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1.
Open Forum Infect Dis ; 10(10): ofad472, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37808894

RESUMO

Background: Evidence for efficacy of single, high-dose liposomal amphotericin B (LAmB) in HIV-associated cryptococcal meningitis and histoplasmosis is growing. No systematic review has examined the safety of this regimen across multiple studies. Methods: We systematically searched Medline, Scopus, and the Cochrane Library from inception to April 2023 for studies reporting grade 3 and 4 adverse events (AEs) with single high-dose LAmB vs traditional amphotericin regimens for HIV-associated fungal infections. Results: Three trials (n = 946) were included. Compared with traditional regimens, single high-dose LAmB was associated with equivalent risk of grade 3 and 4 AEs (risk ratio [RR], 0.75; 95% CI, 0.53-1.06) and lower overall risk of grade 4 AEs (RR, 0.68; 95% CI, 0.55-0.86), grade 4 renal (RR, 0.43; 95% CI, 0.20-0.94) and grade 4 hematological AEs (RR, 0.46; 95% CI, 0.32-0.65). Conclusions: Single, high-dose LAmB is associated with a lower risk of life-threatening AEs compared with other World Health Organization-endorsed amphotericin B-based regimens in invasive HIV-related fungal infection.

2.
Genet Test Mol Biomarkers ; 25(3): 199-210, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33734890

RESUMO

Background: The association between dysregulated microRNAs (miRNAs) and acute myeloid leukemia (AML) is well known. However, our understanding of the regulatory role of miRNAs in the cytogenetically normal AML (CN-AML) subtype pathway is still poor. The current study integrated miRNA and mRNA profiles to explore novel miRNA-mRNA interactions that affect the regulatory patterns of de novo CN-AML. Methods: We utilized a multiplexed nanoString nCounter platform to profile both miRNAs and mRNAs using similar sets of patient samples (n = 24). Correlations were assessed, and an miRNA-mRNA network was constructed. The underlying biological functions of the mRNAs were predicted by gene enrichment. Finally, the interacting pairs were assessed using TargetScan and microT-CDS. We identified 637 significant negative correlations (false discovery rate <0.05). Results: Network analysis revealed a cluster of 12 miRNAs representing the majority of mRNA targets. Within the cluster, five miRNAs (miR-495-3p, miR-185-5p, let-7i-5p, miR-409-3p, and miR-127-3p) were posited to play a pivotal role in the regulation of CN-AML, as they are associated with the negative regulation of myeloid leukocyte differentiation, negative regulation of myeloid cell differentiation, and positive regulation of hematopoiesis. Conclusion: Three novel interactions in CN-AML were predicted as let-7i-5p:HOXA9, miR-495-3p:PIK3R1, and miR-495-3p:CDK6 may be responsible for regulating myeloid cell differentiation in CN-AML.


Assuntos
Leucemia Mieloide Aguda/genética , MicroRNAs/genética , RNA Mensageiro/genética , Adulto , Idoso , Análise Citogenética/métodos , Feminino , Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes/genética , Humanos , Malásia , Masculino , Pessoa de Meia-Idade
3.
J Med Chem ; 64(1): 644-661, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33356246

RESUMO

The phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway is a frequently dysregulated pathway in human cancer, and PI3Kα is one of the most frequently mutated kinases in human cancer. A PI3Kα-selective inhibitor may provide the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family. Here, we describe our efforts to discover a PI3Kα-selective inhibitor by applying structure-based drug design (SBDD) and computational analysis. A novel series of compounds, exemplified by 2,2-difluoroethyl (3S)-3-{[2'-amino-5-fluoro-2-(morpholin-4-yl)-4,5'-bipyrimidin-6-yl]amino}-3-(hydroxymethyl)pyrrolidine-1-carboxylate (1) (PF-06843195), with high PI3Kα potency and unique PI3K isoform and mTOR selectivity were discovered. We describe here the details of the design and synthesis program that lead to the discovery of 1.


