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1.
Prev Sci ; 2022 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-35947281

RESUMO

Although neurobiologic and genetic factors figure prominently in the development of attention deficit/hyperactivity disorder (ADHD), adverse physical health experiences and conditions encountered during childhood may also play a role. Poor health is known to impact the developing brain with potential lifelong implications for behavioral issues. In attempt to better understand the relationship between childhood physical health and the onset and presence of ADHD symptoms, we summarized international peer-reviewed articles documenting relationships between a select group of childhood diseases or health events (e.g., illnesses, injuries, syndromes) and subsequent ADHD outcomes among children ages 0-17 years. Drawing on a larger two-phase systematic review, 57 longitudinal or retrospective observational studies (1978-2021) of childhood allergies, asthma, eczema, head injury, infection, or sleep problems and later ADHD diagnosis or symptomatology were identified and subjected to meta-analysis. Significant associations were documented between childhood head injuries, infections, and sleep problems with both dichotomous and continuous measures of ADHD, and between allergies with dichotomous measures of ADHD. We did not observe significant associations between asthma or eczema with ADHD outcomes. Heterogeneity detected for multiple associations, primarily among continuously measured outcomes, underscores the potential value of future subgroup analyses and individual studies. Collectively, these findings shed light on the importance of physical health in understanding childhood ADHD. Possible etiologic links between physical health factors and ADHD are discussed, as are implications for prevention efforts by providers, systems, and communities.

3.
Emerg Infect Dis ; 27(1)2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33075274

RESUMO

We describe coronavirus disease (COVID-19) among US food manufacturing and agriculture workers and provide updated information on meat and poultry processing workers. Among 742 food and agriculture workplaces in 30 states, 8,978 workers had confirmed COVID-19; 55 workers died. Racial and ethnic minority workers could be disproportionately affected by COVID-19.


Assuntos
Agricultura , COVID-19/epidemiologia , COVID-19/transmissão , Indústria Alimentícia , SARS-CoV-2 , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estados Unidos/epidemiologia , Adulto Jovem
4.
MMWR Morb Mortal Wkly Rep ; 69(12): 335-338, 2020 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-32214081

RESUMO

Cryptosporidium is an enteric pathogen that is transmitted through animal-to-person or person-to-person contact or through ingestion of contaminated water or food. In the United States, Cryptosporidium affects an estimated 750,000 persons each year; however, only approximately 11,000 cases are reported nationally (1,2). Persons infected with Cryptosporidium typically develop symptoms within 2 to 10 days after exposure. Common symptoms include watery diarrhea, abdominal cramps, nausea, vomiting, or fever, which can last 1 to 2 weeks. Cryptosporidiosis is a nationally notifiable disease in the United States. Nebraska presents a unique setting for the evaluation of this pathogen because, compared with other states, Nebraska has a greater reliance on agriculture and a higher proportion of the population residing and working in rural communities. Cryptosporidium species and subtypes are generally indistinguishable using conventional diagnostic methods. Using molecular characterization, Nebraska evaluated the genetic diversity of Cryptosporidium and found a dichotomy in the distribution of cases of cryptosporidiosis caused by Cryptosporidium parvum and Cryptosporidium hominis among rural and urban settings. Characterizing clusters of C. hominis cases revealed that several child care facilities were affected by the same subtype, suggesting community-wide transmission and indicating a need for effective exclusion policies. Several cases of cryptosporidiosis caused by non-C. parvum or non-C. hominis species and genotypes indicated unique animal exposures that were previously unidentified. This study enhanced epidemiologic data by validating known Cryptosporidium sources, confirming outbreaks, and, through repeat interviews, providing additional information to inform cryptosporidiosis prevention and control efforts.


Assuntos
Criptosporidiose/epidemiologia , Criptosporidiose/transmissão , Cryptosporidium/classificação , Cryptosporidium/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Tipagem Molecular , Nebraska/epidemiologia , Fatores de Risco , Adulto Jovem
5.
MMWR Morb Mortal Wkly Rep ; 69(18)2020 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-32379731

