RESUMO
ABSTRACTObjective: Cases of discrimination and hate crimes against Asian Americans have surged ever since the beginning of the COVID-19 pandemic, with deleterious effects. This scoping review synthesizes the literature on how pandemic-related discrimination is associated with the health of Asian Americans.Design: First, application search terms were entered into selected databases. Next, using a set of inclusion criteria, the articles were screened and assessed for eligibility. Data from the selected articles were extracted and summarized to answer the research questions.Results: Thirty-five studies were included. Almost all the studies examined psychological well-being. The remaining studies examined physical and workplace well-being. All the studies found that discrimination was associated with poorer health outcomes.Conclusion: Further research is needed to address the gaps in knowledge about how pandemic-related discrimination is associated with various domains of health among Asian Americans.
Assuntos
COVID-19 , Racismo , Humanos , Racismo/psicologia , COVID-19/epidemiologia , Asiático , PandemiasRESUMO
The purpose of this scoping review is to synthesize knowledge about medical mistrust and health among women who occupy other marginalized identities; namely women who also belong to one or more of the following social groups: people of color, people of low socioeconomic status, people with disabilities, lesbian and bisexual women, and/or women who have sex with women. This scoping review is based on the methodological framework by Arksey and O'Malley (2005. "Scoping Studies: Towards a Methodological Framework." International Journal of Social Research Methodology 8: 19-32. doi:10.1080/1364557032000119616). Specific search terms were entered into selected databases. Based on a set of inclusion criteria, articles were screened and assessed for eligibility. Data from the selected articles were extracted and summarized. Forty studies were included. Thirty-one studies used quantitative methodology, of which more than half used the Group-Based Medical Mistrust Scale. The majority of studies (84%) investigated the intersection of gender with race and ethnicity. Breast cancer and HIV combined accounted for more than half of the included studies. Of those studies that examined the relationship between medical mistrust and a health outcome or health behavior, almost all reported that medical mistrust had a deleterious impact. Medical mistrust among women with intersecting marginalized identities is worthy of further study, and there is still a dearth of knowledge in the role of medical mistrust among a wide range of subgroups of women and health domains.
Assuntos
Minorias Sexuais e de Gênero , Confiança , Humanos , Feminino , Etnicidade , Projetos de PesquisaRESUMO
Neurofibromatosis type 1 (NF1) gene mutations or alterations occur within neurofibromatosis type 1 as well as in many different malignant tumours on the somatic level. In glioblastoma, NF1 loss of function plays a major role in inducing the mesenchymal (MES) subtype and, therefore defining the most aggressive glioblastoma. This is associated with an immune signature and mediated via the NF1-MAPK-FOSL1 axis. Specifically, increased invasion seems to be regulated via mutations in the leucine-rich domain (LRD) of the NF1 gene product neurofibromin. Novel targets for therapy may arise from neurofibromin deficiency-associated cellular mechanisms that are summarised in this review.
Assuntos
Genes da Neurofibromatose 1 , Glioblastoma/genética , Mutação/genética , Neurofibromatose 1/genética , Animais , Humanos , Mesoderma/patologia , Modelos BiológicosRESUMO
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death in the world. The multikinase inhibitor sorafenib only demonstrated marginal improvement in overall survival for advanced disease prompted the search for alternative treatment options. Human mesenchymal stem cells (MSCs) have the ability to home to tumor cells. However, its functional roles on the tumor microenvironment remain controversial. Herein, we showed that conditioned media derived from human fetal MSC (CM-hfMSCs) expressed high level of the insulin growth factor binding proteins IGFBPs and can sequester free insulin-like growth factors (IGFs) to inhibit HCC cell proliferation. The inhibitory effect of IGFBPs on IGF signaling was further evident from the reduction of activated IGF-1R and PI3K/Akt, leading eventually to the induction of cell cycle arrest. We also demonstrated that CM-hfMSCs could enhance the therapeutic efficacy of sorafenib and sunitinib. To the best of our knowledge, this is the first report to show that CM-hfMSCs has a tumor-specific, antiproliferative effect that is not observed with normal human hepatocyte cells and patient-derived matched normal tissues. Our results thus suggest that CM-hfMSCs can provide a useful tool to design alternative/adjuvant treatment strategies for HCC, especially in related function to potentiate the effects of chemotherapeutic drugs.
