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1.
Oncol Nurs Forum ; 46(6): E202-E210, 2019 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-31626616

RESUMEN

OBJECTIVES: To examine the effect of informal cancer caregiving and repetitive negative thinking (RNT) on depressive symptoms and salivary cortisol levels. SAMPLE & SETTING: The sample was recruited from a hospital bone marrow unit and caregiver support organizations. It included 60 informal cancer caregivers (52% partners) of individuals with cancer who provided care for a median of 27.5 hours per week for 12 months, and 46 noncaregiver participants. METHODS & VARIABLES: In this cross-sectional study, participants completed questionnaires assessing RNT and depressive symptoms and provided saliva samples to measure cortisol levels. RESULTS: Cancer caregiving and RNT, but not the interaction, were associated with more depressive symptoms. RNT, but not cancer caregiving, was associated with salivary cortisol. A disordinal interaction effect suggests that cancer caregiving was associated with lower cortisol levels, and RNT in noncaregivers was associated with higher cortisol levels. IMPLICATIONS FOR NURSING: Given that RNT is related to depressive symptoms and cortisol, connecting cancer caregivers who experience RNT to resources and the development and evaluation of brief nurse-led interventions to reduce RNT in informal cancer caregivers seems warranted.

2.
Transl Psychiatry ; 9(1): 256, 2019 Oct 17.
Artículo en Inglés | MEDLINE | ID: mdl-31624234

RESUMEN

Both heritability and environment contribute to risk for schizophrenia. However, the molecular mechanisms of interactions between genetic and non-genetic factors remain unclear. Epigenetic regulation of neuronal genome may be a presumable mechanism in pathogenesis of schizophrenia. Here, we performed analysis of open chromatin landscape of gene promoters in prefrontal cortical (PFC) neurons from schizophrenic patients. We cataloged cell-type-based epigenetic signals of transcriptional start sites (TSS) marked by histone H3-K4 trimethylation (H3K4me3) across the genome in PFC from multiple schizophrenia subjects and age-matched control individuals. One of the top-ranked chromatin alterations was found in the major histocompatibility (MHC) locus on chromosome 6 highlighting the overlap between genetic and epigenetic risk factors in schizophrenia. The chromosome conformation capture (3C) analysis in human brain cells revealed the architecture of multipoint chromatin interactions between the schizophrenia-associated genetic and epigenetic polymorphic sites and distantly located HLA-DRB5 and BTNL2 genes. In addition, schizophrenia-specific chromatin modifications in neurons were particularly prominent for non-coding RNA genes, including an uncharacterized LINC01115 gene and recently identified BNRNA_052780. Notably, protein-coding genes with altered epigenetic state in schizophrenia are enriched for oxidative stress and cell motility pathways. Our results imply the rare individual epigenetic alterations in brain neurons are involved in the pathogenesis of schizophrenia.

3.
Cancer Res ; 79(15): 3862-3876, 2019 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-31175119

RESUMEN

Acute leukemia is a rapidly progressing blood cancer with low survival rates. Unfavorable prognosis is attributed to insufficiently characterized subpopulations of leukemia stem cells (LSC) that drive chemoresistance and leukemia relapse. Here we utilized a genetic reporter that assesses stemness to enrich and functionally characterize LSCs. We observed heterogeneous activity of the ERG+85 enhancer-based fluorescent reporter in human leukemias. Cells with high reporter activity (tagBFPHigh) exhibited elevated expression of stemness and chemoresistance genes and demonstrated increased clonogenicity and resistance to chemo- and radiotherapy as compared with their tagBFPNeg counterparts. The tagBFPHigh fraction was capable of regenerating the original cellular heterogeneity and demonstrated increased invasive ability. Moreover, the tagBFPHigh fraction was enriched for leukemia-initiating cells in a xenograft assay. We identified the ubiquitin hydrolase USP9X as a novel ERG transcriptional target that sustains ERG+85-positive cells by controlling ERG ubiquitination. Therapeutic targeting of USP9X led to preferential inhibition of the ERG-dependent leukemias. Collectively, these results characterize human leukemia cell functional heterogeneity and suggest that targeting ERG via USP9X inhibition may be a potential treatment strategy in patients with leukemia. SIGNIFICANCE: This study couples a novel experimental tool with state-of-the-art approaches to delineate molecular mechanisms underlying stem cell-related characteristics in leukemia cells.

