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1.
Prev Med Rep ; 36: 102473, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37881176

RESUMO

Chronic disease prevalence in young adults is increasing with 15-20 % reporting 1 or more chronic diseases. This study examined cross-sectional and prospective relationships between chronic disease and e-cigarette/cigarette use from young adulthood to adulthood utilizing the U.S.- based National Longitudinal Study of Adolescent to Adult Health (Add Health). Add Health Study wave 3 (2001-2002; ages 18-26), wave 4 (2008; ages 24-34), and wave 5 (2016-2018; ages 33-44) were used. Past 30-day cigarette use at waves 3-5 and past 30-day e-cigarette use at wave 5 were assessed. Two measures of chronic disease were used: asthma (yes/no) and non-asthmatic chronic disease (yes/no) composed of 7 additional chronic diseases (diabetes, migraine, heart problem, hepatitis B/C, high blood pressure, epilepsy, and cancer). Weighted multilevel logistic regression (controlling for age, race/ethnicity, gender, and education) was used to assess cross-sectional associations at wave 3, and then prospective associations of wave 3 chronic disease (asthma and non-asthmatic) with waves 4 and 5 cigarette and wave 5 e-cigarette use. Logistic regressions showed no significant cross-sectional or prospective relationships between asthma and cigarette and e-cigarette use. However, wave 3 non-asthmatic chronic disease was significantly associated with wave 4 cigarette use (aOR 1.38, p <.001, 95 % CI: 1.15, 1.65) and with wave 5 cigarette use (aOR 1.49, p <.001, 95 % CI: 1.21, 1.84) but not e-cigarette use. The association between chronic disease in young adulthood and tobacco use in adulthood differed by type of chronic disease and tobacco product, indicating the need for targeted interventions.

2.
Am J Cancer Res ; 13(9): 4401-4417, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37818061

RESUMO

Gastric cancer (GC) shows high levels of heterogeneity and predicts a poor prognosis. The expressions of EHD3 are found to be misregulated in a number of tumors. However, the clinical significance and potential function of EHD3 expression in GC patients remain unknown. In this study, we found that EHD3 expression was distinctly increased in GC specimens and cell lines in both TCGA datasets and our cohort. High levels of EHD3 expression were linked to worse outcomes for patients with GC in clinical tests. Nomogram based on multivariate assays displayed good predictive accuracy for GC patients, as evidenced by C-indices and calibration graphs. Low levels of EHD3 mRNA were discovered in GC tissues due to EHD3 methylation's negative regulation of EHD3. In addition, EHD3 was observed to be related to several immune cells and might play a role in successful immunotherapy. Functionally, it was verified that knockdown of EHD3 remarkably suppressed the proliferation, migration and invasion of GC cells in vitro and in vivo. Results of Western blot confirmed that knockdown of EHD3 suppressed the expressions of ß-catenin, MMP-9, and N-cadherin, while promoting the expression of E-cadherin. Overall, this research identified a novel GC-related gene EHD3 which might be a novel prognostic biomarker involved in tumor microenvironment. EHD3 promoted the proliferation and metastasis of GC cells through influencing the Wnt/ß-catenin/EMT signaling pathway, suggesting it as a novel treatment target for GC patients.

3.
J Am Coll Health ; 71(5): 1454-1462, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-34398700

RESUMO

Sexual promiscuity stigma constitutes a significant barrier which prevents young women from receiving catch-up human papillomavirus (HPV) vaccinations. Our objective was to explore how this stigma may be particularly detrimental to women in cultures of honor, where women are expected to maintain a reputation of sexual purity.Participants were a sample of 182 young women who had not previously received an HPV vaccination.We measured feminine honor endorsement, HPV sexual promiscuity stigma, HPV vaccination shame, HPV vaccination intentions, and a set of covariates.Analyses revealed that the significant association between feminine honor endorsement and HPV vaccination intentions is fully explained by HPV sexual purity stigma and HPV vaccination shame.These findings indicate that honor-endorsing women are significantly impacted by sexual purity stigma, minimizing intentions to receive HPV vaccinations. These findings also highlight the need for the inclusion of cultural factors in the study of HPV vaccine uptake.