Assuntos
Carcinoma Hepatocelular/patologia , Feto/citologia , Neoplasias Hepáticas/patologia , Células-Tronco Mesenquimais/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais , Carcinoma Hepatocelular/tratamento farmacológico , Proliferação de Células , Meios de Cultivo Condicionados , Técnicas de Silenciamento de Genes , Humanos , Indóis/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Niacinamida/análogos & derivados , Niacinamida/uso terapêutico , Compostos de Fenilureia/uso terapêutico , Pirróis/uso terapêutico , Receptor IGF Tipo 1/genética , Sorafenibe , SunitinibeRESUMO
BACKGROUND: The treatment of glioblastoma multiforme (GBM) is an unmet clinical need. The 5-year survival rate of patients with GBM is less than 3%. Temozolomide (TMZ) remains the standard first-line treatment regimen for gliomas despite the fact that more than 90% of recurrent gliomas do not respond to TMZ after repeated exposure. We have also independently shown that many of the Asian-derived glioma cell lines and primary cells derived from Singaporean high-grade glioma patients are indeed resistant to TMZ. This issue highlights the need to develop new effective anti-cancer treatment strategies. In a recent study, wild-type epidermal growth factor receptor (wtEGFR) has been shown to phosphorylate a truncated EGFR (known as EGFRvIII), leading to the phosphorylation of STAT proteins and progression in gliomagenesis. Despite the fact that combination of EGFR targeting drugs and rapamycin has been used before, the effect of mono-treatment of Nimotuzumab, rapamycin and combination therapy in human glioma expressing different types of EGFR is not well-studied. Herein, we evaluated the efficacy of dual blockage using monoclonal antibody against EGFR (Nimotuzumab) and an mTOR inhibitor (rapamycin) in Caucasian patient-derived human glioma cell lines, Asian patient-derived human glioma cell lines, primary glioma cells derived from the Mayo GBM xenografts, and primary short-term glioma culture derived from high-grade glioma patients. METHODS: The combination effect of Nimotuzumab and rapamycin was examined in a series of primary human glioma cell lines and glioma cell lines. The cell viability was compared to TMZ treatment alone. Endogenous expressions of EGFR in various GBM cells were determined by western blotting. RESULTS: The results showed that combination of Nimotuzumab with rapamycin significantly enhanced the therapeutic efficacy of human glioma cells compared to single treatment. More importantly, many of the Asian patient-derived glioma cell lines and primary cells derived from Singaporean high-grade gliomas, which showed resistance to TMZ, were susceptible to the combined treatments. CONCLUSIONS: In conclusion, our results strongly suggest that combination usage of Nimotuzumab and rapamycin exert higher cytotoxic activities than TMZ. Our data suggest that this combination may provide an alternative treatment for TMZ-resistant gliomas regardless of the EGFR status.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Sirolimo/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dacarbazina/administração & dosagem , Dacarbazina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Mutação , TemozolomidaRESUMO
Human bone marrow-derived mesenchymal stem cells (MSCs) have the unique ability to home toward injuries or tumor sites. We have previously shown that the tumor-tropic property is dependent on the intrinsic expression and activity of the matrix remodeling gene, matrix metalloproteinase 1 (MMP-1). Herein, crosstalk between MMP-1/protease activated receptor 1 (PAR-1) and the G-protein coupled receptor stromal-derived growth factor 1 (SDF-1)/C-X-C chemokine receptor 4 (CXCR-4) in facilitating cell migration was investigated. Gain-of-function and RNA interference (RNAi) technology were used to evaluate the interplay between the key players. The downstream effect on the tumor-tropic migration of MSCs was investigated using modified Boyden chamber assay. Neutralizing PAR-1 activation using monoclonal antibody and targeted knockdown of MMP-1 using RNAi resulted in decreased expression of SDF-1, which was not observed in control-RNAi-transfected cells. Overexpression of CXCR-4 failed to promote MSC migration; the percentage of migrated cells toward tumor cell conditioned medium was similar to the vector-transduced and the CXCR-4-transduced MSCs. Furthermore, inhibition of SDF-1/CXCR-4 signaling using AMD3100 reduced MSC migration through the deregulation of MMP-1 promoter activities, protein expression, and metalloproteinase activity. Collectively, our results showed that MMP-1-mediated MSC tumor tropism is dependent on crosstalk with the SDF-1/CXCR-4 axis.