4.
Women Birth ; 32(5): 404-411, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31202584

RESUMEN

OBJECTIVE: The aim of this study was to investigate the relationship between perceived discrimination in perinatal care and birth outcomes of women giving birth to an Aboriginal baby in South Australia using methods designed to respect Aboriginal culture and communities. DESIGN AND SETTING: Population-based study of women giving birth to Aboriginal infants in South Australia, July 2011-June 2013. Women completed a structured questionnaire with an Aboriginal researcher. Study measures include: standardised measure of perceived discrimination in perinatal care; maternal smoking, cannabis use and exposure to stressful events and social health issues; infant birthweight and gestation. PARTICIPANTS: 344 women (mean age 25, range 15-43 years) living in urban, regional and remote areas of South Australia. RESULTS: Half of women (51%) perceived that they had experienced discrimination or unfair treatment by hospitals or health services providing care during pregnancy and soon after childbirth. Women experiencing three or more stressful events or social health issues were more likely to perceive that care was discriminatory or unfair. Aboriginal women who perceived that they had experienced discrimination in perinatal care were more likely to have a baby with a low birthweight (Adj Odds Ratio 1.9, 95% CI 1.0-3.8) or small for gestational age (Adj Odds Ratio 1.9, 95% CI 1.0-3.5), adjusting for parity, smoking and cannabis use. CONCLUSIONS: The study provides evidence of the 'inverse care law'. Aboriginal women most at risk of poor infant health outcomes were the least likely to perceive that they received care well matched to their needs. Building stronger evidence about what works to create cultural safety in perinatal health care is an urgent priority.


Asunto(s)
Disparidades en Atención de Salud , Madres/psicología , Grupo de Ascendencia Oceánica/psicología , Grupo de Ascendencia Oceánica/estadística & datos numéricos , Satisfacción del Paciente/etnología , Complicaciones del Embarazo/psicología , Calidad de la Atención de Salud , Estrés Psicológico/psicología , Adolescente , Adulto , Femenino , Servicios de Salud del Indígena , Humanos , Lactante , Recién Nacido de Bajo Peso , Recién Nacido , Recién Nacido Pequeño para la Edad Gestacional , Servicios de Salud Materna , Periodo Posparto/psicología , Embarazo , Fumar , Australia del Sur , Encuestas y Cuestionarios , Adulto Joven
5.
FASEB J ; 33(7): 8161-8173, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-30970224

RESUMEN

Human prefrontal cortex (PFC) is associated with broad individual variabilities in functions linked to personality, social behaviors, and cognitive functions. The phenotype variabilities associated with brain functions can be caused by genetic or epigenetic factors. The interactions between these factors in human subjects is, as of yet, poorly understood. The heterogeneity of cerebral tissue, consisting of neuronal and nonneuronal cells, complicates the comparative analysis of gene activities in brain specimens. To approach the underlying neurogenomic determinants, we performed a deep analysis of open chromatin-associated histone methylation in PFC neurons sorted from multiple human individuals in conjunction with whole-genome and transcriptome sequencing. Integrative analyses produced novel unannotated neuronal genes and revealed individual-specific chromatin "blueprints" of neurons that, in part, relate to genetic background. Surprisingly, we observed gender-dependent epigenetic signals, implying that gender may contribute to the chromatin variabilities in neurons. Finally, we found epigenetic, allele-specific activation of the testis-specific gene nucleoporin 210 like (NUP210L) in brain in some individuals, which we link to a genetic variant occurring in <3% of the human population. Recently, the NUP210L locus has been associated with intelligence and mathematics ability. Our findings highlight the significance of epigenetic-genetic footprinting for exploring neurologic function in a subject-specific manner.-Gusev, F. E., Reshetov, D. A., Mitchell, A. C., Andreeva, T. V., Dincer, A., Grigorenko, A. P., Fedonin, G., Halene, T., Aliseychik, M., Goltsov, A. Y., Solovyev, V., Brizgalov, L., Filippova, E., Weng, Z., Akbarian, S., Rogaev, E. I. Epigenetic-genetic chromatin footprinting identifies novel and subject-specific genes active in prefrontal cortex neurons.

6.
J Behav Med ; 42(5): 960-972, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-30848417

RESUMEN

Elevated proinflammatory cytokines and decreased antiinflammatory cytokines are important in the context of perinatal health, and immune dysregulation has been found among perinatal women with low socioeconomic status (SES). Data examining psychological factors that may contribute to cytokines in pregnancy are lacking. Of importance, these associations may be most evident among women with low SES. This study examined the moderating role of SES on associations among presence of meaning in life and repetitive negative thinking with cytokine levels among 67 pregnant women. A cumulative SES index was calculated using income, education, perceived social class, and receipt of governmental support. Measures included the Perseverative Thinking Questionnaire, Meaning in Life Questionnaire, and serum interleukin (IL)-6 as well as IL-4. Using PROCESS, moderation analyses showed significant interactions between psychological factors and SES in predicting serum cytokines. In the context of high SES only, greater repetitive negative thinking was associated with higher levels of the proinflammatory cytokine IL-6 (p = 0.056) while greater meaning in life was associated with higher levels of the antiinflammatory cytokine IL-4 (p = 0.02). Findings from this study suggest that the benefits of these psychological factors on cytokine levels may be most readily observable among women with greater economic stability. Identifying psychological factors that positively contribute to biological functioning in women experiencing heightened economic distress will be crucial in addressing SES-related disparities in perinatal health.

