RESUMO
The COVID-19 pandemic reminded us of the urgent need for new antivirals to control emerging infectious diseases and potential future pandemics. Immunotherapy has revolutionized oncology and could complement the use of antivirals, but its application to infectious diseases remains largely unexplored. Nucleoside analogs are a class of agents widely used as antiviral and anti-neoplastic drugs. Their antiviral activity is generally based on interference with viral nucleic acid replication or transcription. Based on our previous work and computer modeling, we hypothesize that antiviral adenosine analogs, like remdesivir, have previously unrecognized immunomodulatory properties which contribute to their therapeutic activity. In the case of remdesivir, we here show that these properties are due to its metabolite, GS-441524, acting as an Adenosine A2A Receptor antagonist. Our findings support a new rationale for the design of next-generation antiviral agents with dual - immunomodulatory and intrinsic - antiviral properties. These compounds could represent game-changing therapies to control emerging viral diseases and future pandemics.
Assuntos
Monofosfato de Adenosina , Adenosina , Alanina , Antivirais , COVID-19 , SARS-CoV-2 , Antivirais/farmacologia , Antivirais/química , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/imunologia , Adenosina/análogos & derivados , Adenosina/farmacologia , Adenosina/química , Humanos , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Alanina/análogos & derivados , Alanina/farmacologia , Alanina/química , COVID-19/imunologia , COVID-19/virologia , Animais , Agentes de Imunomodulação/farmacologia , Agentes de Imunomodulação/química , Antagonistas do Receptor A2 de Adenosina/farmacologia , Antagonistas do Receptor A2 de Adenosina/química , Antagonistas do Receptor A2 de Adenosina/uso terapêutico , Pandemias , Tratamento Farmacológico da COVID-19 , Chlorocebus aethiops , Replicação Viral/efeitos dos fármacos , Células Vero , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , Receptor A2A de Adenosina/metabolismo , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologiaRESUMO
Primary effusion lymphoma (PEL) is an aggressive malignancy with poor prognosis even under chemotherapy. Kaposi sarcoma-associated herpesvirus (KSHV), one of the human oncogenic viruses, is the principal causative agent. Currently, there is no specific treatment for PEL; therefore, developing new therapies is of great importance. Sphingolipid metabolism plays an important role in determining the fate of tumor cells. Our previous studies have demonstrated that there is a correlation between sphingolipid metabolism and KSHV+ tumor cell survival. To further develop sphingolipid metabolism-targeted therapy, after screening a series of newly synthesized ceramide analogs, here, we have identified compounds with effective anti-PEL activity. These compounds induce significant PEL apoptosis, cell-cycle arrest, and intracellular ceramide production through regulation of ceramide synthesizing or ceramide metabolizing enzymes and dramatically suppress tumor progression without visible toxicity in vivo. These new compounds also increase viral lytic gene expression in PEL cells. Our comparative transcriptomic analysis revealed their mechanisms of action for inducing PEL cell death and identified a subset of novel cellular genes, including AURKA and CDCA3, controlled by sphingolipid metabolism, and required for PEL survival with functional validation. These data provide the framework for the development of promising sphingolipid-based therapies against this virus-associated malignancy.
Assuntos
Aurora Quinase A/metabolismo , Ceramidas/farmacologia , Herpesvirus Humano 8/patogenicidade , Linfoma de Efusão Primária/tratamento farmacológico , Sarcoma de Kaposi/complicações , Esfingolipídeos/farmacologia , Animais , Apoptose , Aurora Quinase A/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Sobrevivência Celular , Ceramidas/química , Feminino , Perfilação da Expressão Gênica , Humanos , Linfoma de Efusão Primária/etiologia , Linfoma de Efusão Primária/metabolismo , Linfoma de Efusão Primária/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Sarcoma de Kaposi/virologia , Células Tumorais Cultivadas , Replicação Viral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
There are well-established disparities in cancer incidence and outcomes by race/ethnicity that result from the interplay between structural, socioeconomic, socio-environmental, behavioural and biological factors. However, large research studies designed to investigate factors contributing to cancer aetiology and progression have mainly focused on populations of European origin. The limitations in clinicopathological and genetic data, as well as the reduced availability of biospecimens from diverse populations, contribute to the knowledge gap and have the potential to widen cancer health disparities. In this review, we summarise reported disparities and associated factors in the United States of America (USA) for the most common cancers (breast, prostate, lung and colon), and for a subset of other cancers that highlight the complexity of disparities (gastric, liver, pancreas and leukaemia). We focus on populations commonly identified and referred to as racial/ethnic minorities in the USA-African Americans/Blacks, American Indians and Alaska Natives, Asians, Native Hawaiians/other Pacific Islanders and Hispanics/Latinos. We conclude that even though substantial progress has been made in understanding the factors underlying cancer health disparities, marked inequities persist. Additional efforts are needed to include participants from diverse populations in the research of cancer aetiology, biology and treatment. Furthermore, to eliminate cancer health disparities, it will be necessary to facilitate access to, and utilisation of, health services to all individuals, and to address structural inequities, including racism, that disproportionally affect racial/ethnic minorities in the USA.