Assuntos
Desenho de Fármacos , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Inibidores de Fosfoinositídeo-3 Quinase/química , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Animais , Linhagem Celular , Cromatografia Líquida de Alta Pressão/métodos , Cristalografia por Raios X , Humanos , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética/métodos , Camundongos , Estrutura Molecular , Inibidores de Fosfoinositídeo-3 Quinase/síntese química , Ratos , Espectrometria de Massas por Ionização por Electrospray/métodos
4.
Science ; 341(6143): 275-8, 2013 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-23869016

RESUMO

Melanocortin receptor accessory proteins (MRAPs) modulate signaling of melanocortin receptors in vitro. To investigate the physiological role of brain-expressed melanocortin 2 receptor accessory protein 2 (MRAP2), we characterized mice with whole-body and brain-specific targeted deletion of Mrap2, both of which develop severe obesity at a young age. Mrap2 interacts directly with melanocortin 4 receptor (Mc4r), a protein previously implicated in mammalian obesity, and it enhances Mc4r-mediated generation of the second messenger cyclic adenosine monophosphate, suggesting that alterations in Mc4r signaling may be one mechanism underlying the association between Mrap2 disruption and obesity. In a study of humans with severe, early-onset obesity, we found four rare, potentially pathogenic genetic variants in MRAP2, suggesting that the gene may also contribute to body weight regulation in humans.


Assuntos
Peso Corporal/genética , Proteínas de Transporte/genética , Obesidade/genética , Proteínas Modificadoras da Atividade de Receptores/metabolismo , Receptor Tipo 4 de Melanocortina/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Adolescente , Animais , Índice de Massa Corporal , Criança , Pré-Escolar , Metabolismo Energético/genética , Feminino , Deleção de Genes , Humanos , Masculino , Camundongos , Camundongos Knockout , Obesidade/metabolismo , Proteínas Modificadoras da Atividade de Receptores/genética , Receptor Tipo 4 de Melanocortina/genética , Adulto Jovem
5.
Cancer Lett ; 322(1): 113-8, 2012 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-22387988

RESUMO

Ser/Thr protein kinase CK2 regulates multiple processes that play important roles in the sensitivity of cancer to epidermal growth factor receptor targeting therapeutics, including PI3K-Akt-mTOR signaling, Hsp90 activity, and inhibition of apoptosis. We hypothesized that top-down inhibition of EGFR, combined with lateral suppression of multiple oncogenic pathways by targeting CK2, would create a pharmacologic synthetic lethal event and result in an improved cancer therapy compared to EGFR inhibition alone. This hypothesis was tested by combining CX-4945, a first-in-class clinical stage inhibitor of CK2, with the EGFR tyrosine kinase inhibitor, erlotinib, in vitro and in vivo in models of non-small cell lung carcinoma, NCI-H2170, and squamous cell carcinoma, A431. Our results demonstrate that combination of CX-4945 with erlotinib results in enhanced attenuation of the PI3K-Akt-mTOR pathway. We also observed an increase in apoptosis, synergistic killing of cancer cells in vitro, as well as improved antitumor efficacy in vivo. Taken together, these data position CK2 as a valid pharmacologic target for drug combinations and support further evaluation of CX-4945 in combination with EGFR targeting agents.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Caseína Quinase II/antagonistas & inibidores , Receptores ErbB/antagonistas & inibidores , Naftiridinas/farmacologia , Neoplasias/tratamento farmacológico , Fosfatidilinositol 3-Quinases/fisiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Quinazolinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/fisiologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cloridrato de Erlotinib , Feminino , Humanos , Camundongos , Neoplasias/patologia , Fenazinas
6.
Mol Cancer Ther ; 11(4): 994-1005, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22267551