7.
Blood ; 133(20): 2198-2211, 2019 05 16.
Artículo en Inglés | MEDLINE | ID: mdl-30796022

RESUMEN

There is a growing body of evidence that the molecular properties of leukemia stem cells (LSCs) are associated with clinical outcomes in acute myeloid leukemia (AML), and LSCs have been linked to therapy failure and relapse. Thus, a better understanding of the molecular mechanisms that contribute to the persistence and regenerative potential of LSCs is expected to result in the development of more effective therapies. We therefore interrogated functionally validated data sets of LSC-specific genes together with their known protein interactors and selected 64 candidates for a competitive in vivo gain-of-function screen to identify genes that enhanced stemness in human cord blood hematopoietic stem and progenitor cells. A consistent effect observed for the top hits was the ability to restrain early repopulation kinetics while preserving regenerative potential. Overexpression (OE) of the most promising candidate, the orphan gene C3orf54/INKA1, in a patient-derived AML model (8227) promoted the retention of LSCs in a primitive state manifested by relative expansion of CD34+ cells, accumulation of cells in G0, and reduced output of differentiated progeny. Despite delayed early repopulation, at later times, INKA1-OE resulted in the expansion of self-renewing LSCs. In contrast, INKA1 silencing in primary AML reduced regenerative potential. Mechanistically, our multidimensional confocal analysis found that INKA1 regulates G0 exit by interfering with nuclear localization of its target PAK4, with concomitant reduction of global H4K16ac levels. These data identify INKA1 as a novel regulator of LSC latency and reveal a link between the regulation of stem cell kinetics and pool size during regeneration.


Asunto(s)
Regulación Leucémica de la Expresión Génica , Péptidos y Proteínas de Señalización Intracelular/genética , Leucemia Mieloide Aguda/genética , Células Madre Neoplásicas/metabolismo , Animales , Puntos de Control del Ciclo Celular , Línea Celular Tumoral , Femenino , Humanos , Leucemia Mieloide Aguda/patología , Masculino , Ratones Endogámicos NOD , Células Madre Neoplásicas/citología , Células Madre Neoplásicas/patología , Regulación hacia Arriba , Quinasas p21 Activadas/análisis
8.
Exp Hematol ; 69: 27-36, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30352278

RESUMEN

Acute myeloid leukemia (AML) is a complex, heterogeneous disease with variable outcomes following curative intent chemotherapy. AML with inv(3) is a genetic subgroup characterized by a very low response rate to current induction type chemotherapy and thus has among the worst long-term survivorship of the AMLs. Here, we describe OCI-AML-20, a new AML cell line with inv(3) and deletion of chromosome 7; the latter is a common co-occurrence in inv(3) AML. In OCI-AML-20, CD34 expression is maintained and required for repopulation in vitro and in vivo. CD34 expression in OCI-AML-20 shows dependence on the co-culture with stromal cells. Transcriptome analysis indicates that the OCI-AML-20 clusters with other AML patient data sets that have poor prognosis, as well as other AML cell lines, including another inv(3) line, MUTZ-3. OCI-AML-20 is a new cell line resource for studying the biology of inv(3) AML that can be used to identify potential therapies for this poor outcome disease.


Asunto(s)
Antígenos CD34/biosíntesis , Línea Celular Tumoral , Deleción Cromosómica , Inversión Cromosómica , Cromosomas Humanos Par 3/genética , Cromosomas Humanos Par 7/genética , Regulación Leucémica de la Expresión Génica , Leucemia Mieloide Aguda , Proteínas de Neoplasias/biosíntesis , Adulto , Antígenos CD34/genética , Línea Celular Tumoral/metabolismo , Línea Celular Tumoral/patología , Cromosomas Humanos Par 3/metabolismo , Cromosomas Humanos Par 7/metabolismo , Técnicas de Cocultivo , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Masculino , Proteínas de Neoplasias/genética , Células del Estroma/metabolismo , Células del Estroma/patología
9.
J Hum Lact ; 35(1): 49-58, 2019 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-29969342