Assuntos
Disparidades nos Níveis de Saúde , Grupos Minoritários/estatística & dados numéricos , Neoplasias/etnologia , Etnicidade/estatística & dados numéricos , Feminino , Humanos , Masculino , Estados Unidos/etnologiaRESUMO
BACKGROUND: Hereditary hemorrhagic telangiectasia is an autosomal dominant vascular disorder caused by heterozygous, loss-of-function mutations in 4 transforming growth factor beta (TGFß) pathway members, including the central transcriptional mediator of the TGFß pathway, Smad4. Loss of Smad4 causes the formation of inappropriate, fragile connections between arteries and veins called arteriovenous malformations (AVMs), which can hemorrhage leading to stroke, aneurysm, or death. Unfortunately, the molecular mechanisms underlying AVM pathogenesis remain poorly understood, and the TGFß downstream effectors responsible for hereditary hemorrhagic telangiectasia-associated AVM formation are currently unknown. METHODS: To identify potential biological targets of the TGFß pathway involved in AVM formation, we performed RNA- and chromatin immunoprecipitation-sequencing experiments on BMP9 (bone morphogenetic protein 9)-stimulated endothelial cells (ECs) and isolated ECs from a Smad4-inducible, EC-specific knockout ( Smad4-iECKO) mouse model that develops retinal AVMs. These sequencing studies identified the angiopoietin-Tek signaling pathway as a downstream target of SMAD4. We used monoclonal blocking antibodies to target a specific component in this pathway and assess its effects on AVM development. RESULTS: Sequencing studies uncovered 212 potential biological targets involved in AVM formation, including the EC surface receptor, TEK (TEK receptor tyrosine kinase) and its antagonistic ligand, ANGPT2 (angiopoietin-2). In Smad4-iECKO mice, Angpt2 expression is robustly increased, whereas Tek levels are decreased, resulting in an overall reduction in angiopoietin-Tek signaling. We provide evidence that SMAD4 directly represses Angpt2 transcription in ECs. Inhibition of ANGPT2 function in Smad4-deficient mice, either before or after AVMs form, prevents and alleviates AVM formation and normalizes vessel diameters. These rescue effects are attributed to a reversion in EC morphological changes, such as cell size and shape that are altered in the absence of Smad4. CONCLUSIONS: Our studies provide a novel mechanism whereby the loss of Smad4 causes increased Angpt2 transcription in ECs leading to AVM formation, increased blood vessel calibers, and changes in EC morphology in the retina. Blockade of ANGPT2 function in an in vivo Smad4 model of hereditary hemorrhagic telangiectasia alleviated these vascular phenotypes, further implicating ANGPT2 as an important TGFß downstream mediator of AVM formation. Therefore, alternative approaches that target ANGPT2 function may have therapeutic value for the alleviation of hereditary hemorrhagic telangiectasia symptoms, such as AVMs.
Assuntos
Angiopoietina-2/antagonistas & inibidores , Malformações Arteriovenosas/prevenção & controle , Proteína Smad4/deficiência , Telangiectasia Hemorrágica Hereditária/complicações , Angiopoietina-2/biossíntese , Angiopoietina-2/genética , Animais , Malformações Arteriovenosas/etiologia , Malformações Arteriovenosas/metabolismo , Malformações Arteriovenosas/patologia , Tamanho Celular , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Endotélio Vascular/citologia , Regulação da Expressão Gênica , Camundongos , Camundongos Knockout , Receptor TIE-2/fisiologia , Transdução de Sinais , Proteína Smad4/genética , Proteína Smad4/fisiologia , Telangiectasia Hemorrágica Hereditária/genética , Transcrição Gênica , Fator de Crescimento Transformador beta/metabolismoRESUMO
Breast cancer affects women globally; the majority of breast cancer-related mortalities are due to metastasis. Acquisition of a mesenchymal phenotype has been implicated in the progression of breast cancer cells to an invasive, metastatic state. Triple-negative breast cancer (TNBC) subtypes have high rates of metastases, recurrence, and have poorer prognoses compared to other breast cancer types, partially due to lack of commonly targeted receptors. Kinases have diverse and pivotal functions in metastasis in TNBC, and discovery of new kinase targets for TNBC is warranted. We previously used a screening approach to identify intermediate-synthesis nonpotent, nonselective small-molecule inhibitors from the Published Kinase Inhibitor Set that reversed the mesenchymal phenotype in TNBC cells. Two of these inhibitors (GSK346294A and GSK448459A) are structurally similar, but have unique kinase activity profiles and exhibited differential biologic effects on TNBC cells, specifically on epithelial-to-mesenchymal transition (EMT). Here, we further interrogate these effects and compare activity of these inhibitors on transwell migration, gene (qRT-PCR) and protein (western blot) expressions, and cancer stem cell-like behavior. We incorporated translational patient-derived xenograft models in these studies, and we focused on the lead inhibitor hit, GSK346294A, to demonstrate the utility of our comparative analysis as a screening modality to identify novel kinase targets and signaling pathways to pursue in TNBC. This study introduces a new method for discovering novel kinase targets that reverse the EMT phenotype; this screening approach can be applied to all cancer types and is not limited to breast cancer.
Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Apoptose , Proliferação de Células , Transição Epitelial-Mesenquimal , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Camundongos , Estrutura Molecular , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fosforilação , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Private well water systems in rural areas that are improperly maintained will result in poor drinking water quality, loss of water supply, and pose human health risk. The purpose of this study was to investigate the occurrence of fecal indicator bacteria (FIB) and opportunistic pathogens in private well water in rural areas surrounding New Orleans, Louisiana. Our results confirmed the ubiquitous nature of Legionella (86.7%) and mycobacteria (68.1%) in private well water in the study area, with gene concentration ranged from 0.60 to 5.53 and 0.67 to 5.95 Log10 of GC/100 mL, respectively. Naegleria fowleri target sequence was detected in 16.8% and Escherichia coli was detected in 43.4% of the water samples. Total coliform, as well as Legionella and mycobacteria genetic markers' concentrations were significantly reduced by 3-minute flushing. Next-generation sequencing (NGS) data indicated that the abundance of bacterial species was significantly increased in water collected in kitchens compared with samples from wells directly. This study provided integrated knowledge on the persistence of pathogenic organisms in private well water. Further study is needed to explore the presence of clinical species of those opportunistic pathogens in private well water systems to elucidate the health risk.
Assuntos
Água Potável , Engenharia Sanitária , Humanos , Legionella/genética , Louisiana , Abastecimento de ÁguaRESUMO
DNA methylation (DNAm) measured in lymphoblastoid cell lines has been repeatedly demonstrated to differ between various human populations. Due to the role that DNAm plays in controlling gene expression, these differences could significantly contribute to ethnic phenotypic differences. However, because previous studies have compared distinct ethnic groups where genetic and environmental context are confounded, their relative contribution to phenotypic differences between ethnicities remains unclear. Using DNAm assayed in whole blood and colorectal tissue of 132 admixed individuals from Colombia, we identified sites where differential DNAm levels were associated with the local ancestral genetic context. Our results are consistent with population specific DNAm being primarily driven by between population genetic differences in cis, with little environmental contribution, and with consistent effects across tissues. The findings offer new insights into a possible mechanism driving phenotypic differences among different ethnic groups, and could help explain ethnic differences in colorectal cancer incidence.
Assuntos
Neoplasias Colorretais/genética , Metilação de DNA/genética , Epigenômica , Genética Populacional , Colômbia/epidemiologia , Neoplasias Colorretais/epidemiologia , Ilhas de CpG/genética , Feminino , Genótipo , Hispânico ou Latino , Humanos , MasculinoRESUMO
Kaposi's sarcoma-associated herpesvirus (KSHV) can cause several human cancers, including primary effusion lymphoma (PEL), which frequently occur in immunocompromised patients. KSHV-infected patients often suffer from polymicrobial infections caused by opportunistic bacterial pathogens. Therefore, it is crucial to understand how these coinfecting microorganisms or their secreted metabolites may affect KSHV infection and the pathogenesis of virus-associated malignancies. Quorum sensing (QS), a cell density-based intercellular communication system, employs extracellular diffusible signaling molecules to regulate bacterial virulence mechanisms in a wide range of bacterial pathogens, such as Pseudomonas aeruginosa, which is one of the most common opportunistic microorganisms found in immunocompromised individuals. In this study, we evaluated and compared the influence on PEL growth and the host/viral interactome of the major QS signaling molecules [N-(3-oxododecanoyl)-l-homoserine lactone (OdDHL), N-butyrylhomoserine lactone (BHL), and 2-heptyl-3-hydroxy-4-quinolone (PQS)] in conditioned medium from wild-type (wt) and QS mutant laboratory strains as well as clinical isolates of P. aeruginosa Our data indicate that P. aeruginosa coinfection may facilitate virus dissemination and establishment of new infection and further promote tumor development through effectively inducing viral lytic gene expression by its QS systems.IMPORTANCE Currently, most studies about KSHV infection and/or virus-associated malignancies depend on pure culture systems or immunodeficient animal models. However, the real situation should be much more complicated in KSHV-infected immunocompromised patients due to frequent polymicrobial infections. It is important to understand the interaction of KSHV and coinfecting microorganisms, especially opportunistic bacterial pathogens. Here we report for the first time that P. aeruginosa and its quorum-sensing signaling molecules display a complicated impact on KSHV-associated lymphoma growth as well as the intracellular host/viral gene expression profile. Our data imply that targeting of coinfecting pathogens is probably necessary during treatment of virus-associated malignancies in these immunocompromised patients.
