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2.
Front Endocrinol (Lausanne) ; 14: 1156120, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37900138

RESUMO

Introduction: Prostate cancer (PCa) presents a significant health challenge in men, with a substantial number of deaths attributed to metastatic castration resistant PCa (mCRPC). Moreover, African American men experience disproportionately high mortality rates due to PCa. This study delves into the pivotal role of SPDEF, a prostate specific Ets transcription factor, and its regulation by DNA methylation in the context of PCa progression. Methods: We performed Epigenetic reprogramming using daily treatment with non-toxic dose of 5Aza-2-deoxycytidine (5Aza-dC) for two weeks to assess its impact on PDEF expression in prostate cancer cells. Next, we conducted functional studies on reprogrammed cells, including cell migration (wound-healing assay), invasion (Boyden-Chamber test), and proliferation (MTT assay) to comprehensively evaluate the consequences of altered PDEF expression. We used bisulfite sequencing (BSP) to examine DNA methylation at SPDEF promoter. Simultaneously, we utilized siRNA-mediated targeting of key DNMTs (DNMT1, DNMT3A, and DNMT3B) to elucidate their specific role in regulating PDEF. We measured mRNA and protein expressions using qRT-PCR and immune-blotting techniques, respectively. Results: In this report, we observed that: a) there is a gradual decrease in SPDEF expression with a concomitant increase in methylated CpG sites within the SPDEF gene during prostate cancer progression from lower to higher Gleason grade; b) Expression of DNMT's (DNMT1, 3a and 3b) is increased during prostate cancer progression, and there is an inverse correlation between SPDEF and DNMT expression; c) SPDEF levels are decreased in RC77/T, a line of PCa cells from African American origin similar to PC3 and DU145 cells (CRPC cells), as compared to LNCaP cells , a line of androgen dependent cells,; d) the 5' CpG island of SPDEF gene are hypermethylated in SPDEF-negative CRPC ( PC3, DU145 and RC77/T) cell lines but the same regions are hypomethylated in SPDEF-positive castrate sensitive (LNCaP) cell line ; (e) expression of SPDEF in PCa cells lacking SPDEF decreases cell migration and invasion, but has no significant effect on cell proliferation, and; (f) treatment with the demethylating agent, 5-aza-2'-deoxycytidine, or silencing of the DNMT's by siRNA, partially restores SPDEF expression in SPDEF-negative PCa cell lines, and decreases cell migration and invasion. Discussion: These results indicate hypermethylation is a prevalent mechanism for decreasing SPDEF expression during prostate cancer progression. The data demonstrate that loss of SPDEF expression in prostate cancer cells, a critical step in cellular plasticity, results from a potentially reversible process of aberrant DNA methylation. These studies suggest DMNT activity as a potential therapeutic vulnerability that can be exploited for limiting cellular plasticity, tumor progression, and therapy resistance in prostate cancer.


Assuntos
Metilação de DNA , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/genética , Linhagem Celular Tumoral , Ilhas de CpG/genética , Decitabina , RNA Interferente Pequeno , Proteínas Proto-Oncogênicas c-ets/genética
3.
J Natl Cancer Inst ; 115(10): 1204-1212, 2023 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-37697664

RESUMO

BACKGROUND: Research indicates that Black cancer patients have higher rates of COVID-19 hospitalization than their White counterparts. However, the extent to which chronic diseases contribute to racial disparities remains uncertain. We aimed to quantify the effect of chronic diseases on racial disparity in COVID-19-associated hospitalization among cancer patients. METHODS: We linked Louisiana Tumor Registry's data with statewide COVID-19 data and hospital in-patient discharge data to identify patients diagnosed with cancer in 2015-2019 who tested positive for COVID-19 in 2020 and those with COVID-19-associated hospitalization. Multivariable logistic regression and mediation methods based on linear structural equations were employed to assess the effects of the number of chronic diseases (0, 1-2, ≥3) and individual chronic diseases. RESULTS: Of 6381 cancer patients who tested positive for COVID-19, 31.6% were non-Hispanic Black cancer patients. Compared with non-Hispanic White cancer patients, non-Hispanic Black cancer patients had a higher prevalence of chronic diseases (79.5% vs 66.0%) and higher COVID-19-associated hospitalization (27.2% vs 17.2%). The odds of COVID-19-associated hospitalization were 80% higher for non-Hispanic Black cancer patients than non-Hispanic White cancer patients (odds ratio = 1.80, 95% confidence interval = 1.59 to 2.04). After adjusting for age, sex, insurance, poverty, obesity, and cancer type, number of chronic diseases explained 37.8% of the racial disparity in COVID-19-associated hospitalization, and hypertension, diabetes, and chronic renal disease were the top 3 chronic diseases explaining 9.6%, 8.9%, and 7.3% of the racial disparity, respectively. CONCLUSION: Chronic diseases played a substantial role in the racial disparity in COVID-19-associated hospitalization among cancer patients, especially hypertension, diabetes, and renal disease. Understanding and addressing the root causes are crucial for targeted interventions, policies, and health-care strategies to reduce racial disparity.