RESUMEN

BACKGROUND:: Breastfeeding plays an important role in both maternal and infant health and well-being. While researchers have examined the relationship between postpartum psychological distress and breastfeeding behaviors, few have investigated links between prenatal distress, postpartum distress, and breastfeeding behaviors over time. RESEARCH AIM:: We aimed to determine if prenatal breastfeeding beliefs and psychological distress during and after pregnancy were associated with initiation and early cessation rates of breastfeeding. METHODS:: In our secondary data analysis, a nonexperimental longitudinal one-group design was used. We assessed pregnant women ( N = 70) during four perinatal visits (early, mid, and late pregnancy and 7-10 weeks postpartum). Participants completed self-report surveys about psychological distress and depressive symptoms at each visit, breastfeeding beliefs during the third visit, and breastfeeding behaviors at the postpartum visit. RESULTS:: Participants who breastfed for ⩾8 weeks had more positive beliefs about breastfeeding prior to delivery than participants with early cessation, who in turn had more positive beliefs than those who never initiated. Participants with early cessation reported heightened levels of pregnancy-specific distress in early pregnancy compared to those who continued breastfeeding or never initiated. Participants who continued breastfeeding for ⩾8 weeks reported less general anxiety and depressive symptoms in postpartum than those who discontinued or never initiated. CONCLUSIONS:: Prenatal beliefs about breastfeeding, pregnancy-specific distress in early pregnancy, and general anxiety and depressive symptoms in postpartum are associated with breastfeeding initiation and continuation. Of clinical relevance, addressing prenatal and postpartum distress in the implementation of breastfeeding practice interventions could improve breastfeeding rates.

10.
Women Birth ; 32(3): e315-e322, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-30104173

RESUMEN

BACKGROUND: Benefits of breastfeeding are well-established. Few studies have examined initiation and duration of breastfeeding of Aboriginal infants. METHODS: Population-based study of women giving birth to an Aboriginal infant in South Australia, July 2011-June 2013. FINDINGS: 344 women took part. Participants were representative in relation to maternal age, infant birthweight and gestation. Eighty-six percent initiated breastfeeding, declining to 54% at 12 weeks postpartum. Women living in remote areas were more likely to be breastfeeding at 12 weeks than women living in Adelaide (Odds Ratio=2.6, 95% Confidence Interval 1.5-4.7). Two-thirds of women (67%) attending standard public antenatal care in regional areas and 61% attending regional Aboriginal Family Birthing Program Services were breastfeeding at 12 weeks, compared to one third of women (36%) attending standard metropolitan public antenatal care and 49% of women attending metropolitan Aboriginal Family Birthing Program Services. Less than half of women (45%) described their postnatal care as 'very good', and 40% were not always able to access support with infant feeding when needed. The most common reasons for switching to formula before 6 weeks were: low milk supply/baby not gaining weight, mastitis/sore breasts or other feeding problems. Mothers also identified their own health as a factor. CONCLUSION: While the findings must be treated with caution due to small numbers, they suggest benefits for women attending Aboriginal Family Birthing Program services in the urban environment where rates of initiation and continued breastfeeding are lowest. Provision of culturally appropriate support to Aboriginal women during and after pregnancy is key to improving outcomes.


Asunto(s)
Lactancia Materna/estadística & datos numéricos , Madres/estadística & datos numéricos , Grupo de Ascendencia Oceánica/estadística & datos numéricos , Factores de Tiempo , Adulto , Peso al Nacer , Lactancia Materna/etnología , Lactancia Materna/psicología , Femenino , Humanos , Lactante , Recién Nacido , Edad Materna , Madres/psicología , Oportunidad Relativa , Embarazo , Atención Prenatal/estadística & datos numéricos , Australia del Sur
11.
Women Birth ; 32(1): 72-79, 2019 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-29699794

RESUMEN

BACKGROUND: Aboriginal women and families are under-represented in Australian research on pregnancy and childbirth. The Aboriginal Families Study aimed to investigate the views and experiences of a representative sample of women giving birth to an Aboriginal baby in South Australia between July 2011 and June 2013, using methods designed to respect Aboriginal culture and communities. METHODS: A team of 12 Aboriginal researchers facilitated community engagement and recruitment of Aboriginal and non-Aboriginal mothers of Aboriginal infants in urban, regional and remote areas of South Australia over a two-year period. RESULTS: A total of 344 women took part, around a quarter of all Aboriginal women giving birth in South Australia in the study period (39% urban, 35% regional and 25% from remote areas). Participants were representative in relation to maternal age (mean age of 25 years, range=15-43 years). Over half of women (56%) first heard about the study via a member of the fieldwork team making contact with them through community connections. Other major sources of recruitment were: Aboriginal health services/programs (20%) and public maternity hospitals (16%). Almost all of the women (95%) recruited via community networks of the fieldwork team completed the questionnaire. In contrast, 51% of women recruited via public hospitals completed the questionnaire (odds ratio=0.1, 95% confidence interval 0.0-0.1, p<0.001). CONCLUSIONS: Aboriginal researchers' community knowledge and leadership is critical to the conduct of successful Aboriginal health research. High levels of participation in research by 'harder to reach' populations are achievable when researchers take time to build relationships and work in partnership with communities.