Assuntos
Movimento Celular , Quimiocina CXCL12/metabolismo , Metaloproteinase 1 da Matriz/metabolismo , Células-Tronco Mesenquimais/metabolismo , Receptores CXCR4/metabolismo , Microambiente Tumoral , Células Cultivadas , Quimiocina CXCL12/genética , Feminino , Humanos , Masculino , Metaloproteinase 1 da Matriz/genética , Células-Tronco Mesenquimais/fisiologia , Pessoa de Meia-Idade , Receptor PAR-1/genética , Receptor PAR-1/metabolismo , Receptores CXCR4/genéticaRESUMO
Tumor tropism of human bone marrow-derived mesenchymal stem cells (MSC) has been exploited for the delivery of therapeutic genes for anticancer therapy. However, the exact contribution of these cells in the tumor microenvironment remains unknown. In this study, we examined the biological effect of MSC on tumor cells. The results showed that MSC inhibited the growth of human glioma cell lines and patient-derived primary glioma cells in vitro. Coadministration of MSC and glioma cells resulted in significant reduction in tumor volume and vascular density, which was not observed when glioma was injected with immortalized normal human astrocytes. Using endothelial progenitor cells (EPC) from healthy donors and HUVEC endothelial cells, the extent of EPC recruitment and capacity to form endothelial tubes was significantly impaired in conditioned media derived from MSC/glioma coculture, suggesting that MSC suppressed tumor angiogenesis through the release of antiangiogenic factors. Further studies using antibody array showed reduced expression of platelet-derived growth factor (PDGF)-BB and interleukin (IL)-1ß in MSC/glioma coculture when compared with controls. In MSC/glioma coculture, PDGF-BB mRNA and the corresponding proteins (soluble and membrane bound forms) as well as the receptors were found to be significantly downregulated when compared with that of glioma cocultured with normal human astrocytes or glioma monoculture. Furthermore, IL-1ß, phosphorylated Akt, and cathepsin B proteins were also reduced in MSC/glioma. Taken together, these data indicated that the antitumor effect of MSC may be mediated through downregulation of PDGF/PDGFR axis, which is known to play a key role in glioma angiogenesis. STEM Cells2013;31:146-155.