RESUMO

Drug combination therapies are commonly used for the treatment of cancers to increase therapeutic efficacy, reduce toxicity, and decrease the incidence of drug resistance. Although drug combination therapies were originally devised primarily by empirical methods, the increased understanding of drug mechanisms and the pathways they modulate provides a unique opportunity to design combinations that are based on mechanistic rationale. We have identified protein kinase CK2 as a promising therapeutic target for combination therapy, because CK2 regulates not just one but many oncogenic pathways and processes that play important roles in drug resistance, including DNA repair, epidermal growth factor receptor signaling, PI3K/AKT/mTOR signaling, Hsp90 machinery activity, hypoxia, and interleukin-6 expression. In this article, we show that CX-4945, a clinical stage selective small molecule inhibitor of CK2, blocks the DNA repair response induced by gemcitabine and cisplatin and synergizes with these agents in models of ovarian cancer. Mechanistic studies show that the enhanced activity is a result of inactivation of XRCC1 and MDC1, two mediator/adaptor proteins that are essential for DNA repair and that require phosphorylation by CK2 for their function. These data position CK2 as a valid pharmacologic target for intelligent drug combinations and support the evaluation of CX-4945 in combination with gemcitabine and platinum-based chemotherapeutics in the clinical setting.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Caseína Quinase II/antagonistas & inibidores , Reparo do DNA/efeitos dos fármacos , Naftiridinas/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Quinase do Ponto de Checagem 2 , Sinergismo Farmacológico , Feminino , Humanos , Camundongos , Naftiridinas/administração & dosagem , Neoplasias/genética , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/genética , Fenazinas , Fosforilação , Distribuição Aleatória , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Biochem Biophys Res Commun ; 415(1): 163-7, 2011 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-22027148

RESUMO

Inflammatory breast cancer is driven by pro-angiogenic and pro-inflammatory cytokines. One of them Interleukin-6 (IL-6) is implicated in cancer cell proliferation and survival, and promotes angiogenesis, inflammation and metastasis. While IL-6 has been shown to be upregulated by several oncogenes, the mechanism behind this phenomenon is not well characterized. Here we demonstrate that the pleotropic Serine/Threonine kinase CK2 is implicated in the regulation of IL-6 expression in a model of inflammatory breast cancer. We used siRNAs targeted toward CK2 and a selective small molecule inhibitor of CK2, CX-4945, to inhibit the expression and thus suppress the secretion of IL-6 in in vitro as well as in vivo models. Moreover, we report that in a clinical trial, CX-4945 was able to dramatically reduce IL-6 levels in plasma of an inflammatory breast cancer patient. Our data shed a new light on the regulation of IL-6 expression and position CX-4945 and potentially other inhibitors of CK2, for the treatment of IL-6-driven cancers and possibly other diseases where IL-6 is instrumental, including rheumatoid arthritis.


Assuntos
Caseína Quinase II/metabolismo , Neoplasias Inflamatórias Mamárias/metabolismo , Interleucina-6/biossíntese , Animais , Caseína Quinase II/antagonistas & inibidores , Caseína Quinase II/genética , Linhagem Celular Tumoral , Ensaios Clínicos Fase II como Assunto , Feminino , Humanos , Neoplasias Inflamatórias Mamárias/sangue , Neoplasias Inflamatórias Mamárias/tratamento farmacológico , Interleucina-6/antagonistas & inibidores , Interleucina-6/sangue , Camundongos , Camundongos Endogâmicos BALB C , Naftiridinas/uso terapêutico , Fenazinas , Inibidores de Proteínas Quinases/uso terapêutico , RNA Interferente Pequeno/genética , Fator de Transcrição STAT3/metabolismo
8.
Am J Orthod Dentofacial Orthop ; 140(1): e49-52, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21724071

RESUMO

INTRODUCTION: Previous studies have used the right and left sides of the same jaw to compare different force levels, types of movement, and durations of forces. However, the amounts of root resorption have not been compared between the right and left sides after applying the same amount of force. The aims of the study were to quantitatively compare the volumes of the root resorption lacunae between the right and left first premolars to determine whether 1 side can serve as a control to the other and to compare the volumes of root resorption lacunae of the first premolars between the maxilla and the mandible. METHODS: Forty-four first premolars, orthodontically indicated for extraction from 11 patients (left and right maxillary and mandibular first premolars from each) were moved buccally by using beta-titanium-molybdenum alloy 0.017 × 0.025-in cantilever springs with continuous heavy (225 g) force. After the experimental period, the teeth were extracted under a strict protocol to prevent root cementum damage and then analyzed by using a microcomputed tomography scan x-ray system (1172; SkyScan, Aartselaar, Belgium) and specially designed software (Convex Hull 2D, University of Sydney, Sydney, Australia) for direct volumetric measurements. RESULTS: There were no statistically significant differences in the mean cube root volumes of root resorption craters between the right and left sides (P = 0.18) or between the maxillary and mandibular jaws (P = 0.10). There was also no statistical significance for the interception (P = 0.41), which indicated that the jaw and the side had independent effects. CONCLUSIONS: The amount of root resorption on the left and right sides of the jaw were similar in both the maxilla and the mandible. Therefore, for future root resorption studies, it is justifiable to use the split-mouth technique so that teeth from 1 side of the jaw can serve as the controls.