Asunto(s)
Investigación Participativa Basada en la Comunidad/estadística & datos numéricos , Grupo de Ascendencia Oceánica/estadística & datos numéricos , Parto , Adolescente , Adulto , Australia , Femenino , Hospitales Públicos , Humanos , Lactante , Liderazgo , Edad Materna , Madres , Oportunidad Relativa , Embarazo , Investigadores/organización & administración , Australia del Sur , Adulto Joven
12.
Psychoneuroendocrinology ; 97: 86-93, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30015009

RESUMEN

INTRODUCTION: Compared to women who have given birth before (i.e., multiparas), those giving birth for the first time (i.e., primiparas) show higher cortisol levels. Psychological factors may play a role; hypothalamic-pituitary-adrenal activation is a well-described stress response. Primiparity also predicts greater risk for postpartum depression, which may be related to greater correspondence between cortisol and mood following prenatal cortisol elevations. The current study examined associations among parity, perinatal cortisol adaptation, pregnancy-specific distress, and postpartum mood. METHODS: This longitudinal study assayed serum cortisol levels among 137 women at early, mid-, and late pregnancy and postpartum. Pregnancy-specific distress and depressive symptoms were assessed. Maternal age, race, body mass index, sleep quality, depressive symptoms, and sampling time of day were statistically controlled. RESULTS: Primiparous women showed higher cortisol levels than multiparous women during mid- (χ2 = 11.8, p < 0.01) and late pregnancy (χ2 = 18.9, p < 0.01) and higher distress across pregnancy (F1,126 = 22.1, p < 0.01). Mediation analyses demonstrated that the association between parity and prenatal cortisol (per area under the curve; AUC) was partially accounted for by distress (ab = 1.0, 95%CI [0.05, 2.9]). Prenatal cortisol (per AUC) did not predict postpartum depressive symptoms (b* = 0.03, p = 0.81), with no difference by parity (b* = 0.03, p = 0.91). At postpartum, a significant interaction between parity and cortisol (b* = 0.40, p = 0.03) revealed no significant association between cortisol and mood among multiparas (b* = -0.11, p = 0.28) but a trend toward a positive association among primiparas (b* = 0.24, p = 0.06). DISCUSSION: Cortisol levels and pregnancy-specific distress are higher in primiparas versus multiparas, with pregnancy-specific distress partially mediating the association between parity and cortisol levels. Cortisol levels and mood display correspondence at postpartum in primiparous but not multiparous women. While observational studies must be interpreted with caution due to potential unmeasured confounders, these findings suggest that future studies examining mechanisms underlying perinatal and postpartum hypothalamic-pituitary-adrenal perturbations and designing interventions aimed at preventing related complications should carefully consider potential differences by parity.


Asunto(s)
Depresión Posparto/metabolismo , Paridad/fisiología , Adulto , Afecto/fisiología , Factores de Edad , Depresión , Femenino , Humanos , Hidrocortisona/análisis , Estudios Longitudinales , Edad Materna , Parto , Periodo Posparto/metabolismo , Periodo Posparto/psicología , Embarazo , Estrés Psicológico/metabolismo
13.
JMIR Res Protoc ; 7(6): e10503, 2018 Jun 08.
Artículo en Inglés | MEDLINE | ID: mdl-29884604

RESUMEN

BACKGROUND: Oropharyngeal cancer is an important, understudied cancer affecting Aboriginal and Torres Strait Islander Australians. The human papillomavirus (HPV) is a significant risk factor for oropharyngeal cancer. Current generation HPV vaccines are effective against the 2 most common types of high-risk HPVs in cancer (hrHPVs 16/18). OBJECTIVES: This study aims (1) to yield population estimates of oncogenic genotypes of HPV in the mouth and oropharynx of defined Aboriginal and Torres Strait Islander populations; (2) to estimate the proportion of oropharyngeal cancer attributable to HPV among these Australian citizens; (3) to estimate the impact of HPV vaccination as currently implemented on rates of oropharyngeal cancer among Aboriginal and Torres Strait Islander Australians; and (4) taking into account impact on oropharyngeal as well as cervical cancer, to evaluate efficacy and cost-effectiveness of targeted extended HPV vaccination to older ages, among our study population. METHODS: Our study design and operation is straightforward, with minimal impost on participants. It involves testing for carriage of hrHPV in the mouth and oropharynx among 1000 Aboriginal South Australians by simple saliva collection and with follow-up at 12 and 24 months, collection of sexual history at baseline, collection of information for estimating health state (quality-of-life) utilities at baseline, genotyping of viruses, predictive outcome and cost-effectiveness modeling, data interpretation and development of vaccination, and follow-up management strategies driven by the Aboriginal community. RESULTS: Participant recruitment for this study commenced in February 2018 and enrollment is ongoing. The first results are expected to be submitted for publication in 2019. CONCLUSIONS: The project will have a number of important outcomes. Synthesis of evidence will enable generation of estimates of the burden of oropharyngeal cancer among Aboriginal and Torres Strait Islander Australians and indicate the likely effectiveness and cost-effectiveness of prevention. This will be important for health services planning, and for Aboriginal health worker and patient education. The results will also point to important areas where research efforts should be focused to improve outcomes in Aboriginal and Torres Strait Islander Australians with oropharyngeal cancer. There will be a strong focus on community engagement and accounting for the preferences of individuals and the community in control of HPV-related cancers. The project has international relevance in that it will be the first to systematically evaluate prevention of both cervical and oropharyngeal cancer in a high-risk Indigenous population taking into account all population, testing, and surveillance options. REGISTERED REPORT IDENTIFIER: RR1-10.2196/10503.