Assuntos
Glioma/patologia , Células-Tronco Mesenquimais/fisiologia , Neovascularização Patológica , Proteínas Proto-Oncogênicas c-sis/genética , Receptores do Fator de Crescimento Derivado de Plaquetas/genética , Animais , Astrócitos , Becaplermina , Células da Medula Óssea/fisiologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/terapia , Catepsina B/biossíntese , Linhagem Celular Tumoral , Técnicas de Cocultura , Regulação para Baixo , Glioma/terapia , Células Endoteliais da Veia Umbilical Humana , Humanos , Interleucina-1beta/biossíntese , Transplante de Células-Tronco Mesenquimais , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Proto-Oncogênicas c-akt/biossíntese , Proteínas Proto-Oncogênicas c-sis/biossíntese , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores do Fator de Crescimento Derivado de Plaquetas/biossíntese , Microambiente TumoralRESUMO
This study examined the relationship of prejudicial attitudes to psychological, social, and physical well-being among 495 college students in the Northeast region of the United States. Prejudicial attitudes included racism, sexism, homophobia, physical disability bias, weight/body-size bias, and anti-immigrant sentiment. As a secondary objective, we examined the associations among the various forms of prejudice and their relationship to key demographic and personal characteristics. We also examined the associations between psychological, social, and physical well-being. The results indicated that specific forms of prejudice, especially racism and sexism, were negative correlates of psychological, social, and/or physical well-being. The results also indicated that there may exist a prejudicial syndrome, linking diverse forms of prejudice. Furthermore, poor functioning in one area of well-being (e.g., psychological health) is related to poor functioning in other areas of well-being (social and physical health). Overall, this study provides important implications for future research and prevention programs in the area of prejudice and well-being.
Assuntos
Preconceito , Percepção Social , Valores Sociais , Estereotipagem , Estudantes/psicologia , Atitude Frente a Saúde , Feminino , Humanos , Masculino , Saúde Mental , Conformidade Social , Estados Unidos , Adulto JovemRESUMO
Glioblastoma (GBM) accounts for more than 50% of all primary malignancies of the brain. Current standard treatment regimen for GBM includes maximal surgical resection followed by radiation and adjuvant chemotherapy. However, due to the heterogeneity of the tumor cells, tumor recurrence is often inevitable. The prognosis of patients with glioma is, thus, dismal. Glioma is a highly angiogenic tumor yet immunologically cold. As such, evolving studies have focused on designing strategies that specifically target the tyrosine kinase receptors of angiokines and encourage immune infiltration. Recent promising results from immunotherapies on other cancer types have prompted further investigations of this therapy in GBM. In this article, we reviewed the pathological angiogenesis and immune reactivity in glioma, as well as its target for drug development, and we discussed future directions in glioma therapy.
RESUMO
Asian Americans, the fastest growing racial group in the USA, face a host of major health disparities. There are several reasons for these disparities, and one possible contributor is provider perceptions of Asian Americans, which in turn can affect their medical decision making when treating Asian American patients. There is evidence for the influence of provider perceptions on medical decision making among patients of other racial minority groups; however, literature on Asian American patients is lacking. The present paper addresses this gap in the literature by using social cognitive theory to outline the mechanisms through which provider perception of Asian American patients can affect diagnostic and treatment decisions. These mechanisms include stereotypes and implicit biases, illusory correlations, and cognitive load. Recommendations for future research and policy development are provided.
Assuntos
Asiático/psicologia , Tomada de Decisão Clínica , Relações Médico-Paciente , Médicos/psicologia , Cognição Social , Humanos , Teoria SocialRESUMO
BACKGROUND: Glioblastoma multiforme is the most malignant cancer of the brain and is notoriously difficult to treat due to the highly proliferative and infiltrative nature of the cells. Herein, we explored the combination treatment of pre-established human glioma xenograft using multiple therapeutic genes whereby the gene expression is regulated by both cell-type and cell cycle-dependent transcriptional regulatory mechanism conferred by recombinant HSV-1 amplicon vectors. RESULTS: We demonstrated for the first time that Ki67-positive proliferating primary human glioma cells cultured from biopsy samples were effectively induced into cell death by the dual-specific function of the pG8-FasL amplicon vectors. These vectors were relatively stable and exhibited minimal cytotoxicity in vivo. Intracranial implantation of pre-transduced glioma cells resulted in better survival outcome when compared with viral vectors inoculated one week post-implantation of tumor cells, indicating that therapeutic efficacy is dependent on the viral spread and mode of viral vectors administration. We further showed that pG8-FasL amplicon vectors are functional in the presence of commonly used treatment regimens for human brain cancer. In fact, the combined therapies of pG8-FasL and pG8-FADD in the presence of temozolomide significantly improved the survival of mice bearing intracranial high-grade gliomas. CONCLUSION: Taken together, our results showed that the glioma-specific and cell cycle-dependent HSV-1 amplicon vector is potentially useful as an adjuvant therapy to complement the current gene therapy strategy for gliomas.