Assuntos
Negro ou Afro-Americano , COVID-19 , Doença Crônica , Hospitalização , Neoplasias , Brancos , Humanos , Negro ou Afro-Americano/estatística & dados numéricos , Doença Crônica/epidemiologia , Doença Crônica/etnologia , Doença Crônica/terapia , COVID-19/epidemiologia , COVID-19/etnologia , COVID-19/terapia , Diabetes Mellitus/epidemiologia , Hospitalização/estatística & dados numéricos , Hipertensão/complicações , Hipertensão/epidemiologia , Neoplasias/epidemiologia , Neoplasias/etnologia , Neoplasias/terapia , Fatores Raciais , Estudos Retrospectivos , Estados Unidos/epidemiologia , Brancos/estatística & dados numéricos
4.
Cancer ; 129(6): 829-833, 2023 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-36632769

RESUMO

BACKGROUND: Louisiana continues to have one of the highest breast cancer mortality rates in the nation, and Black women are disproportionally affected. Louisiana has made advances in improving access to breast cancer screening through the expansion of Medicaid. There remains, however, broad underuse of advanced imaging technology such as screening breast magnetic resonance imaging (MRI), particularly for Black women. METHODS: Breast MRI has been proven to be very sensitive for the early detection of breast cancer in women at high risk. MRI is more sensitive than mammography for aggressive, invasive breast cancer types, which disproportionally affect Black women. Here the authors identify potential barriers to breast MRI screening in Black women, propose strategies to address disparities in access, and advocate for specific recommendations for change. RESULTS: Cost was identified as one of the greatest barriers to screening breast MRI. The authors propose implementation of cost-saving, abbreviated protocols to address cost along with lobbying for further expansion of the Affordable Care Act (ACA) to include coverage for screening breast MRI. In addition, addressing gaps in communication and knowledge and facilitating providers' ability to readily identify women who might benefit from MRI could be particularly impactful for high-risk Black women in Louisiana communities. CONCLUSIONS: Since the adoption of the ACA in Louisiana, Black women have continued to have disproportionally high breast cancer mortality rates. This persistent disparity provides evidence that additional change is needed. This change should include exploring innovative ways to make advanced imaging technology such as breast MRI more accessible and expanding research to specifically address community and culturally specific barriers.


Assuntos
Neoplasias da Mama , Patient Protection and Affordable Care Act , Estados Unidos , Feminino , Humanos , Política Organizacional , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/prevenção & controle , Mamografia , Louisiana/epidemiologia , Detecção Precoce de Câncer/métodos , Imageamento por Ressonância Magnética
5.
Cancer Epidemiol Biomarkers Prev ; 31(8): 1532-1538, 2022 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-35654355

RESUMO

BACKGROUND: Race modifies the association between anthropometric measures of obesity and cancer risk. However, the degree to which abdominal visceral adipose tissue (VAT) and total fat mass (FM) are associated with cancer risk is not known. METHODS: The sample included 3,017 White and 1,347 Black adults who were assessed between 1995 and 2016 and followed for outcome assessment through 2017. Abdominal VAT and FM were measured using imaging techniques. The co-primary endpoints were diagnosis of histologically confirmed invasive cancer (excluding nonmelanoma skin cancer) or death from cancer. Multivariable Cox proportional hazards models quantified the HR of incident cancer and cancer mortality. RESULTS: There were 353 incident cancer cases and 75 cancer deaths in an average of 12.9 years of follow-up. Both VAT [HR, 1.21; 95% confidence interval (CI), 1.09-1.36] and FM (HR, 1.25; 95% CI, 1.10-1.43) were significantly associated with incident cancer, while VAT (HR, 1.28; 95% CI, 1.01-1.61) was significantly associated with cancer mortality after adjustment for several covariates. VAT remained significantly associated with cancer incidence (HR, 1.22; 95% CI, 1.03-1.46) after additional inclusion of FM in the multivariable model, but not vice versa. There were no significant sex- or race-interactions. CONCLUSIONS: VAT was associated with risk of cancer and cancer mortality in this cohort, and the associations did not differ by sex or race. The association between VAT and incident cancer was largely independent of total FM. IMPACT: Our results suggest that utility of anthropometry in assessing obesity-related cancer risk may need to be further refined by including more direct measures of adiposity.