Assuntos
Cemento Dentário/patologia , Braquetes Ortodônticos/efeitos adversos , Reabsorção da Raiz/patologia , Técnicas de Movimentação Dentária/efeitos adversos , Adolescente , Ligas , Análise de Variância , Dente Pré-Molar/diagnóstico por imagem , Dente Pré-Molar/patologia , Fenômenos Biomecânicos , Criança , Ligas Dentárias , Cemento Dentário/diagnóstico por imagem , Análise do Estresse Dentário , Feminino , Humanos , Processamento de Imagem Assistida por Computador/métodos , Masculino , Reabsorção da Raiz/diagnóstico por imagem , Reabsorção da Raiz/etiologia , Estatísticas não Paramétricas , Técnicas de Movimentação Dentária/instrumentação , Raiz Dentária/diagnóstico por imagem , Microtomografia por Raio-X
9.
Mol Cell Biochem ; 356(1-2): 37-43, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21755459

RESUMO

In this article we describe the preclinical characterization of 5-(3-chlorophenylamino) benzo[c][2,6]naphthyridine-8-carboxylic acid (CX-4945), the first orally available small molecule inhibitor of protein CK2 in clinical trials for cancer. CX-4945 was optimized as an ATP-competitive inhibitor of the CK2 holoenzyme (Ki = 0.38 nM). Iterative synthesis and screening of analogs, guided by molecular modeling, led to the discovery of orally available CX-4945. CK2 promotes signaling in the Akt pathway and CX-4945 suppresses the phosphorylation of Akt as well as other key downstream mediators of the pathway such as p21. CX-4945 induced apoptosis and caused cell cycle arrest in cancer cells in vitro. CX-4945 exhibited a dose-dependent antitumor activity in a xenograft model of PC3 prostate cancer model and was well tolerated. In vivo time-dependent reduction in the phosphorylation of the biomarker p21 at T145 was observed by immunohistochemistry. Inhibition of the newly validated CK2 target by CX-4945 represents a fresh therapeutic strategy for cancer.


Assuntos
Caseína Quinase II/antagonistas & inibidores , Naftiridinas/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Bibliotecas de Moléculas Pequenas/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Caseína Quinase II/metabolismo , Caspase 3/metabolismo , Caspase 7/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Naftiridinas/química , Naftiridinas/farmacologia , Fenazinas , Fosforilação/efeitos dos fármacos , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Bibliotecas de Moléculas Pequenas/administração & dosagem , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade
10.
Bioorg Med Chem Lett ; 21(6): 1687-91, 2011 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-21316963

RESUMO

We describe the discovery of novel potent substituted pyrimido[4,5-c]quinoline ATP-competitive inhibitors of protein kinase CK2. A binding model of the inhibitors with the protein was elaborated on the basis of SAR and revealed various modes of interaction with the hinge region. Representative analog 14k (CK2 IC(50)=9 nM) showed anti-viral activity at nanomolar concentrations against HIV-1. Orally available compound 7e (CK2 IC(50)=3 nM) reduced pain in the phase II of a murine formalin model. These preliminary data confirm that properly optimized CK2 inhibitors may be used for anti-viral and pain therapy.