14.
Blood Cancer J ; 8(6): 52, 2018 06 06.
Artículo en Inglés | MEDLINE | ID: mdl-29921955

RESUMEN

Therapy for acute myeloid leukemia (AML) involves intense cytotoxic treatment and yet approximately 70% of AML are refractory to initial therapy or eventually relapse. This is at least partially driven by the chemo-resistant nature of the leukemic stem cells (LSCs) that sustain the disease, and therefore novel anti-LSC therapies could decrease relapses and improve survival. We performed in silico analysis of highly prognostic human AML LSC gene expression signatures using existing datasets of drug-gene interactions to identify compounds predicted to target LSC gene programs. Filtering against compounds that would inhibit a hematopoietic stem cell (HSC) gene signature resulted in a list of 151 anti-LSC candidates. Using a novel in vitro LSC assay, we screened 84 candidate compounds at multiple doses and confirmed 14 drugs that effectively eliminate human AML LSCs. Three drug families presenting with multiple hits, namely antihistamines (astemizole and terfenadine), cardiac glycosides (strophanthidin, digoxin and ouabain) and glucocorticoids (budesonide, halcinonide and mometasone), were validated for their activity against human primary AML samples. Our study demonstrates the efficacy of combining computational analysis of stem cell gene expression signatures with in vitro screening to identify novel compounds that target the therapy-resistant LSC at the root of relapse in AML.


Asunto(s)
Biomarcadores de Tumor , Leucemia Mieloide Aguda/etiología , Leucemia Mieloide Aguda/metabolismo , Células Madre Neoplásicas/metabolismo , Apoptosis/genética , Biomarcadores , Ciclo Celular/genética , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Biología Computacional/métodos , Citarabina/farmacología , Descubrimiento de Drogas , Ensayos de Selección de Medicamentos Antitumorales , Perfilación de la Expresión Génica , Células Madre Hematopoyéticas/metabolismo , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Terapia Molecular Dirigida , Células Madre Neoplásicas/efectos de los fármacos , Transcriptoma
15.
J Neuroimmunol ; 316: 98-106, 2018 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-29406850

RESUMEN

BACKGROUND: Postpartum is a period of unique psychosocial stress characterized by sleep disturbance, risk for depressed mood, and heightened parenting stress. However, data on effects of these exposures on inflammatory immune function are limited. METHODS: This study examined associations among sleep, psychosocial stress (i.e., parenting stress, general perceived stress), mood (i.e., depressive symptoms), serum cytokine levels, and LPS-stimulated proinflammatory cytokine production among 69 women (32 African American, 37 White) assessed at 7-10weeks postpartum. RESULTS: No associations between behavioral measures and serum cytokine levels were observed among women of either race. In African American women, but not Whites, poorer sleep quality, greater parenting stress, and greater depressive symptoms were associated with greater LPS-stimulated IL-6 and IL-8 production (ps≤0.05). Also in African Americans, greater general perceived stress was associated with greater IL-8 production, and greater depressive symptoms with greater stimulated TNF-α production (ps≤0.05). Simple mediation models highlighted the bidirectional relationship between stress and sleep in relation to inflammation among African American women. CONCLUSIONS: Significant effects of both stress/distress and poor sleep quality on proinflammatory cytokine production during postpartum were observed uniquely among African American women. These data are consistent with an allostatic load model which predicts that conditions of chronic stress impart vulnerability to dysregulated responses to novel stressor exposures. The bidirectional nature of the stress-sleep relationship has clinical relevance. Studies examining whether interventions focused on one or both of these psychological factors during postpartum is beneficial for inflammatory profiles would be informative. In addition, examination of these models in relation to maternal health at postpartum, including delivery related wounds and other infections, is warranted.