Assuntos
Adiposidade , Neoplasias , Adulto , Índice de Massa Corporal , Humanos , Incidência , Neoplasias/epidemiologia , Obesidade/complicações , Obesidade/epidemiologia
6.
Am J Prev Med ; 63(1 Suppl 1): S83-S92, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35725146

RESUMO

INTRODUCTION: Breast cancer is a heterogeneous disease, consisting of multiple molecular subtypes. Obesity has been associated with an increased risk for postmenopausal breast cancer, but few studies have examined breast cancer subtypes separately. Obesity is often complicated by type 2 diabetes, but the possible association of diabetes with specific breast cancer subtypes remains poorly understood. METHODS: In this retrospective case-control study, Louisiana Tumor Registry records of primary invasive breast cancer diagnosed in 2010-2015 were linked to electronic health records in the Louisiana Public Health Institute's Research Action for Health Network. Controls were selected from Research Action for Health Network and matched to cases by age and race. Conditional logistic regression was used to identify metabolic risk factors. Data analysis was conducted in 2020‒2021. RESULTS: There was a significant association between diabetes and breast cancer for Luminal A, Triple-Negative Breast Cancer, and human epidermal growth factor 2‒positive subtypes. In multiple logistic regression, including both obesity status and diabetes as independent risk factors, Luminal A breast cancer was also associated with overweight status. Diabetes was associated with increased risk for Luminal A and Triple-Negative Breast Cancer in subgroup analyses, including women aged ≥50 years, Black women, and White women. CONCLUSIONS: Although research has identified obesity and diabetes as risk factors for breast cancer, these results underscore that comorbid risk is complex and may differ by molecular subtype. There was a significant association between diabetes and the incidence of Luminal A, Triple-Negative Breast Cancer, and human epidermal growth factor 2‒positive breast cancer in Louisiana.


Assuntos
Neoplasias da Mama , Diabetes Mellitus Tipo 2 , Obesidade , Neoplasias de Mama Triplo Negativas , Neoplasias da Mama/epidemiologia , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Humanos , Incidência , Louisiana/epidemiologia , Obesidade/epidemiologia , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Fatores de Risco , Neoplasias de Mama Triplo Negativas/epidemiologia
7.
Front Cardiovasc Med ; 9: 756734, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35509276

RESUMO

Racist and discriminatory federal, state, and local housing policies significantly contribute to disparities in cardiovascular disease incidence and mortality for individuals that self-identify as Black or African American. Here we highlight three key housing policies - "redlining," zoning, and the construction of highways - which have wrought a powerful, sustained, and destructive impact on cardiovascular health in Black/African American communities. Redlining and highway construction policies have restricted access to quality health care, increased exposure to carcinogens such as PM2.5, and increased exposure to extreme heat. At the root of these policy decisions are longstanding, toxic societal factors including racism, segregation, and discrimination, which also serve to perpetuate racial inequities in cardiovascular health. Here, we review these societal and structural factors and then link them with biological processes such as telomere shortening, allostatic load, oxidative stress, and tissue inflammation. Lastly, we focus on the impact of inflammation on the immune system and the molecular mechanisms by which the inflamed immune microenvironment promotes the formation of atherosclerotic plaques. We propose that racial residential segregation and discrimination increases tissue inflammation and cytokine production, resulting in dysregulated immune signaling, which promotes plaque formation and cardiovascular disease. This framework has the power to link structural racism not only to cardiovascular disease, but also to cancer.

