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1.
Epidemiol Infect ; 144(5): 1010-3, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25170765

RESUMO

Chagas disease is an important emerging disease in Texas that results in cardiomyopathy in about 30% of those infected with the parasite Trypanosoma cruzi. Between the years 2008 and 2012, about 1/6500 blood donors were T. cruzi antibody-confirmed positive. We found older persons and minority populations, particularly Hispanic, at highest risk for screening positive for T. cruzi antibodies during routine blood donation. Zip code analysis determined that T. cruzi is associated with poverty. Chagas disease has a significant disease burden and is a cause of substantial economic losses in Texas.


Assuntos
Doadores de Sangue/estatística & dados numéricos , Doença de Chagas/epidemiologia , Programas de Rastreamento , Trypanosoma cruzi/isolamento & purificação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antiprotozoários/sangue , Doença de Chagas/parasitologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Estudos Soroepidemiológicos , Fatores Socioeconômicos , Texas/epidemiologia , Adulto Jovem
2.
J Helminthol ; 89(5): 540-4, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25850789

RESUMO

Approximately 440 million people globally are afflicted by hookworm disease, one of the 17 WHO-recognized neglected tropical diseases (NTDs). The iron-deficiency anaemia attributed to this disease contributes to at least 3.2 million disability-adjusted life years (DALYs) according to the Global Burden of Disease Study 2010. The current WHO-recommended control strategies rely primarily on mass drug administration or preventive chemotherapy. However, evidence is starting to accumulate confirming that preventive chemotherapy alone will not be sufficient to reduce the reinfection rates of hookworm, especially in areas of heavy transmission. The global health and research community is currently building a consensus stressing the need for the advancement of research and innovation to bridge the gaps and identify new public health interventions for diseases such as hookworm and other NTDs. This paper presents the strategies used by the Sabin Vaccine Institute Product Development Partnership (Sabin PDP) in their ongoing endeavour for the development of a human hookworm vaccine. Recent updates and the current prospects for success of an effective human hookworm vaccine, as a new technology to be linked to or combined with drug interventions, are presented.


Assuntos
Ancylostomatoidea/imunologia , Infecções por Uncinaria/prevenção & controle , Vacinas/administração & dosagem , Animais , Infecções por Uncinaria/imunologia , Infecções por Uncinaria/parasitologia , Humanos , Doenças Negligenciadas/imunologia , Doenças Negligenciadas/parasitologia , Doenças Negligenciadas/prevenção & controle , Vacinação , Vacinas/genética , Vacinas/imunologia
3.
Parasite Immunol ; 36(12): 708-12, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25040249

RESUMO

Chagas disease (American trypanosomiasis caused by Trypanosoma cruzi) is one of the most important neglected tropical diseases in the Western Hemisphere. The toxicities and limited efficacies of current antitrypanosomal drugs have prompted a search for alternative technologies such as a therapeutic vaccine comprised of T. cruzi antigens, including a recombinant antigen encoding the N-terminal 65 kDa portion of Trypomastigote surface antigen-1 (TSA-1). With at least six known genetically distinct T. cruzi lineages, variability between the different lineages poses a unique challenge for the development of broadly effective therapeutic vaccine. The variability across the major lineages in the current vaccine candidate antigen TSA-1 has not previously been addressed. To assess the variation in TSA-1, we cloned and sequenced TSA-1 from several different T. cruzi strains representing three of the most clinically relevant lineages. Analysis of the different alleles showed limited variation in TSA-1 across the different strains and fit with the current theory for the evolution of the different lineages. Additionally, minimal variation in known antigenic epitopes for the HLA-A 02 allele suggests that interlineage variation in TSA-1 would not impair the range and efficacy of a vaccine containing TSA-1.