Assuntos
Apoptose/fisiologia , Neoplasias Encefálicas/metabolismo , Proteína Ligante Fas/fisiologia , Proteína de Domínio de Morte Associada a Fas/metabolismo , Glioma/genética , Herpesvirus Humano 1/genética , Animais , Apoptose/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Proteína Ligante Fas/genética , Proteína de Domínio de Morte Associada a Fas/genética , Imunofluorescência , Vetores Genéticos/genética , Células HeLa , Humanos , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Camundongos , Camundongos SCID , Células Tumorais CultivadasRESUMO
BACKGROUND: Herpes simplex virus type-1 (HSV-1) amplicon vectors are attractive tools for gene transfer because of their large DNA insert capacity, their broad host range of vector transduction and a minimal immune response as a result of the absence of helper viruses during viral packaging. However, the transient gene expression remains a challenge for the translation of HSV-1 amplicon based therapeutic strategies to a clinical setting. Although oriP/EBV nuclear antigen (EBNA)-1 elements of Epstein-Barr virus (EBV) have been successfully employed to achieve prolonged transgene expression, little is known about the stability of the EBNA-1 elements in the context of HSV-1 amplicon viral vectors. METHODS: We have generated HSV/EBV hybrid vectors expressing the mutant EBNA-1 gene with the luciferase reporter gene bicistronically to enable monitoring of EBNA-1 expression in real-time, both in vitro and in vivo. RESULTS: The results obtained showed that the HSV/EBV hybrid vectors could mediate high levels of transgene expression (ranging from approximately two-fold to nine-fold) in primary human tumor cells and human bone marrow-derived mesenchymal stem cells compared to the control vector. Prolonged transgene expression could also be observed in primary patient-derived human hepatocellular carcinoma xenografts and in the mouse brain parenchyma up to a period of 17 and 365 days, respectively. CONCLUSIONS: Taken together, we have demonstrated that these hybrid vectors could be promising tools as carriers of therapeutic genes in mesenchymal stem cells or even provide an alternative non-integrating platform for the generation of induced pluripotent stem cells.
Assuntos
Vetores Genéticos , Herpesvirus Humano 4/genética , Células-Tronco Mesenquimais/virologia , Simplexvirus/genética , Transgenes , Animais , Neoplasias Encefálicas/patologia , Carcinoma Hepatocelular/patologia , Linhagem Celular , Linhagem Celular Tumoral , Quimera , Antígenos Nucleares do Vírus Epstein-Barr/genética , Antígenos Nucleares do Vírus Epstein-Barr/metabolismo , Estudos de Viabilidade , Feminino , Expressão Gênica , Genes Reporter , Glioma/patologia , Células HeLa , Vírus Auxiliares , Humanos , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Nus , Camundongos SCID , Transdução Genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
Human mesenchymal stem cells (MSCs) have increasingly been used as cellular vectors for the delivery of therapeutic genes to tumors. However, the precise mechanism of mobilization remains poorly defined. In this study, MSCs that expressed similar cell surface markers and exhibited multilineage differentiation potentials were isolated from various donors. Interestingly, different MSC isolates displayed differential migration ability toward human glioma cells. We hypothesized that distinct molecular signals may be involved in the varied tumor tropisms exhibited by different MSC isolates. To test this hypothesis, gene expression profiles of tumor-trophic MSCs were compared with those of non-tumor-trophic MSCs. Among the various differentially regulated genes, matrix metalloproteinase one (MMP1) gene expression and its protein activities were enhanced by 27-fold and 21-fold, respectively, in highly migrating MSCs compared with poorly migrating MSCs. By contrast, there was no change in the transcriptional levels of other MMPs. Functional inactivation of MMP1 abrogated the migratory potential of MSCs toward glioma-conditioned medium. Conversely, the nonmigratory phenotype of poorly migrating MSC could be rescued in the presence of either recombinant MMP1 or conditioned medium from the highly migrating MSCs. Ectopic expression of MMP1 in these poorly migrating cells also rendered the cells responsive to the signaling cues from the glioma cells in vivo. However, blocking the interaction of MMP1 and its cognate receptor PAR1 effectively diminished the migratory ability of MSCs. Taken together, this study provides, for the first time, supporting evidence that MMP1 is critically involved in the migration capacity of MSCs, acting through the MMP1/PAR1 axis.
