. Insomnia with short sleep duration (ISS) was defined as: DIS, or DMS, or EMA; and <6 h sleep duration. RESULTS: Among 577 participants, 21.3% reported insomnia, 41.4% slept less than 6 h, and finally 12.5% suffered from ISS. Serum BDNF levels were significantly lower in subjects with ISS than in those without ISS. The serum BDNF levels in insomniacs were significantly lower than in non-insomniacs for short sleep duration (<6 h), while serum BDNF levels did not differ between insomniacs and non-insomniacs for normal sleep duration (≥6 h). CONCLUSION: This is the first documented study to indicate that ISS is associated with reduced serum BDNF levels. These results may lead to clarification of the underlying pathophysiological relationship between BDNF and poor sleep.

A composite measure of sleep health is associated with symptoms of depression among Japanese female hospital nurses.

BACKGROUND: Individual dimensions of sleep health, including satisfaction, sleepiness/alertness, timing, efficiency, and duration, are associated with depression. We investigated whether a composite sleep health score is associated with symptoms of depression among Japanese female hospital nurses. METHODS: Participants were nurses (n = 2482, all women, age 31.2 ± 8.9 years) working at three general hospitals in Tokyo, Japan. A cross-sectional survey, conducted in 2015, assessed self-reported sleep and symptoms of depression. Sleep health was categorized as "good" or "poor" across five dimensions: satisfaction, daytime sleepiness, mid-sleep time, efficiency, and duration. A composite sleep health score was calculated by summing the number of "poor" dimensions. Depression was defined by depressed mood, loss of interest, or at least one of those symptoms ("depression symptoms"). Associations between sleep health and symptoms of depression were evaluated with multivariate logistic regression analyses, adjusting for sociodemographic factors and hypnotic medication use. RESULTS: In multivariate logistic regression analyses, sleep health symptoms of poor satisfaction, efficiency, and duration were significantly associated with depressed mood; daytime sleepiness and poor efficiency were significantly associated with loss of interest; and poor satisfaction, daytime sleepiness, mid-sleep time, and efficiency were significantly associated with having at least one depressive symptom. The composite sleep health score was associated in a graded fashion with greater odds of depression symptoms. CONCLUSION: Individual and composite sleep health scores were associated with symptoms of depression. Assessing composite measures of multidimensional sleep health may help to better understand the well-known associations between poor sleep and depression and lead to improved intervention strategies.

Exploding Head Syndrome Accompanied by Repeating Panic Attacks: A Case Report.

To the best of our knowledge, we report here for the first time a case of exploding head syndrome (EHS) that caused repeating panic attacks. A 62-year-old woman experienced a sudden sensation of a loud noise just before going to sleep. The frequency of these episodes rapidly increased to multiple times per night, and she soon began to fear sleep, which led to the occurrence of nighttime panic attacks. She was diagnosed with EHS at our sleep clinic, and clonazepam was prescribed accompanied by reassurance about the benign nature of this syndrome. The intensity of the loud noise gradually reduced, and her fear of sleep and panic attacks disappeared at around the same time. In this report, we argue the importance of gaining further knowledge about EHS, including that about complicating psychiatric symptoms and that about its treatment.

Correction: Targeting mantle cell lymphoma metabolism and survival through simultaneous blockade of mTOR and nuclear transporter exportin-1.

[This corrects the article DOI: 10.18632/oncotarget.16602.].

Phosphoethanolamine Accumulation Protects Cancer Cells under Glutamine Starvation through Downregulation of PCYT2.

Tolerance to severe tumor microenvironments, including hypoxia and nutrient starvation, is a common feature of aggressive cancer cells and can be targeted. However, metabolic alterations that support cancer cells upon nutrient starvation are not well understood. Here, by comprehensive metabolome analyses, we show that glutamine deprivation leads to phosphoethanolamine (PEtn) accumulation in cancer cells via the downregulation of PEtn cytidylyltransferase (PCYT2), a rate-limiting enzyme of phosphatidylethanolamine biosynthesis. PEtn accumulation correlated with tumor growth under nutrient starvation. PCYT2 suppression was partially mediated by downregulation of the transcription factor ELF3. Furthermore, PCYT2 overexpression reduced PEtn levels and tumor growth. In addition, PEtn accumulation and PCYT2 downregulation in human breast tumors correlated with poor prognosis. Thus, we show that glutamine deprivation leads to tumor progression by regulating PE biosynthesis via the ELF3-PCYT2 axis. Furthermore, manipulating glutamine-responsive genes could be a therapeutic approach to limit cancer progression.

Cancer stem-like properties and gefitinib resistance are dependent on purine synthetic metabolism mediated by the mitochondrial enzyme MTHFD2.

Tumor recurrence is attributable to cancer stem-like cells (CSCs), the metabolic mechanisms of which currently remain obscure. Here, we uncovered the critical role of folate-mediated one-carbon (1C) metabolism involving mitochondrial methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) and its downstream purine synthesis pathway. MTHFD2 knockdown greatly reduced tumorigenesis and stem-like properties, which were associated with purine nucleotide deficiency, and caused marked accumulation of 5-aminoimidazole carboxamide ribonucleotide (AICAR)-the final intermediate of the purine synthesis pathway. Lung cancer cells with acquired resistance to the targeted drug gefitinib, caused by elevated expression of components of the ß-catenin pathway, exhibited increased stem-like properties and enhanced expression of MTHFD2. MTHFD2 knockdown or treatment with AICAR reduced the stem-like properties and restored gefitinib sensitivity in these gefitinib-resistant cancer cells. Moreover, overexpression of MTHFD2 in gefitinib-sensitive lung cancer cells conferred resistance to gefitinib. Thus, MTHFD2-mediated mitochondrial 1C metabolism appears critical for cancer stem-like properties and resistance to drugs including gefitinib through consumption of AICAR, leading to depletion of the intracellular pool of AICAR. Because CSCs are dependent on MTHFD2, therapies targeting MTHFD2 may eradicate tumors and prevent recurrence.