Assuntos
Variação Antigênica , Doença de Chagas/prevenção & controle , Vacinas Protozoárias/imunologia , Trypanosoma cruzi , Doença de Chagas/imunologia , Epitopos/imunologia , Humanos , Vacinas Protozoárias/química , Glicoproteínas Variantes de Superfície de Trypanosoma/imunologia
4.
Infect Immun ; 80(4): 1606-14, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22311924

RESUMO

Vaccines have been at the forefront of global research efforts to combat malaria, yet despite several vaccine candidates, this goal has yet to be realized. A potentially effective approach to disrupting the spread of malaria is the use of transmission-blocking vaccines (TBV), which prevent the development of malarial parasites within their mosquito vector, thereby abrogating the cascade of secondary infections in humans. Since malaria is transmitted to human hosts by the bite of an obligate insect vector, mosquito species in the genus Anopheles, targeting mosquito midgut antigens that serve as ligands for Plasmodium parasites represents a promising approach to breaking the transmission cycle. The midgut-specific anopheline alanyl aminopeptidase N (AnAPN1) is highly conserved across Anopheles vectors and is a putative ligand for Plasmodium ookinete invasion. We have developed a scalable, high-yield Escherichia coli expression and purification platform for the recombinant AnAPN1 TBV antigen and report on its marked vaccine potency and immunogenicity, its capacity for eliciting transmission-blocking antibodies, and its apparent lack of immunization-associated histopathologies in a small-animal model.


Assuntos
Anticorpos/imunologia , Antígenos CD13/imunologia , Insetos Vetores/enzimologia , Vacinas Antimaláricas/imunologia , Plasmodium vivax/imunologia , Animais , Anopheles/enzimologia , Anopheles/imunologia , Anopheles/parasitologia , Feminino , Humanos , Insetos Vetores/imunologia , Insetos Vetores/parasitologia , Malária/imunologia , Malária/prevenção & controle , Malária/transmissão , Camundongos , Camundongos Endogâmicos BALB C , Plasmodium berghei/imunologia , Vacinas Sintéticas/imunologia
5.
Parasite Immunol ; 34(8-9): 404-11, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22651670

RESUMO

Na-ASP-2 is a major protein secreted by infective third-stage larvae (L3) of the human hookworm Necator americanus upon host entry. It was chosen as a lead vaccine candidate for its ability to elicit protective immune responses. However, clinical development of this antigen as a recombinant vaccine was halted because it caused allergic reactions among some of human volunteers previously infected with N. americanus. To prevent IgE-mediated allergic reactions induced by Na-ASP-2 but keep its immunogenicity as a vaccine antigen, we designed and tested a genetically engineered fusion protein, Fcγ/Na-ASP-2, composed of full-length Na-ASP-2 and truncated human IgG Fcγ1 that targets the negative signalling receptor FcγRIIb expressed on pro-allergic cells. The chimeric recombinant Fcγ/Na-ASP-2 protein was expressed in Pichia pastoris and shared the similar antigenicity as native Na-ASP-2. Compared to Na-ASP-2, the chimeric fusion protein efficiently reduced the release of histamine in human basophils sensitized with anti-Na-ASP-2 IgE obtained from individuals living in a hookworm-endemic area. In dogs infected with canine hookworm, Fcγ/Na-ASP-2 resulted in significantly reduced immediate-type skin reactivity when injected intradermally compared with Na-ASP-2. Hamsters vaccinated with Fcγ/Na-ASP-2 formulated with Alhydrogel(®) produced specific IgG that recognized Na-ASP-2 and elicited similar protection level against N. americanus L3 challenge as native Na-ASP-2.


Assuntos
Basófilos/imunologia , Liberação de Histamina , Imunização , Imunoglobulina E/imunologia , Fragmentos Fc das Imunoglobulinas/imunologia , Necator americanus/imunologia , Vacinação/métodos , Animais , Antígenos de Helmintos/genética , Antígenos de Helmintos/imunologia , Cricetinae , Cães , Expressão Gênica , Humanos , Hipersensibilidade/prevenção & controle , Fragmentos Fc das Imunoglobulinas/genética , Imunoglobulinas , Pichia/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Pele/patologia , Vacinação/efeitos adversos
6.
Trends Cell Biol ; 7(9): 348-52, 1997 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17708979

RESUMO

Most cell types require both mitogenic growth factors and cell adhesion to the extracellular matrix (ECM) for proliferation. Over the past few years, these growth requirements have received renewed attention and can now be explained by studies showing that signals provided by growth factors and the ECM are jointly required to stimulate the cyclin-dependent kinases (CDKs) that mediate cell-cycle progression through G1 phase. This article summarizes our current understanding of the control of G1 cyclins and CDK inhibitors by growth factors and the ECM. In addition, we have highlighted one or two signal-transduction pathways that presently seem closely linked to regulation of the G1 phase cyclin-CDK system.