Assuntos
Analgésicos/farmacologia , Antivirais/farmacologia , Caseína Quinase II/antagonistas & inibidores , Quinolinas/farmacologia , Analgésicos/química , Antivirais/química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Ligação de Hidrogênio , Quinolinas/química , Relação Estrutura-Atividade
11.
J Med Chem ; 54(2): 635-54, 2011 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-21174434

RESUMO

Herein we chronicle the discovery of CX-4945 (25n), a first-in-class, orally bioavailable ATP-competitive inhibitor of protein kinase CK2 in clinical trials for cancer. CK2 has long been considered a prime cancer drug target because of the roles of deregulated and overexpressed CK2 in cancer-promoting prosurvival and antiapoptotic pathways. These biological properties as well as the suitability of CK2's small ATP binding site for the design of selective inhibitors, led us to fashion novel therapeutic agents for cancer. The optimization leading to 25n (K(i) = 0.38 nM) was guided by molecular modeling, suggesting a strong binding of 25n resulting from a combination of hydrophobic interactions, an ionic bridge with Lys68, and hydrogen bonding with the hinge region. 25n was found to be highly selective, orally bioavailable across species (20-51%) and efficacious in xenograft models. The discovery of 25n will allow the therapeutic targeting of CK2 in humans for the first time.


Assuntos
Antineoplásicos/síntese química , Caseína Quinase II/antagonistas & inibidores , Naftiridinas/síntese química , Trifosfato de Adenosina/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Ligação Competitiva , Disponibilidade Biológica , Linhagem Celular Tumoral , Cães , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Camundongos Endogâmicos ICR , Camundongos Nus , Modelos Moleculares , Naftiridinas/química , Naftiridinas/farmacologia , Transplante de Neoplasias , Fenazinas , Ratos , Relação Estrutura-Atividade , Transplante Heterólogo
12.
Cancer Res ; 71(4): 1418-30, 2011 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-21159662

RESUMO

Deregulated ribosomal RNA synthesis is associated with uncontrolled cancer cell proliferation. RNA polymerase (Pol) I, the multiprotein complex that synthesizes rRNA, is activated widely in cancer. Thus, selective inhibitors of Pol I may offer a general therapeutic strategy to block cancer cell proliferation. Coupling medicinal chemistry efforts to tandem cell- and molecular-based screening led to the design of CX-5461, a potent small-molecule inhibitor of rRNA synthesis in cancer cells. CX-5461 selectively inhibits Pol I-driven transcription relative to Pol II-driven transcription, DNA replication, and protein translation. Molecular studies demonstrate that CX-5461 inhibits the initiation stage of rRNA synthesis and induces both senescence and autophagy, but not apoptosis, through a p53-independent process in solid tumor cell lines. CX-5461 is orally bioavailable and demonstrates in vivo antitumor activity against human solid tumors in murine xenograft models. Our findings position CX-5461 for investigational clinical trials as a potent, selective, and orally administered agent for cancer treatment.


Assuntos
Benzotiazóis/farmacologia , Proliferação de Células/efeitos dos fármacos , Naftiridinas/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , RNA Polimerase I/antagonistas & inibidores , RNA Ribossômico/biossíntese , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Benzotiazóis/administração & dosagem , Benzotiazóis/uso terapêutico , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Células HeLa , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Terapia de Alvo Molecular/métodos , Naftiridinas/administração & dosagem , Naftiridinas/uso terapêutico , Neoplasias/metabolismo , RNA Polimerase I/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Cancer Res ; 70(24): 10288-98, 2010 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-21159648