Assuntos
Movimento Celular/fisiologia , Glioma/metabolismo , Metaloproteinase 1 da Matriz/metabolismo , Células-Tronco Mesenquimais/metabolismo , Células da Medula Óssea/citologia , Ensaio de Imunoadsorção Enzimática , Perfilação da Expressão Gênica , Técnicas de Transferência de Genes , Humanos , Transplante de Células-Tronco Mesenquimais , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , TransfecçãoRESUMO
Little is known about the healthcare experiences of Black lesbian and bisexual women. This exploratory study examined the healthcare experiences of a 24-year-old Black lesbian and the interconnection between race, ethnicity, gender, and sexual identity in her lived experiences. Data were gathered through an in-depth audio-recorded interview. Findings revealed the risks of and barriers to self-disclosure in healthcare settings, factors that influence the quality of the patient-provider relationship, and the positive and negative healthcare experiences of this Black American lesbian. This study is an important first step in exploring the healthcare experiences of Black lesbian and bisexual women. The findings of this case study highlight themes and avenues for future research. Clinical implications and suggestions for future research are discussed.
Assuntos
Atitude do Pessoal de Saúde , Negro ou Afro-Americano , Homossexualidade Feminina , Relações Profissional-Paciente , Minorias Sexuais e de Gênero , Adulto , Feminino , Humanos , Estados Unidos , Adulto JovemRESUMO
Glioblastoma (GBM) is the most aggressive tumor of the brain. NF1, a tumor suppressor gene and RAS-GTPase, is one of the highly mutated genes in GBM. Dysregulated NF1 expression promotes cell invasion, proliferation, and tumorigenesis. Loss of NF1 expression in glioblastoma is associated with increased aggressiveness of the tumor. Here, we show that NF1-loss in patient-derived glioma cells using shRNA increases self-renewal, heightens cell invasion, and promotes mesenchymal subtype and epithelial mesenchymal transition-specific gene expression that enhances tumorigenesis. The neurofibromin protein contains at least four major domains, with the GAP-related domain being the most well-studied. In this study, we report that the leucine-rich domain (LRD) of neurofibromin inhibits invasion of human glioblastoma cells without affecting their proliferation. Moreover, under conditions tested, the NF1-LRD fails to hydrolyze Ras-GTP to Ras-GDP, suggesting that its suppressive function is independent of Ras signaling. We further demonstrate that rare variants within the NF1-LRD domain found in a subset of the patients are pathogenic and reduce NF1-LRD's invasion suppressive function. Taken together, our results show, for the first time, that NF1-LRD inhibits glioma invasion, and provides evidence of a previously unrecognized function of NF1-LRD in glioma biology.