RESUMO

Congregate work and residential locations are at increased risk for infectious disease transmission including respiratory illness outbreaks. SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), is primarily spread person to person through respiratory droplets. Nationwide, the meat and poultry processing industry, an essential component of the U.S. food infrastructure, employs approximately 500,000 persons, many of whom work in proximity to other workers (1). Because of reports of initial cases of COVID-19, in some meat processing facilities, states were asked to provide aggregated data concerning the number of meat and poultry processing facilities affected by COVID-19 and the number of workers with COVID-19 in these facilities, including COVID-19-related deaths. Qualitative data gathered by CDC during on-site and remote assessments were analyzed and summarized. During April 9-27, aggregate data on COVID-19 cases among 115 meat or poultry processing facilities in 19 states were reported to CDC. Among these facilities, COVID-19 was diagnosed in 4,913 (approximately 3%) workers, and 20 COVID-19-related deaths were reported. Facility barriers to effective prevention and control of COVID-19 included difficulty distancing workers at least 6 feet (2 meters) from one another (2) and in implementing COVID-19-specific disinfection guidelines.* Among workers, socioeconomic challenges might contribute to working while feeling ill, particularly if there are management practices such as bonuses that incentivize attendance. Methods to decrease transmission within the facility include worker symptom screening programs, policies to discourage working while experiencing symptoms compatible with COVID-19, and social distancing by workers. Source control measures (e.g., the use of cloth face covers) as well as increased disinfection of high-touch surfaces are also important means of preventing SARS-CoV-2 exposure. Mitigation efforts to reduce transmission in the community should also be considered. Many of these measures might also reduce asymptomatic and presymptomatic transmission (3). Implementation of these public health strategies will help protect workers from COVID-19 in this industry and assist in preserving the critical meat and poultry production infrastructure (4).


Assuntos
Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/transmissão , Surtos de Doenças , Indústria de Processamento de Alimentos , Doenças Profissionais/epidemiologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/transmissão , Animais , COVID-19 , Infecções por Coronavirus/prevenção & controle , Surtos de Doenças/prevenção & controle , Humanos , Carne , Doenças Profissionais/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Aves Domésticas , Estados Unidos/epidemiologia
6.
MMWR Morb Mortal Wkly Rep ; 68(7): 169-173, 2019 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-30789878

RESUMO

In March 2017, the Nebraska Department of Health and Human Services (NDHHS) and the Southwest Nebraska Public Health Department were notified of an apparent cluster of Campylobacter jejuni infections in city A and initiated an investigation. Overall, 39 cases were investigated, including six confirmed and 33 probable. Untreated, unboiled city A tap water (i.e., well water) was the only exposure significantly associated with illness (odds ratio [OR] = 7.84; 95% confidence interval [CI] = 1.69-36.36). City A is served by four untreated wells and an interconnected distribution system. Onsite investigations identified that a center pivot irrigation system intended to pump livestock wastewater from a nearby concentrated animal feeding operation onto adjacent farmland had malfunctioned, allowing excessive runoff to collect in a road ditch near two wells that supplied water to the city. These wells were promptly removed from service, after which no subsequent cases occurred. This coordinated response rapidly identified an important risk to city A's municipal water supply and provided the evidence needed to decommission the affected wells, with plans to build a new well to safely serve this community.


Assuntos
Infecções por Campylobacter/epidemiologia , Campylobacter jejuni/isolamento & purificação , Surtos de Doenças , Microbiologia da Água , Abastecimento de Água , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Infecções por Campylobacter/prevenção & controle , Criança , Pré-Escolar , Cidades , Análise por Conglomerados , Surtos de Doenças/prevenção & controle , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Nebraska/epidemiologia , Adulto Jovem
7.
Emerg Infect Dis ; 24(3): 425-431, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29460731

RESUMO

Histoplasmosis is one of the most common mycoses endemic to the United States, but it was reportable in only 10 states during 2016, when a national case definition was approved. To better characterize the epidemiologic features of histoplasmosis, we analyzed deidentified surveillance data for 2011-2014 from the following 12 states: Alabama, Arkansas, Delaware, Illinois, Indiana, Kentucky, Michigan, Minnesota, Mississippi, Nebraska, Pennsylvania, and Wisconsin. We examined epidemiologic and laboratory features and calculated state-specific annual and county-specific mean annual incidence rates. A total of 3,409 cases were reported. Median patient age was 49 (interquartile range 33-61) years, 2,079 (61%) patients were male, 1,273 (57%) patients were hospitalized, and 76 (7%) patients died. Incidence rates varied markedly between and within states. The high hospitalization rate suggests that histoplasmosis surveillance underestimates the true number of cases. Improved surveillance standardization and surveillance by additional states would provide more comprehensive knowledge of histoplasmosis in the United States.