RESUMO

Malignant transformation and maintenance of the malignant phenotype depends on oncogenic and non-oncogenic proteins that are essential to mediate oncogene signaling and to support the altered physiologic demands induced by transformation. Protein kinase CK2 supports key prosurvival signaling pathways and represents a prototypical non-oncogene. In this study, we describe CX-4945, a potent and selective orally bioavailable small molecule inhibitor of CK2. The antiproliferative activity of CX-4945 against cancer cells correlated with expression levels of the CK2α catalytic subunit. Attenuation of PI3K/Akt signaling by CX-4945 was evidenced by dephosphorylation of Akt on the CK2-specific S129 site and the canonical S473 and T308 regulatory sites. CX-4945 caused cell-cycle arrest and selectively induced apoptosis in cancer cells relative to normal cells. In models of angiogenesis, CX-4945 inhibited human umbilical vein endothelial cell migration, tube formation, and blocked CK2-dependent hypoxia-induced factor 1 alpha (HIF-1α) transcription in cancer cells. When administered orally in murine xenograft models, CX-4945 was well tolerated and demonstrated robust antitumor activity with concomitant reductions of the mechanism-based biomarker phospho-p21 (T145). The observed antiproliferative and anti-angiogenic responses to CX-4945 in tumor cells and endothelial cells collectively illustrate that this compound exerts its antitumor effects through inhibition of CK2-dependent signaling in multiple pathways. Finally, CX-4945 is the first orally bioavailable small molecule inhibitor of CK2 to advance into human clinical trials, thereby paving the way for an entirely new class of targeted treatment for cancer.


Assuntos
Caseína Quinase II/antagonistas & inibidores , Neoplasias Inflamatórias Mamárias/tratamento farmacológico , Naftiridinas/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Linhagem Celular Tumoral , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Feminino , Células HeLa , Humanos , Neoplasias Inflamatórias Mamárias/irrigação sanguínea , Neoplasias Inflamatórias Mamárias/enzimologia , Camundongos , Naftiridinas/farmacocinética , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Neoplasias Pancreáticas/irrigação sanguínea , Neoplasias Pancreáticas/enzimologia , Fenazinas , Inibidores de Proteínas Quinases/farmacocinética , Distribuição Aleatória , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Scand J Psychol ; 51(4): 294-303, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20132455

RESUMO

This study examined the relations of parental permissiveness, authoritativeness, authoritarianism, and nurturance with two dimensions of self-esteem - self-liking and self-competence. In a sample of 207 two-parent families, university students and both their parents provided independent reports on all the above variables. Covariance structure analysis was used to eliminate reporter-specific bias and unreliability in predicting student self-esteem from parenting behavior. The results revealed highly redundant positive associations of mothers' and fathers' authoritativeness and nurturance with both self-liking and self-competence. The pattern of these associations suggests that the significance of parental authoritativeness for the child's self-esteem is due mainly to the nurturance it provides. Contrary to expectation, mothers' and fathers' authoritarianism was also positively associated with self-liking. As discussed, however, this is likely to be an artifact of the specific measures and testing methods used.


Assuntos
Autoritarismo , Relações Pais-Filho , Poder Familiar/psicologia , Desenvolvimento da Personalidade , Autoimagem , Adolescente , Análise de Variância , Feminino , Humanos , Masculino , Modelos Psicológicos , Determinação da Personalidade , Inquéritos e Questionários , Adulto Jovem
15.
Cancer Res ; 69(19): 7653-61, 2009 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-19738048

RESUMO

Hallmark deregulated signaling in cancer cells drives excessive ribosome biogenesis within the nucleolus, which elicits unbridled cell growth and proliferation. The rate-limiting step of ribosome biogenesis is synthesis of rRNA (building blocks of ribosomes) by RNA Polymerase I (Pol I). Numerous kinase pathways and products of proto-oncogenes can up-regulate Pol I, whereas tumor suppressor proteins can inhibit rRNA synthesis. In tumorigenesis, activating mutations in certain cancer-associated kinases and loss-of-function mutations in tumor suppressors lead to deregulated signaling that stimulates Pol I transcription with resultant increases in ribosome biogenesis, protein synthesis, cell growth, and proliferation. Certain anticancer therapeutics, such as cisplatin and 5-fluorouracil, reportedly exert, at least partially, their activity through disruption of ribosome biogenesis, yet many prime targets for anticancer drugs within the ribosome synthetic machinery of the nucleolus remain largely unexploited. Herein, we describe CX-3543, a small molecule nucleolus-targeting agent that selectively disrupts nucleolin/rDNA G-quadruplex complexes in the nucleolus, thereby inhibiting Pol I transcription and inducing apoptosis in cancer cells. CX-3543 is the first G-quadruplex interactive agent to enter human clinical trials, and it is currently under evaluation against carcinoid/neuroendocrine tumors in a phase II clinical trial.