8.
EBioMedicine ; 77: 103910, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35248994

RESUMO

BACKGROUND: Low-density neutrophils (LDN) are increased in several inflammatory diseases and may also play a role in the low-grade chronic inflammation associated with obesity. Here we explored their role in obesity, determined their gene signatures, and assessed the effect of bariatric surgery. METHODS: We compared the number, function, and gene expression profiles of circulating LDN in morbidly obese patients (MOP, n=27; body mass index (BMI) > 40 Kg/m2) and normal-weight controls (NWC, n=20; BMI < 25 Kg/m2) in a case-control study. Additionally, in a prospective longitudinal study, we measured changes in the frequency of LDN after bariatric surgery (n=36) and tested for associations with metabolic and inflammatory parameters. FINDINGS: LDN and inflammatory markers were significantly increased in MOP compared to NWC. Transcriptome analysis showed increased neutrophil-related gene expression signatures associated with inflammation, neutrophil activation, and immunosuppressive function. However, LDN did not suppress T cells proliferation and produced low levels of reactive oxygen species (ROS). Circulating LDN in MOP significantly decreased after bariatric surgery in parallel with BMI, metabolic syndrome, and inflammatory markers. INTERPRETATION: Obesity increases LDN displaying an inflammatory gene signature. Our results suggest that LDN may represent a neutrophil subset associated with chronic inflammation, a feature of obesity that has been previously associated with the appearance and progression of co-morbidities. Furthermore, bariatric surgery, as an efficient therapy for severe obesity, reduces LDN in circulation and improves several components of the metabolic syndrome supporting its recognized anti-inflammatory and beneficial metabolic effects. FUNDING: This work was supported in part by grants from the National Institutes of Health (NIH; 5P30GM114732-02, P20CA233374 - A. Ochoa and L. Miele), Pennington Biomedical NORC (P30DK072476 - E. Ravussin & LSU-NO Stanley S. Scott Cancer Center and Louisiana Clinical and Translational Science Center (LACaTS; U54-GM104940 - J. Kirwan).


Assuntos
Cirurgia Bariátrica , Obesidade Mórbida , Cirurgia Bariátrica/métodos , Estudos de Casos e Controles , Humanos , Estudos Longitudinais , Neutrófilos/metabolismo , Obesidade Mórbida/complicações , Obesidade Mórbida/metabolismo , Obesidade Mórbida/cirurgia , Estudos Prospectivos
9.
Obesity (Silver Spring) ; 29(12): 2119-2125, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34693655

RESUMO

OBJECTIVE: This study aimed to determine whether race modifies the association between obesity and cancer death. METHODS: The Pennington Center Longitudinal Study included 18,296 adults; 35.0% were male and 34.3% were Black. The primary end point was death from cancer. RESULTS: During a follow-up of 14.3 years, 346 cancer deaths occurred. Among men, race modified the association of BMI and cancer death (pinteraction = 0.045); compared with a BMI of 22 kg/m2 , a BMI of 35 in White men was associated with a hazard ratio of 1.74 (95% CI: 1.38-2.21), and in Black men, the hazard ratio was 0.64 (95% CI: 0.45-0.90). Among women, race did not modify the association of BMI and cancer death (pinteraction =0.43); however, compared with a BMI of 22, a BMI of 35 in White women was associated with a hazard ratio of 1.42 (95% CI: 1.18-1.70) and in Black women, the hazard ratio was 0.99 (95% CI: 0.82-1.20). CONCLUSIONS: In this diverse cohort of adults, having obesity was associated with an increased risk of cancer death in White men and women. In contrast, having obesity was associated with a reduced risk of cancer death in Black men and did not influence risk in Black women.


Assuntos
Neoplasias , População Branca , Adulto , Negro ou Afro-Americano , Índice de Massa Corporal , Estudos de Coortes , Feminino , Humanos , Estudos Longitudinais , Masculino , Neoplasias/complicações , Obesidade/complicações , Estudos Prospectivos , Fatores de Risco
10.
Front Immunol ; 12: 695972, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34341659