Assuntos
Histoplasma , Histoplasmose/epidemiologia , Histoplasmose/microbiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Geografia Médica , Histoplasmose/história , Histoplasmose/mortalidade , História do Século XXI , Hospitalização , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Vigilância em Saúde Pública , Estados Unidos/epidemiologia , Adulto Jovem
8.
MMWR Morb Mortal Wkly Rep ; 64(47): 1317-8, 2015 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-26632662

RESUMO

Tularemia is a rare, often serious disease caused by a gram-negative coccobacillus, Francisella tularensis, which infects humans and animals in the Northern Hemisphere. Approximately 125 cases have been reported annually in the United States during the last two decades. As of September 30, a total of 100 tularemia cases were reported in 2015 among residents of Colorado (n = 43), Nebraska (n = 21), South Dakota (n = 20), and Wyoming (n = 16) (Figure). This represents a substantial increase in the annual mean number of four (975% increase), seven (200%), seven (186%) and two (70%) cases, respectively, reported in each state during 2004-2014.


Assuntos
Tularemia/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Colorado/epidemiologia , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Nebraska/epidemiologia , South Dakota/epidemiologia , Wyoming/epidemiologia , Adulto Jovem
9.
Pediatr Clin North Am ; 71(3): 469-479, 2024 06.
Artigo em Inglês | MEDLINE | ID: mdl-38754936

RESUMO

This article examines lessons learned from previous pandemics, including the 2009 H1N1 influenza and the coronavirus disease 2019 pandemic. Pediatric providers have a unique and important role and strategies to improve collaboration and communication between public health and pediatric providers are essential during public health emergencies. A robust network of communication channels, effective public health messaging, and pediatric-focused disease related, and program outcome data are key to supporting a coordinated response to future pandemics. Critical issues include real-time communication with and engagement of pediatric providers as well as optimizing best evidence approaches for pediatric care while considering the distinct challenges facing children and their families.


Assuntos
COVID-19 , Saúde da Criança , Pandemias , Pediatria , Saúde Pública , Humanos , COVID-19/prevenção & controle , COVID-19/epidemiologia , Criança , Pandemias/prevenção & controle , Influenza Humana/prevenção & controle , Influenza Humana/epidemiologia , SARS-CoV-2
10.
Am J Public Health ; 103(12): e40-5, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24134344

RESUMO

OBJECTIVES: We measured HIV testing and seropositivity among veterans in Veterans Affairs (VA) care for calendar years 2009 through 2011 and analyzed 2011 results by patient demographics. METHODS: We performed a repeated-measures cross-sectional study using standardized electronic data extraction from the VA electronic health records for all veterans with at least 1 outpatient visit during 2009 through 2011. We analyzed testing rates and seropositivity by demographic characteristics for 2011. RESULTS: Of veterans with an outpatient visit, 20.0% had an HIV test in 2011, compared with 9.2% in 2009. Documented HIV testing rates were highest in women and Blacks. Of confirmed positive test results, 67.0% were in outpatients older than 50 years. Seropositivity was highest among men aged 30 to 49 years, women aged 50 to 69 years, and Black outpatients of both genders. Implementation of an electronic clinical reminder was associated with higher testing rates. CONCLUSIONS: The significant effect of an electronic clinical reminder suggests that such decision support tools can substantially increase testing rates. The frequency of positive test results in older individuals suggests the need for additional work to define optimum approaches to HIV testing in this population.


Assuntos
Soropositividade para HIV/diagnóstico , Programas de Rastreamento/estatística & dados numéricos , United States Department of Veterans Affairs , Adulto , Idoso , Estudos Transversais , Registros Eletrônicos de Saúde/estatística & dados numéricos , Feminino , Soropositividade para HIV/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais , Grupos Raciais , Distribuição por Sexo , Estados Unidos/epidemiologia
14.
J Med Toxicol ; 16(3): 248-254, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32193828

RESUMO

INTRODUCTION: E-cigarette, or vaping, product use associated lung injury (EVALI) has become a recent concern among public health officials. Factors that contribute to the concern include an increasing number of cases over time, the severity of the illness, and an unknown understanding of the pathophysiology and etiology of the illness. CASE SERIES: We cared for three adolescent patients with acute respiratory failure secondary to EVALI. All three patients were treated with high-dose steroids in addition to antimicrobials, which resulted in clinical improvement and resolution of their respiratory failure. Pulmonary function testing was performed on these previously healthy patients both acutely and subacutely. Additionally, we report the results from the laboratory analysis of one vaping device fluid which revealed previously unpublished components within these products. DISCUSSION: EVALI is a recent public health concern without a known etiology which can cause life-threatening lung injury in patients without prior lung pathology. We hope these cases will highlight the importance of return precautions in adolescents with vague respiratory symptoms and provide a cautionary tale to providers while they counsel patients regarding the use of these products.