Assuntos
Benzoxazinas/farmacologia , Neoplasias/tratamento farmacológico , Quinolonas/farmacologia , RNA Ribossômico/antagonistas & inibidores , RNA Ribossômico/biossíntese , Animais , Apoptose/efeitos dos fármacos , Benzoxazinas/farmacocinética , Linhagem Celular Tumoral , Nucléolo Celular/efeitos dos fármacos , Nucléolo Celular/metabolismo , DNA Polimerase I/antagonistas & inibidores , DNA Polimerase I/genética , DNA Polimerase I/metabolismo , DNA Topoisomerases Tipo I/metabolismo , DNA Topoisomerases Tipo II/metabolismo , Feminino , Quadruplex G/efeitos dos fármacos , Células HL-60 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Camundongos SCID , Neoplasias/genética , Neoplasias/metabolismo , Fosfoproteínas/antagonistas & inibidores , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Quinolonas/farmacocinética , Proteínas de Ligação a RNA/antagonistas & inibidores , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Telômero/efeitos dos fármacos , Transcrição Gênica/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Nucleolina
16.
Artigo em Inglês | MEDLINE | ID: mdl-19058612

RESUMO

The aims of this study were to determine the types of cancers and hematological disorders in patients attending a pediatric hematology-oncology clinic. This was a prospective study at the Pediatric Institute, General Hospital Kuala Lumpur, Malaysia from June 2005-November 2006. During the 18-month study, 803 patients attended the clinic, 730 had oncological problems and 73 had hematological problems. The age range was from 2 months to 28 years (median 6 years). The patients were Malay (66%), Chinese (23%), Indian (10%) and other races (1%). Of the oncological patients, 51% had either leukemia (n=293) or lymphoma (n=77). The other most common diagnoses were retinoblastoma, followed by Wilm's tumor and germ cell tumors. Six patients (0.8%) developed a second malignant neoplasm. Of the hematological patients, 60% had platelet disorders, most commonly chronic immune thrombocytopenic purpura. Twenty-four per cent had bone marrow failure and 16% had red cell disorders.


Assuntos
Neoplasias Hematológicas/epidemiologia , Neoplasias/epidemiologia , Adolescente , Adulto , Institutos de Câncer , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Malásia/epidemiologia , Masculino , Estudos Prospectivos , Adulto Jovem
17.
Dev Psychol ; 44(2): 507-22, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18331140

RESUMO

Parent and teacher data for 14,990 children from the National Longitudinal Survey of Children and Youth were used in multilevel analyses to examine the relationship between ethnicity, children's aggression and emotional problems, and parenting. Using parent and teacher report, relationships between ethnicity and child behavior were present but modest. The association between parental harshness and child aggression differed between ethnic groups and across informants. Using teacher report of outcomes, parental harshness was positively related to child aggression in European Canadian families but negatively related in South Asian Canadian families. For all ethnic groups, parental harshness was positively related to children's aggression when parent report of outcomes was used, but relationships varied in strength across ethnic groups. The relationship of parental harshness with child emotional problems did not differ across groups, irrespective of informant. The results are discussed within the context of an ecological model of parenting.


Assuntos
Sintomas Afetivos/etnologia , Agressão/psicologia , Povo Asiático/psicologia , Comparação Transcultural , Poder Familiar/etnologia , População Branca/psicologia , Sintomas Afetivos/psicologia , Canadá , Criança , Pré-Escolar , Feminino , Humanos , Estudos Longitudinais , Masculino , Poder Familiar/psicologia
18.
Mol Cancer Ther ; 6(9): 2505-14, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17766839