Asunto(s)
Citocinas/sangre , Periodo Posparto/inmunología , Periodo Posparto/psicología , Privación de Sueño/inmunología , Estrés Psicológico/inmunología , Afroamericanos , Grupo de Ascendencia Continental Europea , Femenino , Humanos , Lipopolisacáridos/farmacología
16.
Psychoneuroendocrinology ; 87: 43-52, 2018 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-29035711

RESUMEN

Adverse perinatal health outcomes are heightened among women with psychosocial risk factors, including childhood adversity and a lack of social support. Biological aging could be one pathway by which such outcomes occur. However, data examining links between psychosocial factors and indicators of biological aging among perinatal women are limited. The current study examined the associations of childhood socioeconomic status (SES), childhood trauma, and current social support with telomere length in peripheral blood mononuclear cells (PBMCs) in a sample of 81 women assessed in early, mid, and late pregnancy as well as 7-11 weeks postpartum. Childhood SES was defined as perceived childhood social class and parental educational attainment. Measures included the Childhood Trauma Questionnaire, Center for Epidemiologic Studies-Depression Scale, Multidimensional Scale of Perceived Social Support, and average telomere length in PBMCs. Per a linear mixed model, telomere length did not change across pregnancy and postpartum visits; thus, subsequent analyses defined telomere length as the average across all available timepoints. ANCOVAs showed group differences by perceived childhood social class, maternal and paternal educational attainment, and current family social support, with lower values corresponding with shorter telomeres, after adjustment for possible confounds. No effects of childhood trauma or social support from significant others or friends on telomere length were observed. Findings demonstrate that while current SES was not related to telomeres, low childhood SES, independent of current SES, and low family social support were distinct risk factors for cellular aging in women. These data have relevance for understanding potential mechanisms by which early life deprivation of socioeconomic and relationship resources affect maternal health. In turn, this has potential significance for intergenerational transmission of telomere length. The predictive value of markers of biological versus chronological age on birth outcomes warrants investigation.


Asunto(s)
Senescencia Celular/fisiología , Embarazo/fisiología , Homeostasis del Telómero/fisiología , Adulto , Familia , Femenino , Humanos , Renta , Acontecimientos que Cambian la Vida , Parto/fisiología , Atención Perinatal , Atención Posnatal , Atención Prenatal , Factores de Riesgo , Clase Social , Apoyo Social , Factores Socioeconómicos , Telómero/fisiología , Acortamiento del Telómero/fisiología
17.
Health Psychol ; 37(2): 114-124, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-28967771

RESUMEN

OBJECTIVE: Childhood trauma is associated with negative perinatal health outcomes including mood disorders and shorter gestation. However, effects of early life exposures on maternal biology are poorly delineated. This study examined associations between childhood trauma and inflammation, as well as the mediating role of obesity in this relationship. METHOD: This study examined a racially diverse sample of 77 pregnant women assessed in early, mid, and late pregnancy. Assessments included the Childhood Trauma Questionnaire, Center for Epidemiologic Studies-Depression Scale, serum CRP, IL-6, and TNF-α, and prepregnancy BMI. RESULTS: Per linear mixed models, while no direct relationships were observed between childhood trauma with IL-6 or TNF-α, physical (95% CI: 0.007, 0.080) and emotional (95% CI: 0.005, 0.046) abuse as well as emotional neglect (95% CI: 0.010, 0.051) predicted elevated CRP. Effects remained after adjustment for race, income, education, smoking status, medical conditions, and depressive symptoms. PROCESS analyses showed BMI mediated the relationship between physical abuse and both serum CRP (95% CI: 0.014, 0.062) and IL-6 (95% CI: 0.009, 0.034). CONCLUSIONS: Exposure to childhood trauma, particularly emotional abuse, physical abuse, and emotional neglect, is associated with inflammation in pregnant women. Obesity served as 1 pathway by which physical abuse contributed to elevations in serum CRP and IL-6. Interventions targeting maternal obesity prior to pregnancy may help mitigate the effects of childhood trauma on perinatal health. These findings have relevance for understanding biological and behavioral pathways by which early life exposures contribute to maternal health. (PsycINFO Database Record


Asunto(s)
Adultos Sobrevivientes del Maltrato a los Niños/psicología , Proteína C-Reactiva/metabolismo , Maltrato a los Niños/psicología , Inflamación/psicología , Interleucina-6/metabolismo , Obesidad/etiología , Fragmentos de Péptidos/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Adolescente , Adulto , Femenino , Humanos , Obesidad/patología , Obesidad/psicología , Embarazo , Encuestas y Cuestionarios , Adulto Joven
18.
Vaccine ; 35(39): 5283-5290, 2017 09 18.
Artículo en Inglés | MEDLINE | ID: mdl-28778612