Assuntos
Vapor do Cigarro Eletrônico/efeitos adversos , Sistemas Eletrônicos de Liberação de Nicotina , Lesão Pulmonar/etiologia , Pulmão/fisiopatologia , Insuficiência Respiratória/etiologia , Vaping/efeitos adversos , Doença Aguda , Adolescente , Fatores Etários , Vapor do Cigarro Eletrônico/análise , Humanos , Pulmão/diagnóstico por imagem , Lesão Pulmonar/diagnóstico por imagem , Lesão Pulmonar/fisiopatologia , Lesão Pulmonar/terapia , Masculino , Recuperação de Função Fisiológica , Insuficiência Respiratória/diagnóstico por imagem , Insuficiência Respiratória/fisiopatologia , Insuficiência Respiratória/terapia , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
15.
Retrovirology ; 6: 76, 2009 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-19674458

RESUMO

The development of novel techniques and systems to study human infectious diseases in both an in vitro and in vivo settings is always in high demand. Ideally, small animal models are the most efficient method of studying human afflictions. This is especially evident in the study of the human retroviruses, HIV-1 and HTLV-1, in that current simian animal models, though robust, are often expensive and difficult to maintain. Over the past two decades, the construction of humanized animal models through the transplantation and engraftment of human tissues or progenitor cells into immunocompromised mouse strains has allowed for the development of a reconstituted human tissue scaffold in a small animal system. The utilization of small animal models for retroviral studies required expansion of the early CB-17 scid/scid mouse resulting in animals demonstrating improved engraftment efficiency and infectivity. The implantation of uneducated human immune cells and associated tissue provided the basis for the SCID-hu Thy/Liv and hu-PBL-SCID models. Engraftment efficiency of these tissues was further improved through the integration of the non-obese diabetic (NOD) mutation leading to the creation of NODSCID, NOD/Shi-scid IL2rgamma-/-, and NOD/SCID beta2-microglobulinnull animals. Further efforts at minimizing the response of the innate murine immune system produced the Rag2-/-gammac-/- model which marked an important advancement in the use of human CD34+ hematopoietic stem cells. Together, these animal models have revolutionized the investigation of retroviral infections in vivo.


Assuntos
Modelos Animais de Doenças , Infecções por Retroviridae , Animais , Proteínas de Ligação a DNA/deficiência , HIV-1/crescimento & desenvolvimento , Vírus Linfotrópico T Tipo 1 Humano/crescimento & desenvolvimento , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID
16.
J Virol ; 82(14): 7155-66, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18480452

RESUMO

The human immunodeficiency virus type 1 (HIV-1) Tat is a 14-kDa viral protein that acts as a potent transactivator by binding to the transactivation-responsive region, a structured RNA element located at the 5' end of all HIV-1 transcripts. Tat transactivates viral gene expression by inducing the phosphorylation of the C-terminal domain of RNA polymerase II through several Tat-activated kinases and by recruiting chromatin-remodeling complexes and histone-modifying enzymes to the HIV-1 long terminal repeat. Histone acetyltransferases, including p300 and hGCN5, not only acetylate histones but also acetylate Tat at lysine positions 50 and 51 in the arginine-rich motif. Acetylated Tat at positions 50 and 51 interacts with a specialized protein module, the bromodomain, and recruits novel factors having this particular domain, such as P/CAF and SWI/SNF. In addition to having its effect on transcription, Tat has been shown to be involved in splicing. In this study, we demonstrate that Tat interacts with cyclin-dependent kinase 13 (CDK13) both in vivo and in vitro. We also found that CDK13 increases HIV-1 mRNA splicing and favors the production of the doubly spliced protein Nef. In addition, we demonstrate that CDK13 acts as a possible restriction factor, in that its overexpression decreases the production of the viral proteins Gag and Env and subsequently suppresses virus production. Using small interfering RNA against CDK13, we show that silencing of CDK13 leads to a significant increase in virus production. Finally, we demonstrate that CDK13 mediates its effect on splicing through the phosphorylation of ASF/SF2.