RESUMO

The phosphatidylinositol 3-kinase (PI3K) pathway is activated in many human tumors and mediates processes such as cell proliferation, survival, adhesion, and motility. The natural product, wortmannin, has been widely used to study the functional consequences of PI3K inhibition in both normal and transformed cells in culture but is not a suitable cancer chemotherapeutic agent due to stability and toxicity issues. PX-866, an improved wortmannin analogue, displays significant antitumor activity in xenograft models. Here, we directly compare PX-866 and wortmannin in human cancer cell lines cultured in monolayer or as three-dimensional spheroids. Both PI3K inhibitors failed to inhibit monolayer cell growth at concentrations up to 100 nmol/L but strongly suppressed spheroid growth at low nanomolar concentrations, with PX-866 showing greater potency than wortmannin. Relative to wortmannin, PX-866 treatment results in a more sustained loss of Akt phosphorylation, suggesting that the increased potency of PX-866 is related to a more durable inhibition of PI3K signaling. PX-866 and wortmannin both inhibit spheroid growth without causing cytotoxicity, similar to known cytostatic agents, such as rapamycin. PX-866 also inhibits cancer cell motility at subnanomolar concentrations. These findings suggest that the antitumor activities of PX-866 stem from prolonged inhibition of the PI3K pathway and inhibition of cell motility. In addition, we propose that the use of three-dimensional tumor models is more predictive of in vivo growth inhibition by PI3K inhibitors in cancer cell lines lacking phosphatase and tensin homologue activity or expression.


Assuntos
Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Gonanos/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Esferoides Celulares/efeitos dos fármacos , Androstadienos/farmacologia , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Neoplasias/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Células Tumorais Cultivadas/efeitos dos fármacos , Wortmanina
19.
J Pediatr Hematol Oncol ; 29(1): 2-4, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17230058

RESUMO

In the last decade, chemotherapy in combination with focal therapy (chemoreduction) has been increasingly used in intraocular retinoblastoma to avoid enucleation and radiotherapy. The aim of this study was to assess the feasibility and outcome of chemoreduction in Malaysian children with retinoblastoma. This was a prospective study from August 2001 to January 2006. Twenty children (25 eyes) were given 4 cycles of chemoreduction, after which the response was assessed. Fourteen eyes showed a complete response, 10 eyes showed a partial response, and 1 eye had progressive disease. Twelve eyes developed progressive disease later, 9 after an initial complete response and 3 after a partial response. Overall, progressive disease occurred in 52%. There were 2 treatment failures, in Reese-Elsworth groups 3 and 4. Both eyes required enucleation. One eye in group 5 required second line chemotherapy to achieve a complete response. No eyes were irradiated. Five children (25%) defaulted follow-up, one of whom returned with disseminated disease. In conclusion, 4 cycles of chemoreduction achieved a durable complete response in only 12% of eyes. Chemoreduction is feasible in Malaysia but requires good patient compliance and close follow-up.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Retina/terapia , Retinoblastoma/terapia , Carboplatina/administração & dosagem , Terapia Combinada , Crioterapia , Intervalo Livre de Doença , Etoposídeo/administração & dosagem , Feminino , Seguimentos , Humanos , Lactente , Terapia a Laser , Malásia , Masculino , Estudos Prospectivos , Retinoblastoma/mortalidade , Vincristina/administração & dosagem
20.
Cancer Genet Cytogenet ; 156(2): 129-33, 2005 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-15642392

RESUMO

Eighty-eight multi-ethnic Malaysian pediatric acute lymphoblastic leukemia (ALL) patients were screened for the TEL-AML1 rearrangement by reverse transcription-polymerase chain reaction (RT-PCR). Fluorescence in situ hybridization (FISH) was used as an independent screen for 30 cases and to confirm RT-PCR positive cases. Seventeen patients, or 19%, were found to be t(12;21) positive. Ethnically the group comprised 12 Malays, 4 Chinese, and 1 Indian. All patients, including 1 with an unusual blast cell morphology who suffered an early relapse and death, were characteristic TEL-AML1 cases in cell count, age, ALL subset classification, and fusion transcript expressed. This study shows that in Malaysia, TEL-AML1 is found in the same distinct ALL subset and at a similar frequency as in other diverse childhood ALL cohorts.


Assuntos
Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Medula Óssea/patologia , Criança , Pré-Escolar , China/etnologia , Subunidade alfa 2 de Fator de Ligação ao Core , Etnicidade/genética , Feminino , Rearranjo Gênico , Humanos , Imunofenotipagem , Índia/etnologia , Malásia , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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