Assuntos
Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Leucina/metabolismo , Mutação , Invasividade Neoplásica/genética , Neurofibromina 1/genética , Animais , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Glioblastoma/patologia , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Neurofibromina 1/metabolismoRESUMO
Angiopoietins (ANG-1 and ANG-2) and their TIE-2 receptor tyrosine kinase have wide-ranging effects on tumor malignancy that includes angiogenesis, inflammation, and vascular extravasation. These multifaceted pathways present a valuable opportunity in developing novel inhibition strategies for cancer treatment. However, the regulatory role of ANG-1 and ANG-2 in tumor angiogenesis remains controversial. There is a complex interplay between complementary yet conflicting roles of both the ANGs in shaping the outcome of angiogenesis. Embryonic vascular development suggests that ANG-1 is crucial in engaging interaction between endothelial and perivascular cells. However, recruitment of perivascular cells by ANG-1 has recently been implicated in its antiangiogenic effect on tumor growth. It is becoming clear that TIE-2 signaling may function in a paracrine and autocrine manner directly on tumor cells because the receptor has been increasingly found in tumor cells. In addition, alpha(5)beta(1) and alpha(v)beta(5) integrins were recently recognized as functional receptors for ANG-1 and ANG-2. Therefore, both the ligands may have wide-ranging functions in cellular activities that affect overall tumor development. Collectively, these TIE-2-dependent and TIE-2-independent activities may account for the conflicting findings of ANG-1 and ANG-2 in tumor angiogenesis. These uncertainties have impeded development of a clear strategy to target this important angiogenic pathway. A better understanding of the molecular basis of ANG-1 and ANG-2 activity in the pathophysiologic regulation of angiogenesis may set the stage for novel therapy targeting this pathway.
Assuntos
Angiopoietinas/metabolismo , Neoplasias/irrigação sanguínea , Neovascularização Patológica/patologia , Receptores de TIE/metabolismo , Angiopoietinas/química , Animais , Humanos , Receptores de TIE/químicaRESUMO
Our previous studies have shown that transgene expression could be targeted to proliferating cells when cell cycle transcriptional regulatory elements were incorporated into herpes simplex virus type 1 (HSV-1) amplicon backbone vectors. In the study reported here, we further demonstrated the transcriptional activation of transgene expression in association with the onset of cellular proliferation using the mouse partial hepatectomy model. Moreover, transcriptional regulation could be rendered specific to human hepatocellular carcinoma (HCC) cells by inserting the chimeric gene Gal4/NF-YA under the regulation of the HCC-specific hybrid promoter. The hybrid promoter, which consists of four copies of the apolipoprotein E (ApoE) enhancer element inserted upstream of the human α1-antitrypsin(hAAT) promoter, induced an higher level of transcription than other liver-specific promoters such as alpha-fetoprotein (AFP) and albumin (Alb) promoter. As a consequence, the enhancement of tissue-specific expression in the context of Gal4/NF-YA fusion proteins enabled the monitoring of transgene expression using a bioluminescence imaging system. Furthermore, these vectors have been shown to be non-toxic and exhibited potent infectivity for proliferating primary HCC cells and HCC cell lines. Together, these results demonstrated that the new hybrid vectors could provide options for the design of safe and efficient systemic gene therapeutic strategies for human HCC.
RESUMO
There are significant health disparities among Southeast Asian Americans. As an initial step toward understanding the psychosocial factors associated with these disparities, the present study examined primary care providers' perspectives of health status, healthcare utilization, health-related behaviors, and stressors among one subset of Southeast Asian Americans-Cambodian American women between the ages of 18 and 24 years. Interviews with five primary care providers indicated that cultural, historical, psychological and social issues were associated with health outcomes and health behaviors. Results also pointed to clinical considerations and research directions that would improve treatment and understanding of health problems among young Cambodian American women.