Assuntos
Proteína Quinase CDC2/metabolismo , HIV-1/crescimento & desenvolvimento , Splicing de RNA , RNA Mensageiro/metabolismo , RNA Viral/metabolismo , Replicação Viral/fisiologia , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo , Células HeLa , Humanos , Imunoprecipitação , Ligação Proteica
17.
Retrovirology ; 5: 40, 2008 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-18498648

RESUMO

BACKGROUND: The rate of transcription of the HIV-1 viral genome is mediated by the interaction of the viral protein Tat with the LTR and other transcriptional machinery. These specific interactions can be affected by the state of post-translational modifications on Tat. Previously, we have shown that Tat can be phosphorylated and acetylated in vivo resulting in an increase in the rate of transcription. In the present study, we investigated whether Tat could be methylated on lysine residues, specifically on lysine 50 and 51, and whether this modification resulted in a decrease of viral transcription from the LTR. RESULTS: We analyzed the association of Tat with histone methyltransferases of the SUV39-family of SET domain containing proteins in vitro. Tat was found to associate with both SETDB1 and SETDB2, two enzymes which exhibit methyltransferase activity. siRNA against SETDB1 transfected into cell systems with both transient and integrated LTR reporter genes resulted in an increase in transcription of the HIV-LTR in the presence of suboptimal levels of Tat. In vitro methylation assays with Tat peptides containing point mutations at lysines 50 and 51 showed an increased incorporation of methyl groups on lysine 51, however, both residues indicated susceptibility for methylation. CONCLUSION: The association of Tat with histone methyltransferases and the ability for Tat to be methylated suggests an interesting mechanism of transcriptional regulation through the recruitment of chromatin remodeling proteins to the HIV-1 promoter.


Assuntos
Repetição Terminal Longa de HIV , HIV-1/fisiologia , Lisina/metabolismo , Proteínas Metiltransferases/metabolismo , Transcrição Gênica , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo , Linhagem Celular , Genes Reporter , HIV-1/genética , Histona-Lisina N-Metiltransferase , Humanos , Lisina/genética , Metilação , Ligação Proteica , Proteínas Metiltransferases/química , Proteínas Metiltransferases/genética , Processamento de Proteína Pós-Traducional , Estrutura Terciária de Proteína , RNA Interferente Pequeno/genética , Ativação Transcricional , Ativação Viral , Produtos do Gene tat do Vírus da Imunodeficiência Humana/química , Produtos do Gene tat do Vírus da Imunodeficiência Humana/genética
18.
Virol J ; 5: 41, 2008 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-18348731

RESUMO

It has been demonstrated that the p53 pathway plays an important role in HIV-1 infection. Previous work from our lab has established a model demonstrating how p53 could become inactivated in HIV-1 infected cells through binding to Tat. Subsequently, p53 was inactivated and lost its ability to transactivate its downstream target gene p21/waf1. P21/waf1 is a well-known cdk inhibitor (CKI) that can lead to cell cycle arrest upon DNA damage. Most recently, the p21/waf1 function was further investigated as a molecular barrier for HIV-1 infection of stem cells. Therefore, we reason that the restoration of the p53 and p21/waf1 pathways could be a possible theraputical arsenal for combating HIV-1 infection. In this current study, we show that a small chemical molecule, 9-aminoacridine (9AA) at low concentrations, could efficiently reactivate p53 pathway and thereby restoring the p21/waf1 function. Further, we show that the 9AA could significantly inhibit virus replication in activated PBMCs, likely through a mechanism of inhibiting the viral replication machinery. A mechanism study reveals that the phosphorylated p53ser15 may be dissociated from binding to HIV-1 Tat protein, thereby activating the p21/waf1 gene. Finally, we also show that the 9AA-activated p21/waf1 is recruited to HIV-1 preintegration complex, through a mechanism yet to be elucidated.