Assuntos
4-Butirolactona/análogos & derivados , Regulação da Expressão Gênica , Herpesvirus Humano 8/fisiologia , Linfoma de Efusão Primária/etiologia , Linfoma de Efusão Primária/patologia , Quinolonas/metabolismo , Percepção de Quorum , 4-Butirolactona/metabolismo , Carga Bacteriana , Infecções por Herpesviridae/etiologia , Infecções por Herpesviridae/metabolismo , Infecções por Herpesviridae/patologia , Humanos , Linfoma de Efusão Primária/metabolismo , Infecções por Pseudomonas/complicações , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/patogenicidade , Transdução de Sinais , Proteínas Virais/genética , Proteínas Virais/metabolismo , VirulênciaRESUMO
BACKGROUND AND AIM: Chronic Helicobacter pylori infection causes gastric mucosal inflammation as an important antecedent of gastric cancer. We aimed to evaluate associations of blood markers of inflammation with gastric intestinal metaplasia and dysplasia in H. pylori-infected individuals. METHODS: We compared pre-treatment serum levels of immune-related and inflammation-related markers between 99 individuals with intestinal metaplasia or dysplasia and 75 control individuals with non-atrophic gastritis within an H. pylori eradication trial in Mexico. Serum levels of 28 markers measured with Luminex bead-based assays were categorized in tertiles as low (T1), middle (T2), and high (T3). Logistic regression models were used to calculate age-adjusted and sex-adjusted odds ratios and 95% confidence intervals. All statistical tests were two-sided, and significance values were adjusted for multiple comparisons using false discovery rate methods. RESULTS: Five markers were nominally associated (Ptrend < 0.05) with the presence of advanced premalignant gastric lesions. Adjusted odds ratios (95% confidence interval) of T2 and T3 versus T1 were 4.09 (1.65-10.17) and 3.08 (1.23-7.68) for CCL3/MIP1A, 3.21 (1.33-7.75) and 2.69 (1.10-6.57) for CCL20/MIP3A levels, 1.79 (0.77-4.18) and 2.39 (1.02-5.60) for IL-1ß, 1.34 (0.56-3.19) and 3.02 (1.29-7.12) for IL-4, and 1.07 (0.44-2.59) and 3.07 (1.32-7.14) for IL-5, respectively. Two (IL-4 and IL-5) of the five markers had false discovery rate adjusted Ptrend < 0.2. CONCLUSIONS: Our results suggest that certain Th2 and other cytokines may have a role in promoting carcinogenesis in the setting of H. pylori infection. Additional research is needed to replicate these findings, extend to pre-diagnostic samples, and elucidate the underlying mechanisms.
Assuntos
Biomarcadores Tumorais/sangue , Lesões Pré-Cancerosas/diagnóstico , Lesões Pré-Cancerosas/etiologia , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/etiologia , Proteínas Adaptadoras de Transdução de Sinal/sangue , Idoso , Idoso de 80 Anos ou mais , Quimiocina CCL20/sangue , Quimiocina CCL3/sangue , Doença Crônica , Feminino , Gastrite/microbiologia , Infecções por Helicobacter , Helicobacter pylori , Humanos , Inflamação , Interleucina-1beta/sangue , Interleucina-4/sangue , Interleucina-5/sangue , Intestinos/patologia , Masculino , Metaplasia , Pessoa de Meia-Idade , Células Th2RESUMO
Motivation: Testing SNP-SNP interactions is considered as a key for overcoming bottlenecks of genetic association studies. However, related statistical methods for testing SNP-SNP interactions are underdeveloped. Results: We propose the SNP Interaction Pattern Identifier (SIPI), which tests 45 biologically meaningful interaction patterns for a binary outcome. SIPI takes non-hierarchical models, inheritance modes and mode coding direction into consideration. The simulation results show that SIPI has higher power than MDR (Multifactor Dimensionality Reduction), AA_Full, Geno_Full (full interaction model with additive or genotypic mode) and SNPassoc in detecting interactions. Applying SIPI to the prostate cancer PRACTICAL consortium data with approximately 21 000 patients, the four SNP pairs in EGFR-EGFR , EGFR-MMP16 and EGFR-CSF1 were found to be associated with prostate cancer aggressiveness with the exact or similar pattern in the discovery and validation sets. A similar match for external validation of SNP-SNP interaction studies is suggested. We demonstrated that SIPI not only searches for more meaningful interaction patterns but can also overcome the unstable nature of interaction patterns. Availability and Implementation: The SIPI software is freely available at http://publichealth.lsuhsc.edu/LinSoftware/ . Contact: hlin1@lsuhsc.edu. Supplementary information: Supplementary data are available at Bioinformatics online.