RESUMEN

BACKGROUND: In the US, influenza vaccination is recommended annually to everyone ≥6months. Prior receipt of influenza vaccine can dampen antibody responses to subsequent vaccination. This may have implications for pregnant women and their newborns, groups at high risk for complications from influenza infection. OBJECTIVE: This study examined effects of prior vaccination on maternal and cord blood antibody levels in a cohort of pregnant women in the US. STUDY DESIGN: Influenza antibody titers were measured in 141 pregnant women via the hemagglutination inhibition (HAI) assay prior to receipt of quadrivalent influenza vaccine, 30days post-vaccination, and at delivery (maternal and cord blood). Logistic regression analyses adjusting for age, BMI, parity, gestational age at vaccination, and year of vaccination compared HAI titers, seroprotection, and seroconversion in women with versus without vaccination in the prior year. RESULTS: Compared to those without vaccination in the previous year (n=50), women with prior vaccination (n=91) exhibited higher baseline antibody titers and/or seroprotection rates against all four strains after controlling for covariates. Prior vaccination also predicted lower antibody responses and seroconversion rates at one month post-vaccination. However, at delivery, there were no significant differences in antibody titers or seroprotection rates in women or newborns, and no meaningful differences in the efficiency of antibody transfer, as indicated by the ratio of cord blood to maternal antibody titers at the time of delivery. CONCLUSION: In this cohort of pregnant women, receipt of influenza vaccine the previous year predicted higher baseline antibody titers and decreased antibody responses at one month post-vaccination against all influenza strains. However, prior maternal vaccination did not significantly affect either maternal antibody levels at delivery or antibody levels transferred to the neonate. This study is registered with the NIH as a clinical trial (NCT02148874).


Asunto(s)
Formación de Anticuerpos/inmunología , Vacunas contra la Influenza/uso terapéutico , Gripe Humana/inmunología , Gripe Humana/prevención & control , Adulto , Formación de Anticuerpos/fisiología , Femenino , Edad Gestacional , Pruebas de Inhibición de Hemaglutinación , Humanos , Recién Nacido , Subtipo H1N1 del Virus de la Influenza A/inmunología , Subtipo H1N1 del Virus de la Influenza A/patogenicidad , Subtipo H3N2 del Virus de la Influenza A/inmunología , Subtipo H3N2 del Virus de la Influenza A/patogenicidad , Vacunas contra la Influenza/inmunología , Masculino , Embarazo , Seroconversión , Vacunación/métodos , Adulto Joven
20.
Nature ; 547(7661): 104-108, 2017 07 06.
Artículo en Inglés | MEDLINE | ID: mdl-28658204

RESUMEN

In acute myeloid leukaemia, long-term survival is poor as most patients relapse despite achieving remission. Historically, the failure of therapy has been thought to be due to mutations that produce drug resistance, possibly arising as a consequence of the mutagenic properties of chemotherapy drugs. However, other lines of evidence have pointed to the pre-existence of drug-resistant cells. For example, deep sequencing of paired diagnosis and relapse acute myeloid leukaemia samples has provided direct evidence that relapse in some cases is generated from minor genetic subclones present at diagnosis that survive chemotherapy, suggesting that resistant cells are generated by evolutionary processes before treatment and are selected by therapy. Nevertheless, the mechanisms of therapy failure and capacity for leukaemic regeneration remain obscure, as sequence analysis alone does not provide insight into the cell types that are fated to drive relapse. Although leukaemia stem cells have been linked to relapse owing to their dormancy and self-renewal properties, and leukaemia stem cell gene expression signatures are highly predictive of therapy failure, experimental studies have been primarily correlative and a role for leukaemia stem cells in acute myeloid leukaemia relapse has not been directly proved. Here, through combined genetic and functional analysis of purified subpopulations and xenografts from paired diagnosis/relapse samples, we identify therapy-resistant cells already present at diagnosis and two major patterns of relapse. In some cases, relapse originated from rare leukaemia stem cells with a haematopoietic stem/progenitor cell phenotype, while in other instances relapse developed from larger subclones of immunophenotypically committed leukaemia cells that retained strong stemness transcriptional signatures. The identification of distinct patterns of relapse should lead to improved methods for disease management and monitoring in acute myeloid leukaemia. Moreover, the shared functional and transcriptional stemness properties that underlie both cellular origins of relapse emphasize the importance of developing new therapeutic approaches that target stemness to prevent relapse.


Asunto(s)
Linaje de la Célula , Leucemia Mieloide Aguda/patología , Recurrencia Local de Neoplasia/patología , Células Madre Neoplásicas/patología , Animales , Células Clonales/metabolismo , Células Clonales/patología , Femenino , Humanos , Inmunofenotipificación , Leucemia Mieloide Aguda/genética , Ratones , Mutación , Células Progenitoras Mieloides/metabolismo , Células Progenitoras Mieloides/patología , Recurrencia Local de Neoplasia/genética , Células Madre Neoplásicas/metabolismo
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