Assuntos
Aminacrina/farmacologia , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , HIV-1/efeitos dos fármacos , Antivirais/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , HIV-1/fisiologia , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/virologia , Fosforilação , Transcrição Reversa/efeitos dos fármacos , Transdução de Sinais , Linfócitos T/efeitos dos fármacos , Linfócitos T/virologia , Proteína Supressora de Tumor p53/metabolismo , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo
19.
AIDS Res Ther ; 5: 12, 2008 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-18544167

RESUMO

Human T-cell leukemia virus type-1 (HTLV-1) induces adult T-cell leukemia/lymphoma (ATL/L), a fatal lymphoproliferative disorder, and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a chronic progressive disease of the central nervous system after a long period of latent infection. Although the mechanism of transformation and leukemogenesis is not fully elucidated, there is evidence to suggest that the viral oncoprotein Tax plays a crucial role in these processes through the regulation of several pathways including NF-kappaB and the cell cycle pathways. The observation that NF-kappaB, which is strongly induced by Tax, is indispensable for the maintenance of the malignant phenotype of HTLV-1 by regulating the expression of various genes involved in cell cycle regulation and inhibition of apoptosis provides a possible molecular target for these infected cells. To develop potential new therapeutic strategies for HTLV-1 infected cells, in this present study, we initially screened a battery of NF-kappaB and CDK inhibitors (total of 35 compounds) to examine their effects on the growth and survival of infected T-cell lines. Two drugs namely BMS-345541 and Purvalanol A exhibited higher levels of growth inhibition and apoptosis in infected cell as compared to uninfected cells. BMS-345541 inhibited IKKbeta kinase activity from HTLV-1 infected cells with an IC50 (the 50% of inhibitory concentration) value of 50 nM compared to 500 nM from control cells as measured by in vitro kinase assays. The effects of Purvalanol A were associated with suppression of CDK2/cyclin E complex activity as previously shown by us. Combination of both BMS-345541 and Purvalanol A showed a reduced level of HTLV-1 p19 Gag production in cell culture. The apparent apoptosis in these infected cells were associated with increased caspase-3 activity and PARP cleavage. The potent and selective apoptotic effects of these drugs suggest that both BMS-345541 and Purvalanol A, which target both NF-kappaB and CDK complex and the G1/S border, might be promising new agents in the treatment of these infected patients.

20.
PLoS One ; 5(6): e11379, 2010 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-20614009

RESUMO

BACKGROUND: Approximately half of hereditary breast cancers have mutations in either BRCA1 or BRCA2. BRCA1 is a multifaceted tumor suppressor protein that has implications in processes such as cell cycle, transcription, DNA damage response and chromatin remodeling. This multifunctional nature of BRCA1 is achieved by exerting its many effects through modulation of transcription. Many cellular events are dictated by covalent modification of proteins, an important mechanism in regulating protein and genome function; of which protein methylation is an important posttranslational modification with activating or repressive effects. METHODS/PRINCIPAL FINDINGS: Here we demonstrate for the first time that BRCA1 is methylated both in breast cancer cell lines and breast cancer tumor samples at arginine and lysine residues through immunoprecipitation and western blot analysis. Arginine methylation by PRMT1 was observed in vitro and the region of BRCA1 504-802 shown to be highly methylated. PRMT1 was detected in complex with BRCA1 504-802 through in vitro binding assays and co-immunoprecipitated with BRCA1. Inhibition of methylation resulted in decreased BRCA1 methylation and alteration of BRCA1 binding to promoters in vivo as shown through chromatin immunoprecipitation assays. Knockdown of PRMT1 also resulted in increased BRCA1 binding to particular promoters in vivo. Finally, following methylation inhibition, Sp1 was found to preferentially associate with hypo-methylated BRCA1 and STAT1 was found to preferentially associate with hyper-methylated BRCA1. CONCLUSIONS/SIGNIFICANCE: These results suggest that methylation may influence either the ability of BRCA1 to bind to specific promoters or protein-protein interactions which alters the recruitment of BRCA1 to these promoters. Thus, given the importance of BRCA1 to genomic stability, methylation of BRCA1 may ultimately affect the tumor suppressor ability of BRCA1.


Assuntos
Proteína BRCA1/metabolismo , Neoplasias da Mama/metabolismo , Proteína BRCA1/fisiologia , Western Blotting , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Imunoprecipitação , Metilação , Regiões Promotoras Genéticas , Proteína-Arginina N-Metiltransferases/metabolismo , Proteínas Repressoras/metabolismo
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