RESUMO

COVID-19 ranges from asymptomatic in 35% of cases to severe in 20% of patients. Differences in the type and degree of inflammation appear to determine the severity of the disease. Recent reports show an increase in circulating monocytic-myeloid-derived suppressor cells (M-MDSC) in severe COVID 19 that deplete arginine but are not associated with respiratory complications. Our data shows that differences in the type, function and transcriptome of granulocytic-MDSC (G-MDSC) may in part explain the severity COVID-19, in particular the association with pulmonary complications. Large infiltrates by Arginase 1+ G-MDSC (Arg+G-MDSC), expressing NOX-1 and NOX-2 (important for production of reactive oxygen species) were found in the lungs of patients who died from COVID-19 complications. Increased circulating Arg+G-MDSC depleted arginine, which impaired T cell receptor and endothelial cell function. Transcriptomic signatures of G-MDSC from patients with different stages of COVID-19, revealed that asymptomatic patients had increased expression of pathways and genes associated with type I interferon (IFN), while patients with severe COVID-19 had increased expression of genes associated with arginase production, and granulocyte degranulation and function. These results suggest that asymptomatic patients develop a protective type I IFN response, while patients with severe COVID-19 have an increased inflammatory response that depletes arginine, impairs T cell and endothelial cell function, and causes extensive pulmonary damage. Therefore, inhibition of arginase-1 and/or replenishment of arginine may be important in preventing/treating severe COVID-19.


Assuntos
COVID-19/imunologia , Granulócitos/imunologia , Células Supressoras Mieloides/imunologia , SARS-CoV-2/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antivirais/administração & dosagem , Arginase/antagonistas & inibidores , Arginase/metabolismo , Arginina/administração & dosagem , Arginina/sangue , Arginina/metabolismo , Infecções Assintomáticas , COVID-19/sangue , COVID-19/diagnóstico , Estudos de Casos e Controles , Quimioterapia Combinada/métodos , Inibidores Enzimáticos/administração & dosagem , Feminino , Granulócitos/metabolismo , Voluntários Saudáveis , Humanos , Interferon Tipo I/metabolismo , Masculino , Pessoa de Meia-Idade , Células Supressoras Mieloides/metabolismo , Índice de Gravidade de Doença , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Tratamento Farmacológico da COVID-19
11.
Proc Natl Acad Sci U S A ; 118(25)2021 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-34088793

RESUMO

Low plasma arginine bioavailability has been implicated in endothelial dysfunction and immune dysregulation. The role of arginine in COVID-19 is unknown, but could contribute to cellular damage if low. Our objective was to determine arginine bioavailability in adults and children with COVID-19 vs. healthy controls. We hypothesized that arginine bioavailability would be low in patients with COVID-19 and multisystem inflammatory syndrome in children (MIS-C). We conducted a prospective observational study of three patient cohorts; arginine bioavailability was determined in asymptomatic healthy controls, adults hospitalized with COVID-19, and hospitalized children/adolescents <21 y old with COVID-19, MIS-C, or asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection identified on admission screen. Mean patient plasma amino acids were compared to controls using the Student's t test. Arginine-to-ornithine ratio, a biomarker of arginase activity, and global arginine bioavailability ratio (GABR, arginine/[ornithine+citrulline]) were assessed in all three groups. A total of 80 patients were included (28 controls, 32 adults with COVID-19, and 20 pediatric patients with COVID-19/MIS-C). Mean plasma arginine and arginine bioavailability ratios were lower among adult and pediatric patients with COVID-19/MIS-C compared to controls. There was no difference between arginine bioavailability in children with COVID-19 vs. MIS-C. Adults and children with COVID-19 and MIS-C in our cohort had low arginine bioavailability compared to healthy adult controls. This may contribute to immune dysregulation and endothelial dysfunction in COVID-19. Low arginine-to-ornithine ratio in patients with COVID-19 or MIS-C suggests an elevation of arginase activity. Further study is merited to explore the role of arginine dysregulation in COVID-19.


Assuntos
Aminoácidos/sangue , COVID-19/sangue , Hospitalização , SARS-CoV-2/metabolismo , Adulto , COVID-19/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
12.
Obesity (Silver Spring) ; 29(6): 960-965, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34029447