Assuntos
Asiático , Atitude do Pessoal de Saúde , Nível de Saúde , Aceitação pelo Paciente de Cuidados de Saúde/etnologia , Atenção Primária à Saúde , Adolescente , Adulto , Idoso , Camboja/etnologia , Dieta , Relações Familiares , Feminino , Comportamentos Relacionados com a Saúde/etnologia , Conhecimentos, Atitudes e Prática em Saúde/etnologia , Acessibilidade aos Serviços de Saúde , Humanos , Pessoa de Meia-Idade , Cooperação do Paciente/etnologia , Percepção , Apoio Social , Estresse Psicológico/etnologia , Transtornos Relacionados ao Uso de Substâncias/etnologia , Estados Unidos/epidemiologia , Adulto JovemRESUMO
We previously generated a herpes simplex virus type 1 (HSV-1)-based amplicon vector (denoted pC8-36) in which gene expression from the minimal cyclin A promoter is repressed by preventing the binding of a trans-activating protein, Gal4-NF-YA, to it through selective interaction with the transcriptional repressor protein CDF-1. Because CDF-1 is absent in actively dividing cells, transgene expression conferred by the pC8-36 vector is therefore cell cycle dependent. As gene therapy evolves to become a promising therapeutic modality for many human diseases, there is an increasing need to further improve the kinetics of gene regulation. In the present study, we examined whether the availability of more binding sites for CDF-1 repressor proteins could enhance transgene expression. Using an overlap extension polymerase chain reaction (PCR) method, the CDE and CHR elements within the minimum cyclin A promoter were multimerized to contain two, three, and six copies of the designated CDE/CHR sequence. Interestingly, our results demonstrated that six-copy CDE/CHR sequence motifs (pC8-6CC-Luc) conferred an approximately 20-fold increase in the ratio of cell cycle regulation compared with the previous reported construct. Further, the overall transcriptional activities mediated by pC8-6CC-Luc were stronger compared with the native human survivin promoter, which consists of three copies of the CDE element and one copy of the CHR element. pC8-6CC-Luc contained, in essence, only the synthetic six-copy CDE/CHR sequence motif (about 262 bp). In comparison with other native endogenous promoters, which usually contain many other transcription binding sites, pC8-6CC-Luc amplicon vectors should confer better regulated and consistent transgene expression and may be considered a gene delivery vector of choice to target actively proliferating tumor cells.
Assuntos
Ciclo Celular/genética , Terapia Genética , Vetores Genéticos/genética , Herpesvirus Humano 1/genética , Neoplasias/terapia , Animais , Sequência de Bases , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células , Ciclina A/genética , Feminino , Engenharia Genética , Humanos , Proteínas Inibidoras de Apoptose , Luciferases/análise , Luciferases/genética , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Associadas aos Microtúbulos/genética , Dados de Sequência Molecular , Proteínas de Neoplasias/genética , Proteínas Repressoras/metabolismo , Survivina , Sequências de Repetição em Tandem , Transgenes/genética , VírionRESUMO
Herpes simplex virus (HSV)-1 amplicon vectors could be packaged in the presence of replication-competent helper virus or in a helper virus-free system. In the latter system, cytotoxicity due to the expression of de novo viral gene expression is greatly reduced due to the absence of helper virus. However, the titers produced are relatively low in the range of 10(7) and 10(8)TU/ml after sucrose gradient concentration. This may become a limitation to certain gene transfer applications, such as brain disorder studies since the volume of vectors that could be administered is restricted. In contrast, amplicon viral vectors of high titers can be easily generated in the presence of helper viruses. Despite the potential cytotoxicity caused by the presence of helper virus in the latter method of viral packaging, studies involving vector targeting would still require the complementing function of helper virus for the generation of recombinant HSV-1 amplicon vectors with modified viral envelopes. In view of this, the optimal method of purifying Herpes-based viral vectors that confers minimal cytotoxicity for systemic route of viral vector administration is examined. Parameters such as the ratio of amplicon versus helper viruses, the percentage of viral lost, and the extent of liver cytotoxicity induced by these viral vectors purified using different methods were investigated. In addition, the maximum recombinant HSV-1 viral dosage was also determined in vivo. Taken together, these findings may be of importance to the efficient production of contaminant-free HSV-1 amplicon viral vectors required for animal and human studies.