Assuntos
Epistasia Genética , Estudos de Associação Genética/métodos , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Software , Estatística como Assunto , Receptores ErbB/genética , Predisposição Genética para Doença , Humanos , Masculino , Metaloproteinase 16 da Matriz/genética , Modelos Genéticos , Neoplasias da Próstata/metabolismoRESUMO
Kaposi sarcoma-associated herpesvirus (KSHV) is a principal causative agent of primary effusion lymphoma (PEL) with a poor prognosis in immunocompromised patients. However, it still lacks effective treatment which urgently requires the identification of novel therapeutic targets for PEL. Here, we report that the hepatocyte growth factor (HGF)/c-MET pathway is highly activated by KSHV in vitro and in vivo. The selective c-MET inhibitor, PF-2341066, can induce PEL apoptosis through cell cycle arrest and DNA damage, and suppress tumor progression in a xenograft murine model. By using microarray analysis, we identify many novel genes that are potentially controlled by HGF/c-MET within PEL cells. One of the downstream candidates, ribonucleoside-diphosphate reductase subunit M2 (RRM2), also displays the promising therapeutic value for PEL treatment. Our findings provide the framework for development of HGF/c-MET-focused therapy and implementation of clinical trials for PEL patients.
Assuntos
Fator de Crescimento de Hepatócito/antagonistas & inibidores , Linfoma de Efusão Primária/patologia , Piperidinas/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Piridinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Adulto , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Ensaio Cometa , Crizotinibe , Dano ao DNA/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Infecções por Herpesviridae/complicações , Herpesvirus Humano 8 , Humanos , Immunoblotting , Hospedeiro Imunocomprometido , Linfoma de Efusão Primária/imunologia , Masculino , Camundongos , Camundongos SCID , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Pirazóis , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto JovemRESUMO
BACKGROUND: Racial variation in the relationship between blood glucose and hemoglobin A1c (HbA1c) complicates diabetes diagnosis and management in racially mixed populations. Understanding why HbA1c is persistently higher in blacks than whites could help reduce racial disparity in diabetes outcomes. OBJECTIVE: Test the hypothesis that neighborhood disadvantage is associated with inflammation and poor metabolic control in a racially mixed population of pediatric type 1 diabetes patients. METHODS: Patients (n = 86, 53 white, 33 black) were recruited from diabetes clinics. Self-monitored mean blood glucose (MBG) was downloaded from patient glucose meters. Blood was collected for analysis of HbA1c and C-reactive protein (CRP). Patient addresses and census data were used to calculate a concentrated disadvantage index (CDI). High CDI reflects characteristics of disadvantaged neighborhoods. RESULTS: HbA1c and MBG were higher (p < 0.0001) in blacks [10.4% (90.3 mmol/mol), 255 mg/dL] than whites [8.9% (73.9 mmol/mol), 198 mg/dL). CDI was higher in blacks (p < 0.0001) and positively correlated with HbA1c (r = 0.40, p = 0.0002) and MBG (r = 0.35, p = 0.0011) unless controlled for race. CDI was positively associated with CRP by linear regression within racial groups. CRP was not different between racial groups, and was not correlated with MBG, but was positively correlated with HbA1c when controlled for race (p = 0.04). CONCLUSIONS: Neighborhood disadvantage was associated with inflammation and poor metabolic control in pediatric type 1 diabetes patients. Marked racial differences in potential confounding factors precluded differentiation between genetic and environmental effects. Future studies should recruit patients matched for neighborhood characteristics and treatment regimen to more comprehensively assess racial variation in HbA1c.
Assuntos
População Negra , Glicemia/metabolismo , Diabetes Mellitus Tipo 1/etnologia , Inflamação/etnologia , Populações Vulneráveis , População Branca , Adolescente , Adulto , População Negra/estatística & dados numéricos , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/complicações , Feminino , Hemoglobinas Glicadas/metabolismo , Disparidades nos Níveis de Saúde , Humanos , Inflamação/complicações , Masculino , Nova Orleans/epidemiologia , Grupos Raciais/estatística & dados numéricos , Características de Residência , Autocuidado/estatística & dados numéricos , Fatores Socioeconômicos , Populações Vulneráveis/etnologia , Populações Vulneráveis/estatística & dados numéricos , População Branca/estatística & dados numéricos , Adulto JovemRESUMO