RESUMO

OBJECTIVE: Anthropometric measures of obesity, including BMI and waist circumference (WC), do not quantify excess adiposity and metabolic abnormalities consistently across racial populations. This study tested the hypothesis that participant race modifies the association of anthropometric measures of obesity and cancer risk. METHODS: This prospective cohort (The Pennington Center Longitudinal Study) included 18,296 adults, 6,405 (35.0%) male sex and 6,273 (34.3%) Black race. The primary exposures were BMI (weight in kilograms/height in meters squared) and WC (centimeters). The primary end point was the time from study enrollment to diagnosis of histologically confirmed invasive cancer. RESULTS: During a median follow-up of 14.0 years (interquartile range: 9.8-19.0 years), invasive cancer occurred in 1,350 participants. Among men, race modified the association of BMI (Pinteraction = 0.02) and WC (Pinteraction = 0.01) with cancer incidence; compared with a BMI of 22 kg/m2 , a BMI of 35 kg/m2 in White men was associated with a hazard ratio of 1.83 (95% CI: 1.58-2.12), whereas in Black men, the hazard ratio was 0.89 (95% CI: 0.72-1.11). Among women, race did not modify the association of BMI (Pinteraction = 0.41) or WC (Pinteraction = 0.36) with cancer incidence. CONCLUSIONS: In this diverse cohort of adults, participant race and sex modified the prognostic associations of anthropometric measures of obesity and cancer risk.


Assuntos
Negro ou Afro-Americano/estatística & dados numéricos , Neoplasias/epidemiologia , Neoplasias/etiologia , Obesidade/epidemiologia , População Branca/estatística & dados numéricos , Adulto , Idoso , Índice de Massa Corporal , Peso Corporal , Estudos de Coortes , Feminino , Humanos , Incidência , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Neoplasias/etnologia , Obesidade/complicações , Obesidade/etnologia , Estudos Prospectivos , Fatores de Risco , Estados Unidos/epidemiologia , Adulto Jovem
13.
medRxiv ; 2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33791717

RESUMO

COVID-19 ranges from asymptomatic in 35% of cases to severe in 20% of patients. Differences in the type and degree of inflammation appear to determine the severity of the disease. Recent reports show an increase in circulating monocytic-myeloid-derived suppressor cells (M-MDSC) in severe COVID 19, that deplete arginine but are not associated with respiratory complications. Our data shows that differences in the type, function and transcriptome of Granulocytic-MDSC (G-MDSC) may in part explain the severity COVID-19, in particular the association with pulmonary complications. Large infiltrates by Arginase 1 + G-MDSC (Arg + G-MDSC), expressing NOX-1 and NOX-2 (important for production of reactive oxygen species) were found in the lungs of patients who died from COVID-19 complications. Increased circulating Arg + G-MDSC depleted arginine, which impaired T cell receptor and endothelial cell function. Transcriptomic signatures of G-MDSC from patients with different stages of COVID-19, revealed that asymptomatic patients had increased expression of pathways and genes associated with type I interferon (IFN), while patients with severe COVID-19 had increased expression of genes associated with arginase production, and granulocyte degranulation and function. These results suggest that asymptomatic patients develop a protective type I IFN response, while patients with severe COVID-19 have an increased inflammatory response that depletes arginine, impairs T cell and endothelial cell function, and causes extensive pulmonary damage. Therefore, inhibition of arginase-1 and/or replenishment of arginine may be important in preventing/treating severe COVID-19.

14.
Mol Cancer Ther ; 20(7): 1295-1304, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33879557

RESUMO

Immune-checkpoint inhibitor (ICI) therapy has been widely used to treat different human cancers, particularly advanced solid tumors. However, clinical studies have reported that ICI immunotherapy benefits only ∼15% of patients with colorectal cancer, specifically those with tumors characterized by microsatellite instability (MSI), a molecular marker of defective DNA mismatch repair (dMMR). For the majority of patients with colorectal cancer who carry proficient MMR (pMMR), ICIs have shown little clinical benefit. In this study, we examined the efficacy of sulindac to enhance the response of pMMR colorectal cancer to anti-PD-L1 immunotherapy. We utilized a CT26 syngeneic mouse tumor model to compare the inhibitory effects of PD-L1 antibody (Ab), sulindac, and their combination on pMMR colorectal cancer tumor growth. We found that mice treated with combination therapy showed a significant reduction in tumor volume, along with increased infiltration of CD8+ T lymphocytes in the tumor tissues. We also demonstrated that sulindac could downregulate PD-L1 by blocking NF-κB signaling, which in turn led to a decrease in exosomal PD-L1. Notably, PD-L1 Ab can be bound and consumed by exosomal PD-L1 in the blood circulation. Therefore, in combination therapy, sulindac downregulating PD-L1 leads to increased availability of PD-L1 Ab, which potentially improves the overall efficacy of anti-PD-L1 therapy. We also show that low-dose sulindac does not appear to have a systemic inhibitory effect on prostaglandin E2 (PGE2). In conclusion, our findings provide unique insights into the mechanism of action and efficacy for sulindac as an immunomodulatory agent in combination with anti-PD-L1 therapy for the treatment of pMMR colorectal cancer.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Antineoplásicos/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Reparo de Erro de Pareamento de DNA/efeitos dos fármacos , Inibidores de Checkpoint Imunológico/farmacologia , Sulindaco/farmacologia , Animais , Antineoplásicos Imunológicos/uso terapêutico , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Camundongos , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacos
15.
PLoS One ; 16(3): e0247640, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33661923