Assuntos
Infecções por Papillomavirus , Vacinas contra Papillomavirus , Humanos , Feminino , Infecções por Papillomavirus/prevenção & controle , Conhecimentos, Atitudes e Prática em Saúde , Universidades , Estudantes , Aceitação pelo Paciente de Cuidados de Saúde , Vacinação , Vacinas contra Papillomavirus/uso terapêutico
4.
Front Psychol ; 13: 943613, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35992482

RESUMO

Cognitive neuroscience has inspired a number of methodological advances to extract the highest signal-to-noise ratio from neuroimaging data. Popular techniques used to summarize behavioral data include sum-scores and item response theory (IRT). While these techniques can be useful when applied appropriately, item dimensionality and the quality of information are often left unexplored allowing poor performing items to be included in an itemset. The purpose of this study is to highlight how the application of two-stage approaches introduces parameter bias, differential item functioning (DIF) can manifest in cognitive neuroscience data and how techniques such as the multiple indicator multiple cause (MIMIC) model can identify and remove items with DIF and model these data with greater sensitivity for brain-behavior relationships. This was performed using a simulation and an empirical study. The simulation explores parameter bias across two separate techniques used to summarize behavioral data: sum-scores and IRT and formative relationships with those estimated from a MIMIC model. In an empirical study participants performed an emotional identification task while concurrent electroencephalogram data were acquired across 384 trials. Participants were asked to identify the emotion presented by a static face of a child across four categories: happy, neutral, discomfort, and distress. The primary outcomes of interest were P200 event-related potential (ERP) amplitude and latency within each emotion category. Instances of DIF related to correct emotion identification were explored with respect to an individual's neurophysiology; specifically an item's difficulty and discrimination were explored with respect to an individual's average P200 amplitude and latency using a MIMIC model. The MIMIC model's sensitivity was then compared to popular two-stage approaches for cognitive performance summary scores, including sum-scores and an IRT model framework and then regressing these onto the ERP characteristics. Here sensitivity refers to the magnitude and significance of coefficients relating the brain to these behavioral outcomes. The first set of analyses displayed instances of DIF within all four emotions which were then removed from all further models. The next set of analyses compared the two-stage approaches with the MIMIC model. Only the MIMIC model identified any significant brain-behavior relationships. Taken together, these results indicate that item performance can be gleaned from subject-specific biomarkers, and that techniques such as the MIMIC model may be useful tools to derive complex item-level brain-behavior relationships.

5.
Addict Behav ; 127: 107210, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34959076

RESUMO

INTRODUCTION: The study identified groups of JUUL using young adults based on their use patterns and compared harm perceptions, JUUL dependence, and other tobacco product use among these groups. METHODS: Online cross-sectional survey data were gathered in March 2019 from 667 undergraduate students who used JUUL weekly (50.4% females, average age: 20.3 years) at a southwest U.S. university. RESULTS: Latent class analysis identified four groups of young adults who used JUUL: 1) Light Social JUUL Using Young Adults (LS, 52.5%) who used JUUL occasionally with friends when drinking alcohol, 2) Daily Sensation Seekers (DSS, 16.2%) who used JUUL daily with alcohol, 3) Daily Activity Driven JUUL Using Young Adults (DAD, 26.0%) who used JUUL daily while drinking, watching media, or studying, and 4) Daily All Occasion JUUL Using Young Adults (DAO, 5.3%) who used JUUL heavily, daily and in various occasions. While all four groups reported some extent of JUUL dependence, DAO reported the highest dependence and were more likely than LS to have used cigarettes and other e-cigarettes besides JUUL. They also tended to believe different pod flavors could cause different types of lung damage while the other groups were unsure/disagreed with this belief. LS were more likely than DSS and DAD to believe that JUUL use indicated openness to new experiences. CONCLUSION: Young adults with different JUUL use patterns perceived JUUL harms differently and faced varied risks of JUUL dependence and other tobacco product use. Effective cessation interventions should be adapted to meet the needs of these groups.


Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Produtos do Tabaco , Tabagismo , Vaping , Adulto , Estudos Transversais , Feminino , Humanos , Masculino , Adulto Jovem
6.
Eur J Protistol ; 79: 125796, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33975057

RESUMO

Blastocystis is a common enteric protist that inhabits the gastrointestinal tract of approximately 1 billion people worldwide. In this study, a total of 1,070 patients from two hospitals in Zhengzhou, Central China were enrolled to know molecular characteristics of Blastocystis sp. The microorganism was identified and subtyped with a PCR amplification and sequencing of the small subunit ribosomal deoxyribonucleic acid (SSU-rDNA). The overall minimum prevalence of Blastocystis sp. in participants was 3.1% (33/1070). Although there were no significant differences on Blastocystis sp. infections among study sites, age groups, and gender, the higher infection was observed in the patients with gastrointestinal diseases (8.8%, 15/170). Sequence analysis of the 33 isolates revealed three known subtypes, such as ST1 (n = 7), ST3 (n = 23), and ST7 (n = 3). Among them, ST3 was the dominant subtype being detected in 23 isolates (69.7%), followed by ST1 (21.2%, 7/33) and ST7 (9.1%, 3/33). The phylogenetic analysis demonstrated that three subtypes (ST1, ST3 and ST7) were clustered with their reference sequences with good bootstrap support. The subtype determination of Blastocystis sp. isolates by the phylogenetic analysis was well supported by online platform. The present study provides the first molecular report of Blastocystis sp. infections in hospital patients in Central China.


Assuntos
Infecções por Blastocystis/parasitologia , Blastocystis/classificação , Blastocystis/genética , Blastocystis/isolamento & purificação , Infecções por Blastocystis/epidemiologia , China/epidemiologia , DNA de Protozoário/genética , DNA Ribossômico/genética , Feminino , Humanos , Masculino , Tipagem Molecular , Filogenia , Prevalência , Especificidade da Espécie
7.
Educ Psychol Meas ; 81(1): 5-38, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33456060

RESUMO

Conventional approaches for selecting a reference indicator (RI) could lead to misleading results in testing for measurement invariance (MI). Several newer quantitative methods have been available for more rigorous RI selection. However, it is still unknown how well these methods perform in terms of correctly identifying a truly invariant item to be an RI. Thus, Study 1 was designed to address this issue in various conditions using simulated data. As a follow-up, Study 2 further investigated the advantages/disadvantages of using RI-based approaches for MI testing in comparison with non-RI-based approaches. Altogether, the two studies provided a solid examination on how RI matters in MI tests. In addition, a large sample of real-world data was used to empirically compare the uses of the RI selection methods as well as the RI-based and non-RI-based approaches for MI testing. In the end, we offered a discussion on all these methods, followed by suggestions and recommendations for applied researchers.

8.
J Cancer ; 11(12): 3492-3501, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32284745

RESUMO

The incidence of papillary thyroid carcinoma (PTC) has been increased rapidly in recent decades. Long noncoding RNAs (lncRNA) are a class of non-protein-coding transcripts and play critical roles in regulating gene expression and influence biological behaviors of multiple cancers, including PTC. Here, we discovered that lncRNA SNHG3 was significantly downregulated in PTC tissues and cell lines, the expression of SNHG3 was negatively correlated with the TNM stage and poor prognosis of PTC patients. Functional studies illustrated that the depletion of SNHG3 via CRISPR/Cas9 technology promoted the proliferation, migration and invasion abilities of PTC cells. Tumor xenograft models confirmed the tumor-promoting role of silenced SNHG3 in vivo. Further mechanistic analyses revealed that knockout of SNHG3 activated the AKT/mTOR/ERK pathway in PTC cell lines and the mTOR inhibitor AZD8055 abrogated the tumor-promoting effect induced by SNHG3 inhibition. Taken together, our findings identified a lncRNA SNHG3 that functions its tumor-suppressor role during PTC development and SNHG3 might serve as a promising candidate for target therapy of PTC.