7.
J Cell Biol ; 146(6): 1255-64, 1999 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-10491389

RESUMO

We have examined the regulation of p21(cip1) by soluble mitogens and cell anchorage as well as the relationship between the expression of p21(cip1) and activation of the ERK subfamily of MAP kinases. We find that p21(cip1) expression in G1 phase can be divided into two discrete phases: an initial induction that requires growth factors and the activation of ERK, and then a subsequent decline that is enhanced by cell anchorage in an ERK-independent manner. In contrast to the induction of cyclin D1, the induction of p21(cip1) is mediated by transient ERK activity. Comparative studies with wild-type and p21(cip1)-null fibroblasts indicate that adhesion-dependent regulation of p21(cip1) is important for proper control of cyclin E-cdk2 activity. These data lead to a model in which mitogens and anchorage act in a parallel fashion to regulate G1 phase expression of p21(cip1). They also show that (a) growth factors and growth factor/extracellular matrix cooperation can have different roles in regulating G1 phase ERK activity and (b) both transient and sustained ERK signals have functionally significant roles in controlling cell cycle progression through G1 phase.


Assuntos
Quinases relacionadas a CDC2 e CDC28 , Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Ciclinas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Matriz Extracelular/metabolismo , Fase G1/efeitos dos fármacos , Substâncias de Crescimento/farmacologia , Regulação para Cima/efeitos dos fármacos , Animais , Proteínas Quinases Dependentes de Cálcio-Calmodulina/antagonistas & inibidores , Adesão Celular/fisiologia , Linhagem Celular , Ciclina D1/metabolismo , Ciclina E/metabolismo , Quinase 2 Dependente de Ciclina , Inibidor de Quinase Dependente de Ciclina p21 , Quinases Ciclina-Dependentes/metabolismo , Ciclinas/genética , Ativação Enzimática/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/enzimologia , Fibroblastos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mitógenos/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos
8.
Vaccine ; 37(43): 6500-6509, 2019 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-31515141

RESUMO

BACKGROUND: Schistosomiasis caused by Schistosoma mansoni (Sm) is a chronic, debilitating and potentially deadly neglected tropical disease. The licensure of a vaccine to prevent schistosomiasis would represent a major breakthrough in public health. METHODS: The safety and immunogenicity of a candidate Sm vaccine were assessed in this phase I, double-blind, dose-escalation trial. Seventy-two healthy Sm-naïve 18-50 year olds were randomized to receive 3 doses ∼ 8 weeks apart of saline placebo, or 10 µg, 30 µg, or 100 µg of recombinant Sm-Tetraspanin-2 vaccine formulated on aluminum hydroxide adjuvant (Sm-TSP-2/Al) with or without 5 µg of glucopyranosyl lipid A aqueous formulation (GLA-AF). Clinical and serologic responses were assessed for 1 year after dose 3. RESULTS: Vaccines were safe and well-tolerated. The most common reactions were injection site tenderness and pain, and headache and fatigue. Tenderness and pain were more frequent in groups receiving vaccine with GLA-AF than placebo (p = 0.0036 and p = 0.0014, respectively). Injection site reactions among those given Sm-TSP-2/Al with GLA-AF lasted 1.22 and 1.33 days longer than those receiving Sm-TSP-2/Al without GLA-AF or placebo (p < 0.001 for both). Dose- and adjuvant-related increases in serum IgG against Sm-TSP-2 were observed. Peak IgG levels occurred 14 days after dose 3. Seroresponse frequencies were low among recipients of Sm-TSP-2/Al without GLA-AF, but higher among subjects receiving 30 µg or 100 µg of Sm-TSP-2/Al with GLA-AF. More seroresponses were observed among those given 30 µg or 100 µg of Sm-TSP-2/Al with GLA-AF compared to placebo (p = 0.023 and p < 0.001, respectively). Seroresponse frequencies were 0%, 30%, 50%, and 89%, respectively, among those given placebo, or 10 µg, 30 µg or 100 µg of Sm-TSP-2/Al with GLA-AF, suggesting a dose-response relationship for Sm-TSP-2/Al with GLA-AF (p = 0.0001). CONCLUSIONS: Sm-TSP-2/Al with or without GLA-AF was safe and well tolerated in a Sm-naïve population. A vaccine like the one under development may represent our best hope to eliminating this neglected tropical disease.