RESUMO

BACKGROUND: Neutralizing-antibody (nAb) is the major focus of most ongoing COVID-19 vaccine trials. However, nAb response against SARS-CoV-2, when present, decays rapidly. Given the myriad roles of antibodies in immune responses, it is possible that antibodies could also mediate protection against SARS-CoV-2 via effector mechanisms such as antibody-dependent cellular cytotoxicity (ADCC), which we sought to explore here. METHODS: Plasma of 3 uninfected controls and 20 subjects exposed to, or recovering from, SARS-CoV-2 infection were collected from U.S. and sub-Saharan Africa. Immunofluorescence assay was used to detect the presence of SARS-CoV-2 specific IgG antibodies in the plasma samples. SARS-CoV-2 specific neutralizing capability of these plasmas was assessed with SARS-CoV-2 spike pseudotyped virus. ADCC activity was assessed with a calcein release assay. RESULTS: SARS-CoV-2 specific IgG antibodies were detected in all COVID-19 subjects studied. All but three COVID-19 subjects contained nAb at high potency (>80% neutralization). Plasma from 19/20 of COVID-19 subjects also demonstrated strong ADCC activity against SARS-CoV-2 spike glycoprotein, including two individuals without nAb against SARS-CoV-2. CONCLUSION: Both neutralizing and non-neutralizing COVID-19 plasmas can mediate ADCC. Our findings argue that evaluation of potential vaccines against SARS-CoV-2 should include investigation of the magnitude and durability of ADCC, in addition to nAb.


Assuntos
Citotoxicidade Celular Dependente de Anticorpos , COVID-19/sangue , SARS-CoV-2/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , COVID-19/imunologia , Feminino , Células HEK293 , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Glicoproteína da Espícula de Coronavírus/imunologia , Adulto Jovem
16.
Obesity (Silver Spring) ; 29(6): 944-953, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33616242

RESUMO

Obesity is a risk factor for developing several cancers. The dysfunctional metabolism and chronic activation of inflammatory pathways in obesity create a milieu that supports tumor initiation, progression, and metastasis. Obesity-associated metabolic, endocrine, and inflammatory mediators, besides interacting with cells leading to a malignant transformation, also modify the intrinsic metabolic and functional characteristics of immune myeloid cells. Here, the evidence supporting the hypothesis that obesity metabolically primes and promotes the expansion of myeloid cells with immunosuppressive and pro-oncogenic properties is discussed. In consequence, the accumulation of these cells, such as myeloid-derived suppressor cells and some subtypes of adipose-tissue macrophages, creates a microenvironment conducive to tumor development. In this review, the role of lipids, insulin, and leptin, which are dysregulated in obesity, is emphasized, as well as dietary nutrients in metabolic reprogramming of these myeloid cells. Moreover, emerging evidence indicating that obesity enhances immunotherapy response and hypothesized mechanisms are summarized. Priorities in deeper exploration involving the mechanisms of cross talk between metabolic disorders and myeloid cells related to cancer risk in patients with obesity are highlighted.