9.
Assessment ; 26(7): 1217-1233, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-28598216

RESUMO

This study explored the impact of partial factorial invariance on cross-group comparisons of latent variables, including latent means, latent variances, structural relations (or correlations) with other constructs, and regression coefficients as predicting external variables. The results indicate that the estimates of factor mean differences are sensitive to violations of invariance on both factor loadings and intercepts. Noninvariant factor loadings were also found to influence the cross-group comparisons of factor variances and regression coefficients (slopes, in the raw metric) with external variables. However, cross-group comparisons of standardized slopes and interfactor correlations were not subject to noninvariance. Under conditions of partial invariance, we further compared the performance of four different model specification strategies. In general, fitting partially invariant models with all noninvariant parameters that were freely estimated yielded more accurate estimates of the parameters of interest. The implications of the major findings of this work, as well as recommendations and guidelines for future empirical researchers, are discussed below.


Assuntos
Análise Fatorial , Análise de Regressão , Humanos , Método de Monte Carlo
10.
Multivariate Behav Res ; 54(2): 224-245, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30569738

RESUMO

In this study, we introduce an interval estimation approach based on Bayesian structural equation modeling to evaluate factorial invariance. For each tested parameter, the size of noninvariance with an uncertainty interval (i.e. highest density interval [HDI]) is assessed via Bayesian parameter estimation. By comparing the most credible values (i.e. 95% HDI) with a region of practical equivalence (ROPE), the Bayesian approach allows researchers to (1) support the null hypothesis of practical invariance, and (2) examine the practical importance of the noninvariant parameter. Compared to the traditional likelihood ratio test, simulation results suggested that the proposed Bayesian approach could offer additional insight into evaluating factorial invariance, thus, leading to more informative conclusions. We provide an empirical example to demonstrate the procedures necessary to implement the proposed method in applied research. The importance of and influences on the choice of an appropriate ROPE are discussed.


Assuntos
Teorema de Bayes , Análise Fatorial , Análise de Classes Latentes , Humanos
11.
Multivariate Behav Res ; 52(4): 430-444, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28429965

RESUMO

Specification search problems refer to two important but under-addressed issues in testing for factorial invariance: how to select proper reference indicators and how to locate specific non-invariant parameters. In this study, we propose a two-step procedure to solve these issues. Step 1 is to identify a proper reference indicator using the Bayesian structural equation modeling approach. An item is selected if it is associated with the highest likelihood to be invariant across groups. Step 2 is to locate specific non-invariant parameters, given that a proper reference indicator has already been selected in Step 1. A series of simulation analyses show that the proposed method performs well under a variety of data conditions, and optimal performance is observed under conditions of large magnitude of non-invariance, low proportion of non-invariance, and large sample sizes. We also provide an empirical example to demonstrate the specific procedures to implement the proposed method in applied research. The importance and influences are discussed regarding the choices of informative priors with zero mean and small variances. Extensions and limitations are also pointed out.


Assuntos
Análise Fatorial , Modelos Estatísticos , Adulto , Idoso , Análise de Variância , Teorema de Bayes , Simulação por Computador , Interpretação Estatística de Dados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
12.
Front Psychol ; 7: 1052, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27462291

RESUMO

Approximate number system (ANS) acuity and mathematical ability have been found to be closely associated in recent studies. However, whether and how these two measures are causally related still remain less addressed. There are two hypotheses about the possible causal relationship: ANS acuity influences mathematical performances, or access to math education sharpens ANS acuity. Evidences in support of both hypotheses have been reported, but these two hypotheses have never been tested simultaneously. Therefore, questions still remain whether only one-direction or reciprocal causal relationships existed in the association. In this work, we provided a new evidence on the causal relationship between ANS acuity and arithmetic ability. ANS acuity and mathematical ability of elementary-school students were measured sequentially at three time points within one year, and all possible causal directions were evaluated simultaneously using cross-lagged regression analysis. The results show that ANS acuity influences later arithmetic ability while the reverse causal direction was not supported. Our finding adds a strong evidence to the causal association between ANS acuity and mathematical ability, and also has important implications for educational intervention designed to train ANS acuity and thereby promote mathematical ability.