Breast cancer is the most frequent malignancy in women worldwide. Distinct intrinsic subtypes of breast cancer have different prognoses, and their relative prevalence varies significantly among ethnic groups. Little is known about the prevalence of breast cancer intrinsic subtypes and their association with clinicopathological data and genetic ancestry in Latin Americans. Immunohistochemistry surrogates from the 2013 St. Gallen International Expert Consensus were used to classify breast cancers in 301 patients from Colombia into intrinsic subtypes. We analyzed the distribution of subtypes by clinicopathological variables. Genetic ancestry was estimated from a panel of 80 ancestry informative markers. Luminal B breast cancer subtype was the most prevalent in our population (37.2%) followed by luminal A (26.3%), non-basal triple negative (NBTN) (11.6%), basal like (9%), human epidermal growth factor receptor 2 (HER2) enriched (8.6%) and unknown (7.3%). We found statistical significant differences in distribution between Colombian region (P = 0.007), age at diagnosis (P = 0.0139), grade (P < 0.001) and recurrence (P < 0.001) according to intrinsic subtype. Patients diagnosed with HER2-enriched, basal-like and NBTN breast cancer had the highest African ancestry. Future studies analyzing the molecular profiles of breast cancer in Colombian women will help us understand the molecular basis of this subtype distribution and compare the molecular characteristics of the different intrinsic subtypes in Colombian patients.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/epidemiologia , Recidiva Local de Neoplasia/epidemiologia , Prognóstico , Adulto , Idoso , População Negra/genética , Neoplasias da Mama/classificação , Neoplasias da Mama/genética , Colômbia/epidemiologia , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/classificação , Recidiva Local de Neoplasia/genética , Receptor ErbB-2/genética , Receptores de Estrogênio/genética , Receptores de Progesterona/genéticaRESUMO
Gastric cancer incidence varies considerably among populations, even those with comparable rates of Helicobacter pylori infection. To test the hypothesis that genetic variation plays a role in gastric disease, we assessed the relationship between genotypes and gastric histopathology in a Colombian study population, using a genotyping array of immune-related single nucleotide polymorphisms (SNPs). Two synonymous SNPs (rs6061243 and rs6587239) were associated with progression of premalignant gastric lesions in a dominant-effects model after correction for multiple comparisons (p = 2.63E-07 and p = 7.97E-07, respectively); effect sizes were ß = -0.863 and ß = -0.815, respectively, where ß is an estimate of effect on histopathology scores, which ranged from 1 (normal) to 5 (dysplasia). In our replication cohort, a second Colombian population, both SNPs were associated with histopathology when additively modeled (ß = -0.256, 95 % CI = -0.47, -0.039; and ß = -0.239, 95 % CI = -0.45, -0.024), and rs6587239 was significantly associated in a dominant-effects model (ß = -0.330, 95 % CI = -0.66, 0.00). Because promoter methylation of GATA5 has previously been associated with gastric cancer, we also tested for the association of methylation status with more advanced histopathology scores in our samples and found a significant relationship (p = 0.001). A multivariate regression model revealed that the effects of both the promoter methylation and the exonic SNPs in GATA5 were independent. A SNP-by-methylation interaction term was also significant. This interaction between GATA5 variants and GATA5 promoter methylation indicates that the association of either factor with gastric disease progression is modified by the other.
Assuntos
Metilação de DNA/genética , Epigenômica , Fator de Transcrição GATA5/genética , Infecções por Helicobacter/genética , Neoplasias Gástricas/genética , Adulto , Feminino , Estudos de Associação Genética , Genótipo , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/patologia , Helicobacter pylori/patogenicidade , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Fatores de Risco , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/patologiaRESUMO
BACKGROUND: Helicobacter pylori is the primary cause of gastric cancer, but about 9% of cases harbor Epstein-Barr virus (EBV) in the tumor cells. There is limited evidence on the possible interaction or antagonism between these infectious agents in gastric carcinogenesis. METHODS: We compared H. pylori serologic profiles of EBV-positive (n = 58) and EBV-negative (n = 111) noncardia gastric cancer patients from the United States National Cancer Institute's International EBV-Gastric Cancer Consortium. EBV positivity of tumors was assessed by in situ hybridization. Serum levels of 15 antibodies to immunogenic proteins of H. pylori (Cad, CagA, Cagδ, CagM, Catalase, GroEL, HcpC, HP0231, HP0305, HpaA, HyuA, NapA, Omp, UreA, VacA) were assessed using bead-based multiplex serology. Logistic regression models were used to adjust odds ratios (OR) for country, age, sex, and year of diagnosis. RESULTS: Seropositivity to individual proteins ranged up to 90% overall. Antibodies to Catalase were borderline associated with tumor EBV positivity (adjusted OR = 3.15, p = .0024, Bonferroni corrected p = .036). Distributions of other antibodies did not vary by tumor EBV status. CONCLUSION: Similarity of host-response indicates the essential etiological role of H. pylori in EBV-positive gastric cancer.