Assuntos
Anticorpos Anti-Helmínticos/sangue , Glucosídeos/imunologia , Imunogenicidade da Vacina , Lipídeo A/imunologia , Esquistossomose/prevenção & controle , Vacinas/imunologia , Adjuvantes Imunológicos/administração & dosagem , Adolescente , Adulto , Animais , Antígenos de Helmintos/imunologia , Estudos de Coortes , Citocinas/imunologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Schistosoma mansoni , Vacinas/efeitos adversos , Adulto Jovem
9.
Oncogene ; 26(35): 5060-9, 2007 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-17334399

RESUMO

The inheritance of one defective BRCA1 or BRCA2 allele predisposes an individual to developing breast and ovarian cancers. BRCA1 is a multifunctional tumor suppressor protein, which through interaction with a vast array of proteins has implications in processes such as cell cycle, transcription, DNA damage response and chromatin remodeling. Conversely, the oncogene, cyclin D1 is overexpressed in about 35% of all breast cancer cases. In this study, we provide detailed analyses on the phosphorylation state of BRCA1 by cyclin D1/cdk4 complexes. In particular, we have identified Ser 632 of BRCA1 as a cyclin D1/cdk4 phosphorylation site in vitro. Using chromatin immunoprecipitation assays, we observed that the inhibition of cyclin D1/cdk4 activity resulted in increased BRCA1 DNA binding at particular promoters in vivo. In addition, we identified multiple novel genes that are bound by BRCA1 in vivo. Collectively, these results indicate that cyclin D1/cdk4-mediated phosphorylation of BRCA1 inhibits the ability of BRCA1 to be recruited to particular promoters in vivo. Therefore, cyclin D1/Cdk4 phosphorylation of BRCA1 could provide a mechanism to interfere with the DNA-dependent activities of BRCA1.


Assuntos
Proteína BRCA1/metabolismo , Neoplasias da Mama/metabolismo , Ciclina D1/metabolismo , Sequência de Aminoácidos , Proteína BRCA1/análise , Neoplasias da Mama/química , Neoplasias da Mama/genética , Ciclo Celular , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Ciclina D1/análise , Quinase 4 Dependente de Ciclina/metabolismo , DNA/metabolismo , Fase G1 , Regulação Neoplásica da Expressão Gênica , Humanos , Dados de Sequência Molecular , Fosforilação , Regiões Promotoras Genéticas , Fase de Repouso do Ciclo Celular
10.
Mol Cell Biol ; 21(22): 7607-16, 2001 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11604497

RESUMO

Soluble mitogens and adhesion-dependent organization of the actin cytoskeleton are required for cells to enter S phase in fibroblasts. The induction of cyclin A is also required for S-phase entry, and we now report that distinct effects of mitogens and the actin cytoskeleton on the phosphorylation of CREB and pocket proteins regulate the extent and timing of cyclin A promoter activity, respectively. First, we show that CREB phosphorylation and binding to the cyclic AMP response element (CRE) determines the extent, but not the timing, of cyclin A promoter activity. Second, we show that pocket protein inactivation regulates the timing, but not the extent, of cyclin A promoter activity. CREB phosphorylation and CRE occupancy are regulated by soluble mitogens alone, while the phosphorylation of pocket proteins requires both mitogens and the organized actin cytoskeleton. Mechanistically, cytoskeletal integrity controls pocket protein phosphorylation by allowing for sustained ERK signaling and, thereby, the expression of cyclin D1. Our results lead to a model of cyclin A gene regulation in which mitogens play a permissive role by stimulating early G(1)-phase phosphorylation of CREB and a distinct regulatory role by cooperating with the organized actin cytoskeleton to regulate the duration of ERK signaling, the expression of cyclin D1, and the timing of pocket protein phosphorylation.