13.
PLoS One ; 9(12): e114457, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25502932

RESUMO

Tetracycline analogues (TCNAs) have been shown to inhibit matrix metalloproteinases and to induce apoptosis in several cancer cell types. In the present study, the cytotoxic effects of TCNAs doxycycline (DOXY), minocycline (MINO) and chemically modified tetracycline-3 (COL-3) were investigated in the human acute myeloid leukemia HL-60 cell line. Cells were incubated with TCNAs in final concentrations of 0.5-100 µg/ml for 24 h. Viability of the leukemic cells was inhibited in a concentration-dependent manner using resazurin assay. The estimated IC50s were 9.2 µg/ml for DOXY, 9.9 µg/ml for MINO and 1.3 µg/ml for COL-3. All three TCNAs induced potent cytotoxic effects and cell death. Apoptosis, which was assessed by morphological changes and annexin V positivity, was concentration- and time-dependent following incubation with any one of the drugs. TCNAs induced DNA double strand breaks soon after treatment commenced as detected by γH2AX and western blot. The loss of mitochondrial membrane potential (Δψm), caspase activation and cleavage of PARP and Bcl-2 were observed; however, the sequence of events differed among the drugs. Pancaspase inhibitor Z-VAD-FMK improved survival of TCNAs-treated cells and decreased TCNAs-induced apoptosis. In summary, we demonstrated that TCNAs had a cytotoxic effect on the HL-60 leukemic cell line. Apoptosis was induced via mitochondria-mediated and caspase-dependent pathways in HL-60 cells by all three TCNAs. COL-3 exerted the strongest anti-proliferative and pro-apoptotic effects in concentrations that have been achieved in human plasma in reported clinical trials. These results indicate that there is a therapeutic potential of TCNAs in leukemia.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Doxiciclina/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Minociclina/farmacologia , Tetraciclinas/farmacologia , Caspases/metabolismo , Células HL-60 , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Mitocôndrias/metabolismo
14.
PLoS One ; 9(4): e93403, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24695616

RESUMO

Narcissism, characterized by grandiose self-image and entitled feelings to others, has been increasingly prevalent in the past decades. This study examined genetic and environmental bases of two dimensions of narcissism: intrapersonal grandiosity and interpersonal entitlement. A total of 304 pairs of twins from Beijing, China completed the Narcissistic Grandiosity Scale and the Psychological Entitlement Scale. Both grandiosity (23%) and entitlement (35%) were found to be moderately heritable, while simultaneously showing considerable non-shared environmental influences. Moreover, the genetic and environmental influences on the two dimensions were mostly unique (92-93%), with few genetic and environmental effects in common (7-8%). The two dimensions of narcissism, intrapersonal grandiosity and interpersonal entitlement, are heritable and largely independent of each other in terms of their genetic and environmental sources. These findings extend our understanding of the heritability of narcissism on the one hand. On the other hand, the study demonstrates the rationale for distinguishing between intrapersonal and interpersonal dimensions of narcissism, and possibly personality in general as well.


Assuntos
Comportamento/fisiologia , Narcisismo , Transtornos da Personalidade/genética , Transtornos da Personalidade/psicologia , Adolescente , Adulto , China , Meio Ambiente , Feminino , Genética Comportamental/métodos , Humanos , Relações Interpessoais , Masculino , Psicometria/métodos , Autoimagem , Gêmeos/genética , Gêmeos/psicologia , Adulto Jovem
15.
Multivariate Behav Res ; 49(1): 67-77, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-26745674