Assuntos
Anticorpos Antibacterianos/sangue , Helicobacter pylori/imunologia , Herpesvirus Humano 4/isolamento & purificação , Neoplasias Gástricas/patologia , Neoplasias Gástricas/virologia , Idoso , Feminino , Infecções por Helicobacter/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Estados UnidosRESUMO
BACKGROUND: There are more than 1 million persons living with HIV/AIDS (PLWHA) in the United States and approximately 40 % of them have a history of alcohol use disorders (AUD). Chronic heavy alcohol consumption and HIV/AIDS both result in reduced lean body mass and muscle dysfunction, increasing the incidence of comorbid conditions. Previous studies from our laboratory using rhesus macaques infected with Simian Immunodeficiency Virus (SIV) demonstrated that chronic binge alcohol (CBA) administration in the absence of antiretroviral therapy exacerbates skeletal muscle (SKM) wasting at end-stage SIV disease. The aim of this study was to characterize how CBA alters global gene regulatory networks that lead to SKM wasting at end-stage disease. Administration of intragastric alcohol or sucrose to male rhesus macaques began 3 months prior to SIV infection and continued throughout the duration of study. High-output array analysis was used to determine CBA-dependent changes in mRNA expression, miRNA expression, and promoter methylation status of SKM at end-stage disease (~10 months post-SIV) from healthy control (control), sucrose-administered, SIV-infected (SUC/SIV), and CBA-administered/SIV-infected (CBA/SIV) macaques. RESULTS: In addition to previously reported effects on the extracellular matrix and the promotion of a pro-inflammatory environment, we found that CBA adversely affects gene regulatory networks that involve "universal" cellular functions, protein homeostasis, calcium and ion homeostasis, neuronal growth and signaling, and satellite cell growth and survival. CONCLUSIONS: The results from this study provide an overview of the impact of CBA on gene regulatory networks involved in biological functions, including transcriptional and epigenetic processes, illustrating the genetic and molecular mechanisms associated with CBA-dependent SKM wasting at end-stage SIV infection.
Assuntos
Etanol/administração & dosagem , Redes Reguladoras de Genes/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Atrofia Muscular/genética , Síndrome de Imunodeficiência Adquirida dos Símios/complicações , Animais , Modelos Animais de Doenças , Etanol/farmacologia , Perfilação da Expressão Gênica/veterinária , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Macaca mulatta , Masculino , Atrofia Muscular/etiologia , Análise de Sequência com Séries de Oligonucleotídeos/veterinária , Síndrome de Imunodeficiência Adquirida dos Símios/patologia , Vírus da Imunodeficiência Símia , Sacarose/administração & dosagemRESUMO
BACKGROUND: Chronic binge alcohol (CBA) administration exacerbates skeletal muscle (SKM) wasting at the terminal stage of simian immunodeficiency virus (SIV) infection in rhesus macaques. This is associated with a pro-inflammatory and oxidative milieu which we have previously shown to be associated with a disrupted balance between anabolic and catabolic mechanisms. In this study, we attempted to characterize the SKM gene expression signature in CBA-administered SIV-infected macaques, using the same animals from the previous study. METHODS: Administration of intragastric alcohol or sucrose to male rhesus macaques began 3 months prior to SIV infection and continued throughout the duration of study. Gene transcriptomes of SKM excised at necropsy (~10 months post-SIV) from healthy na\xEFve control (Control), sucrose-administered, SIV-infected (SUC-SIV), and CBA-administered, SIV-infected (CBA-SIV) macaques were evaluated in microarray data sets. The Protein Analysis Through Evolutionary Relationships classification tool was used to filter differentially regulated genes based on their predicted function into select biological processes relevant to SKM wasting which were inflammation, extracellular matrix (ECM) remodeling, and metabolism. RESULTS: In total, 1,124 genes were differentially regulated between SUC-SIV and Controls, 2,022 genes were differentially expressed between the CBA-SIV and Controls, and 836 genes were differentially expressed between CBA-SIV and SUC-SIV animals. The relevance of altered gene expression was reflected in the up-regulation of pro-inflammatory CCL-2, CCL-8, CX3CL1, SELE, HP, and TNFRS10A mRNA expression. In addition, ECM remodeling was reflected in the up-regulation of TIMP-1, MMP 2, and MMP 9 mRNA expression and transforming growth factor-beta 1 protein expression. In addition, hydroxyproline content and picrosirius staining reflected increased collagen deposition in the CBA-SIV muscle tissue. CONCLUSIONS: The results of the study demonstrate SKM inflammation as an important underlying mechanism for muscle wasting. In addition, the study provides evidence of SKM fibrotic transformation as a factor in CBA-induced accentuation of SIV-associated muscle wasting.
Assuntos
Consumo Excessivo de Bebidas Alcoólicas/metabolismo , Etanol/toxicidade , Mediadores da Inflamação/metabolismo , Proteínas Musculares/biossíntese , Músculo Esquelético/metabolismo , Síndrome de Imunodeficiência Adquirida dos Símios/metabolismo , Animais , Consumo Excessivo de Bebidas Alcoólicas/epidemiologia , Doença Crônica , Etanol/administração & dosagem , Regulação da Expressão Gênica , Macaca , Macaca mulatta , Masculino , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/virologia , Síndrome de Imunodeficiência Adquirida dos Símios/epidemiologia , Vírus da Imunodeficiência SímiaRESUMO
BACKGROUND: Serum arginase levels have been shown to be elevated in conditions, such as trauma, cancer, chronic wounds, pregnancy, and diabetes. This also has been found to be true in atopic diseases, such as asthma and allergic rhinitis. OBJECTIVE: To study arginase activity in patients with atopic dermatitis (AD). METHODS: In this pilot study, arginase activity levels in 15 pediatric patients with AD were compared with those in controls to determine whether arginase levels in AD are altered as in patients with other atopic diseases. RESULTS: In contrast to the other diseases studied, arginase activity was found to be decreased in granulocytes and in the plasma of patients with AD compared with controls. This finding was coupled with a trend toward higher L-arginine plasma levels. CONCLUSION: In AD, a different mechanism of arginine metabolism seems to be stimulated, leading to the formation of nitric oxide pathway components causing suppression of the arginase pathway and impairment in skin hydration, collagen synthesis, and wound healing.