Assuntos
Actinas/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Ciclina A/genética , Citocalasina D/farmacologia , Citoesqueleto/metabolismo , Mitógenos/farmacologia , Proteínas Nucleares/metabolismo , Regiões Promotoras Genéticas , Proteína do Retinoblastoma/metabolismo , Células 3T3 , Animais , Linhagem Celular , Citoesqueleto/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases , Camundongos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Fosforilação , Proteína p107 Retinoblastoma-Like , Fatores de Tempo , Transcrição Gênica
11.
Mol Biol Cell ; 10(10): 3197-204, 1999 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-10512860

RESUMO

Cyclin D1 expression is jointly regulated by growth factors and cell adhesion to the extracellular matrix in many cell types. Growth factors are thought to regulate cyclin D1 expression because they stimulate sustained extracellular signal-regulated kinase (ERK) activity. However, we show here that growth factors induce transient ERK activity when added to suspended fibroblasts and sustained ERK activity only when added to adherent fibroblasts. Cell attachment to fibronectin or anti-alpha5beta1 integrin is sufficient to sustain the ERK signal and to induce cyclin D1 in growth factor-treated cells. Moreover, when we force the sustained activation of ERK, by conditional expression of a constitutively active MAP kinase/ERK kinase, we overcome the adhesion requirement for expression of cyclin D1. Thus, at least in part, fibroblasts are mitogen and anchorage dependent, because integrin action allows for a sustained ERK signal and the expression of cyclin D1 in growth factor-treated cells.


Assuntos
Ciclina D1/metabolismo , Substâncias de Crescimento/farmacologia , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Receptores de Fibronectina/metabolismo , Células 3T3 , Animais , Adesão Celular , Ciclo Celular , Divisão Celular , Ativação Enzimática , Matriz Extracelular/metabolismo , Fibronectinas/metabolismo , Imunofluorescência , Humanos , Camundongos , Fosforilação , Receptores Proteína Tirosina Quinases/metabolismo , Transfecção
14.
Oncogene ; 8(3): 731-6, 1993 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-8437856

RESUMO

Leukemogenesis is a complex process involving an accumulation of genetic lesions affecting both growth and differentiation in cells of the hematopoietic lineage. Our laboratory has established a non-producer v-myb-transformed cell line (BM2/C3A) which, when injected into the chicken embryo, does not produce leukemia. Recently, a spontaneous variant of this cell line, called BM2L, was obtained from in vivo experiments. BM2L produces an acute monoblastic leukemia when injected into the chicken embryo. BM2L cells do not differentiate in vivo or in vitro, but continue to proliferate under conditions in culture that allow for the differentiation of BM2/C3A cells into macrophages. In addition, BM2L cells have reduced requirements for exogenous growth factors. BM2L cells contain the v-myb allele and express v-Myb protein, but leukemogenicity does not involve point mutations in v-myb. The BM2 model, consisting of two non-producer cell lines differing in vivo in their leukemogenicity, provides a novel system for identifying genes that play a role in the induction or suppression of leukemogenesis.


Assuntos
Transformação Celular Neoplásica , Leucemia Monocítica Aguda/genética , Oncogenes , Proteínas Oncogênicas de Retroviridae/genética , Alelos , Animais , Sequência de Bases , Adesão Celular , Diferenciação Celular , Linhagem Celular Transformada , Embrião de Galinha , Leucemia Monocítica Aguda/etiologia , Dados de Sequência Molecular , Proteínas Oncogênicas v-myb , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-myb
15.
DNA Cell Biol ; 14(8): 701-7, 1995 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-7646817

RESUMO

Although the ski oncogene plays a role in cell proliferation, morphological transformation, and myogenic differentiation, the myogenic activities of the proto-oncogene c-ski have yet to be elucidated. c-ski is expressed within myoblasts during embryogenesis. Transcripts from the proto-oncogene can be detected in somites early in myogenic commitment, as well as in terminally differentiated skeletal muscle. However, c-ski mRNAs expressed in cells of the myogenic lineage are indistinguishable from c-ski transcripts in other cell types, raising the possibility that muscle-specific c-ski transcripts are expressed transiently. Avian cell lines QM7 and QM5 were used as a model to analyze changes in expression and alternative exon usage of c-ski during synchronous muscle differentiation. Upon serum deprivation, QM7 cells undergo myogenic differentiation. In contrast, QM5 cells cease proliferation but do not differentiate. Results show that levels of expression and alternative splicing of c-ski transcripts remain unchanged during cell cycle arrest or myogenic differentiation.


Assuntos
Ciclo Celular , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica , Músculos/citologia , Proteínas Proto-Oncogênicas/genética , Proto-Oncogenes/genética , Processamento Alternativo , Animais , Sequência de Bases , Diferenciação Celular , Divisão Celular , Linhagem Celular , Éxons/genética , Dados de Sequência Molecular , Codorniz , RNA Mensageiro/análise , RNA Mensageiro/genética
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