RESUMO

Multivariate time series data offer researchers opportunities to study dynamics of various systems in social and behavioral sciences. Dynamic factor model (DFM), as an idiographic approach for studying intraindividual variability and dynamics, has typically been applied to time series data obtained from a single unit. When multivariate time series data are collected from multiple units, how to synchronize dynamical information becomes a silent issue. To address this issue, the current study presented a multilevel dynamic factor model (MDFM) that analyzes multiple multivariate time series in multilevel SEM frameworks. MDFM not only disentangles within- and between-person variability but also models dynamics of the intraindividual processes. To illustrate the uses of MDFMs, we applied lag0, lag1, and lag2 MDFMs to empirical data on affect collected from 205 dating couples who had at least 50 consecutive days of observations. We also considered a model extension where the dynamical coefficients were allowed to be randomly varying in the population. The empirical analysis yielded interesting findings regarding affect regulation and coregulation within couples, demonstrating promising uses of MDFMs in analyzing multiple multivariate time series. In the end, we discussed a number of methodological issues in the applications of MDFMs and pointed out possible directions for future research.

16.
J Adolesc ; 32(5): 1267-86, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19223067

RESUMO

This study investigated age and gender differences in the quality of attachment to mothers, fathers, and peers, and the association of attachment with measures of self-evaluation in 584 Chinese adolescents in junior high, high school, and university. Their responses to the Inventory of Parent and Peer Attachment indexed attachment quality, and self-evaluation was measured by the Rosenberg Self-Esteem Scale and the Self-Liking and Self-Competence Scale. Consistent with findings with Western samples, our analyses revealed (a) lower parent-child relationship quality in middle (compared to early) adolescence, (b) a significant association of parental and peer attachment with self-evaluation, and (c) gender differences in attachment to peers, with females reporting stronger attachment than males. Chinese females reported stronger maternal attachment than did males, and for females the quality of maternal attachment was more strongly related to self-evaluation than any other attachment relationship. During high school, peer attachment quality - rather than parental - was preeminently associated with self-evaluation. The findings of this study indicate that in a context of considerable consistency of findings with Western studies, parent-child attachment in Chinese adolescents is also influenced by culture-specific practices that influence parent-youth relationships and their meaning to the child.


Assuntos
Apego ao Objeto , Autoimagem , Autoavaliação (Psicologia) , Adolescente , China , Coleta de Dados , Feminino , Humanos , Masculino , Países Baixos , Relações Pais-Filho , Adulto Jovem
17.
Pharmacol Res ; 58(1): 32-7, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18588979

RESUMO

Roscovitine is a cyclin-dependent kinase (Cdk) and signal-regulated kinase (Erk1/2) inhibitor that has been shown to be effective against several cancer types including brain tumors. We have shown previously that roscovitine crosses the blood brain barrier (BBB) and is rapidly eliminated from both plasma and brain in adult rats. However, age-dependent kinetics and its effects on the brain have not been reported. In the present study, we investigated the pharmacokinetics of roscovitine in adult and in 14 days old rats after the administration of a single dose of 25 mg/kg. Moreover, we studied the effect of the drug on Cdk5 and Erk1/2 activities in three brain regions, hippocampus, frontal cortex and cerebellum. The pharmacokinetics of roscovitine followed a two-compartment model in both plasma and brain in both adult and young rats. The terminal elimination half-life was 7 h in brain as well as in plasma in rat pups compared to < 0.5 h observed in adult rats. Brain exposure expressed as AUC brain/AUC plasma was 100% in rat pups compared to 20% found in adult rats. Roscovitine induced a significant Cdk5 inhibition and significant Erk1/2 activation in all studied pups brain regions at 2 h. This is the first study describing age-dependent pharmacokinetics of roscovitine and showing the high brain exposure of infant rats to the drug. Thus, roscovitine may be a promising candidate for the treatment of brain tumors in children.