Assuntos
Arginase/sangue , Dermatite Atópica/sangue , Dermatite Atópica/enzimologia , Adolescente , Arginina/sangue , Criança , Pré-Escolar , Dermatite Atópica/imunologia , Ativação Enzimática , Eosinófilos , Feminino , Granulócitos/enzimologia , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Lactente , Contagem de Leucócitos , Masculino , Índice de Gravidade de DoençaRESUMO
Embryonic development of articular cartilage has not been well understood and the role of doublecortin (DCX) in determination of chondrocyte phenotype is unknown. Here, we use a DCX promoter-driven eGFP reporter mouse model to study the dynamic gene expression profiles in mouse embryonic handplates at E12.5 to E13.5 when the condensed mesenchymal cells differentiate into either endochondral chondrocytes or joint interzone cells. Illumina microarray analysis identified a variety of genes that were expressed differentially in the different regions of mouse handplate. The unique expression patterns of many genes were revealed. Cytl1 and 3110032G18RIK were highly expressed in the proximal region of E12.5 handplate and the carpal region of E13.5 handplate, whereas Olfr538, Kctd15, and Cited1 were highly expressed in the distal region of E12.5 and the metacarpal region of E13.5 handplates. There was an increasing gradient of Hrc expression in the proximal to distal direction in E13.5 handplate. Furthermore, when human DCX protein was expressed in human adipose stem cells, collagen II was decreased while aggrecan, matrilin 2, and GDF5 were increased during the 14-day pellet culture. These findings suggest that DCX may play a role in defining chondrocyte phenotype.
Assuntos
Condrócitos/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Neuropeptídeos/metabolismo , Animais , Diferenciação Celular , Células Cultivadas , Condrócitos/citologia , Proteínas do Domínio Duplacortina , Proteína Duplacortina , Embrião de Mamíferos/metabolismo , Desenvolvimento Embrionário , Genes Reporter , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Células-Tronco Mesenquimais/citologia , Camundongos , Proteínas Associadas aos Microtúbulos/genética , Neuropeptídeos/genética , Fenótipo , TranscriptomaRESUMO
OBJECTIVE: Maternal exposure during pregnancy is a strong determinant of offspring health outcomes. Such exposure induces changes in the offspring epigenome resulting in gene expression and functional changes. In this study, we investigated the effect of maternal Western hypercaloric diet (HCD) programming during the perinatal period on neuronal plasticity and cardiometabolic health in adult offspring. METHODS: C57BL/6J dams were fed HCD for 1 month prior to mating with regular diet (RD) sires and kept on the same diet throughout pregnancy and lactation. At weaning, offspring were maintained on either HCD or RD for 3 months resulting in 4 treatment groups that underwent cardiometabolic assessments. DNA and RNA were extracted from the hypothalamus to perform whole genome methylation, mRNA, and miRNA sequencing followed by bioinformatic analyses. RESULTS: Maternal programming resulted in male-specific hypertension and hyperglycemia, with both males and females showing increased sympathetic tone to the vasculature. Surprisingly, programmed male offspring fed HCD in adulthood exhibited lower glucose levels, less insulin resistance, and leptin levels compared to non-programmed HCD-fed male mice. Hypothalamic genes involved in inflammation and type 2 diabetes were targeted by differentially expressed miRNA, while genes involved in glial and astrocytic differentiation were differentially methylated in programmed male offspring. These data were supported by our findings of astrogliosis, microgliosis and increased microglial activation in programmed males in the paraventricular nucleus (PVN). Programming induced a protective effect in male mice fed HCD in adulthood, resulting in lower protein levels of hypothalamic TGFß2, NF-κB2, NF-κBp65, Ser-pIRS1, and GLP1R compared to non-programmed HCD-fed males. Although TGFß2 was upregulated in male mice exposed to HCD pre- or post-natally, only blockade of the brain TGFß receptor in RD-HCD mice improved glucose tolerance and a trend to weight loss. CONCLUSIONS: Our study shows that maternal HCD programs neuronal plasticity in the offspring and results in male-specific hypertension and hyperglycemia associated with hypothalamic inflammation in mechanisms and pathways distinct from post-natal HCD exposure. Together, our data unmask a compensatory role of HCD programming, likely via priming of metabolic pathways to handle excess nutrients in a more efficient way.