Assuntos
Antineoplásicos/farmacocinética , Encéfalo/enzimologia , Quinase 5 Dependente de Ciclina/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Purinas/farmacocinética , Fatores Etários , Animais , Animais Recém-Nascidos , Antineoplásicos/sangue , Área Sob a Curva , Cerebelo/enzimologia , Ativação Enzimática , Feminino , Lobo Frontal/enzimologia , Meia-Vida , Hipocampo/enzimologia , Masculino , Inibidores de Proteínas Quinases/sangue , Purinas/sangue , Ratos , Roscovitina , Distribuição Tecidual
18.
Cancer Chemother Pharmacol ; 60(6): 841-9, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17318617

RESUMO

Myelosuppression is one the most frequent side effects of chemotherapy. New agents that more selectively target cancer cells have been developed in attempt to improve the effects and to decrease the side effects of cancer treatment. Roscovitine is a purine analogue and cyclin-dependent kinase inhibitor. Several studies have shown its cytotoxic effect in cancer cell lines in vitro and in xenograft models in vivo. In this study, we investigated the effect of roscovitine on hematopoietic progenitors in vitro and in vivo in mice. The clonogenic capacity of hematopoietic progenitors was studied using burst-forming unit-erythroid (BFU-E), colony-forming unit granulocyte, macrophage (CFU-GM) and colony-forming unit granulocyte, erythroid, macrophage, megakaryocyte (CFU-GEMM). In vitro, bone marrow cells were exposed to roscovitine (25-250 microM) in Iscove's modified Dulbecco's media for 4 h or to roscovitine (1-100 microM) in MethoCult media for 12 days. No effect on colony formation was observed after exposure to roscovitine for 4 h; however, concentration- and cell type-dependent effects were observed after 12 days. Roscovitine in concentration of 100 microM inhibited the growth of all types of colonies, while lower concentrations have shown differential effect on hematopoietic progenitors. The most sensitive were CFU-GEMM, followed by BFU-E and then CFU-GM. In vivo, mice were treated with single dose of roscovitine (50, 100 or 250 mg/kg) and the effect on bone marrow was studied on day 1, 3, 6, 9 or 12 after the treatment. In the second part of experiment, the mice were treated with roscovitine 350 mg/kg/day divided into two daily doses for 4 days. The bone marrow was examined on day 1 and 5 after the last dose of roscovitine. On day 1, BFU-E decreased to less than 50% of the controls (P = 0.019). No decrease in BFU-E formation was observed on day 5. No significant effect was observed on CFU-GM and CFU-GEMM growth after the treatment with multiple doses of roscovitine. Single doses of roscovitine or dimethylsulfoxide did not affect the colony formation. We also studied the distribution of roscovitine to the bone marrow after a dose of 50 mg/kg was administered intraperitoneally. Only 1.5% of the drug was detected in the bone marrow. Thus, the roscovitine effect on hematopoietic progenitors in bone marrow in vivo is only transient. One reason may be that only a small fraction of roscovitine reaches the bone marrow. Another explanation may be the short half-life observed for roscovitine that might not allow enough cell exposure to the drug. However, the toxicity of roscovitine to hematopoietic progenitors in vitro is within the same exposure range as cytotoxicity to cancer cells. Thus, precaution should be taken in clinical trials, especially when combinations with myelosuppressive cytostatics are used.


Assuntos
Células da Medula Óssea/efeitos dos fármacos , Quinases Ciclina-Dependentes/antagonistas & inibidores , Células-Tronco Hematopoéticas/efeitos dos fármacos , Inibidores de Proteínas Quinases/efeitos adversos , Purinas/efeitos adversos , Animais , Área Sob a Curva , Medula Óssea/metabolismo , Células da Medula Óssea/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Ensaio de Unidades Formadoras de Colônias , Relação Dose-Resposta a Droga , Esquema de Medicação , Células Precursoras Eritroides/efeitos dos fármacos , Células Precursoras Eritroides/metabolismo , Feminino , Granulócitos/efeitos dos fármacos , Granulócitos/metabolismo , Meia-Vida , Células-Tronco Hematopoéticas/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Purinas/administração & dosagem , Purinas/farmacocinética , Roscovitina , Fatores de Tempo , Distribuição Tecidual
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