Assuntos
Imunoterapia , Células Supressoras Mieloides/fisiologia , Neoplasias/etiologia , Obesidade/imunologia , Tecido Adiposo/metabolismo , Animais , Carcinogênese/imunologia , Carcinogênese/metabolismo , Carcinogênese/patologia , Humanos , Imunoterapia/métodos , Mediadores da Inflamação/metabolismo , Leptina/metabolismo , Macrófagos/metabolismo , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Células Supressoras Mieloides/patologia , Metástase Neoplásica , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/prevenção & controle , Obesidade/complicações , Obesidade/metabolismo , Obesidade/terapia , Fatores de Risco , Microambiente Tumoral/imunologia
17.
Cell Immunol ; 362: 104302, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33592540

RESUMO

MDSC are a heterogeneous population of immature myeloid cells that are released by biological stress such as tissue damage and inflammation. Conventionally, MDSC are known for their detrimental role in chronic inflammation and neoplastic conditions. However, their intrinsic functions in immunoregulation, wound healing, and angiogenesis are intended to protect from over-reactive immune responses, maintenance of immunotolerance, tissue repair, and homeostasis. Paradoxically, under certain conditions, MDSC can impair protective immune responses and exacerbate the disease. The transition from protective to harmful MDSC is most likely driven by environmental and epigenetic mechanisms induced by prolonged exposure to unresolved inflammatory triggers. Here, we review several examples of the dual impact of MDSC in conditions such as maternal-fetal tolerance, self-antigens immunotolerance, obesity-associated cancer, sepsis and trauma. Moreover, we also highlighted the evidence indicating that MDSC have a role in COVID-19 pathophysiology. Finally, we have summarized the evidence indicating epigenetic mechanisms associated with MDSC function.


Assuntos
Células Supressoras Mieloides/imunologia , Animais , COVID-19/imunologia , Epigênese Genética , Feminino , Humanos , Tolerância Imunológica/imunologia , Inflamação/imunologia , Masculino , Neoplasias/imunologia , Obesidade/imunologia , Gravidez , Cicatrização/imunologia
18.
J Immunother Cancer ; 9(1)2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33495297

RESUMO

BACKGROUND: Poly(ADP-ribose) polymerase (PARP) inhibitors (eg, olaparib) are effective against BRCA-mutated cancers at/near maximum tolerated doses by trapping PARP-1 on damaged chromatin, benefitting only small patient proportions. The benefits of targeting non-DNA repair aspects of PARP with metronomic doses remain unexplored. METHODS: Colon epithelial cells or mouse or human bone marrow (BM)-derived-myeloid-derived suppressor cells (MDSCs) were stimulated to assess the effect of partial PARP-1 inhibition on inflammatory gene expression or immune suppression. Mice treated with azoxymethane/four dextran-sulfate-sodium cycles or APCMin/+ mice bred into PARP-1+/- or treated with olaparib were used to examine the role of PARP-1 in colitis-induced or spontaneous colon cancer, respectively. Syngeneic MC-38 cell-based (microsatellite instability, MSIhigh) or CT-26 cell-based (microsatellite stable, MSS) tumor models were used to assess the effects of PARP inhibition on host responses and synergy with anti-Programmed cell Death protein (PD)-1 immunotherapy. RESULTS: Partial PARP-1 inhibition, via gene heterozygosity or a moderate dose of olaparib, protected against colitis-mediated/APCMin -mediated intestinal tumorigenesis and APCMin -associated cachexia, while extensive inhibition, via gene knockout or a high dose of olaparib, was ineffective or aggravating. A sub-IC50-olaparib dose or PARP-1 heterozygosity was sufficient to block tumorigenesis in a syngeneic colon cancer model by modulating the suppressive function, but not intratumoral migration or differentiation, of MDSCs, with concomitant increases in intratumoral T cell function and cytotoxicity, as assessed by granzyme-B/interferon-γ levels. Adoptive transfer of WT-BM-MDSCs abolished the protective effects of PARP-1 heterozygosity. The mechanism of MDSC modulation involved a reduction in arginase-1/inducible nitric oxide synthase/cyclo-oxygenase-2, but independent of PARP-1 trapping on chromatin. Although a high-concentration olaparib or the high-trapping PARP inhibitor, talazoparib, activated stimulator of interferon gene (STING) in BRCA-proficient cells and induced DNA damage, sub-IC50 concentrations of either drug failed to induce activation of the dsDNA break sensor. STING expression appeared dispensable for MDSC suppressive function and was not strictly required for olaparib-mediated effects. Ironically, STING activation blocked human and mouse MDSC function with no additive effects with olaparib. A metronomic dose of olaparib was highly synergistic with anti-PD-1-based immunotherapy, leading to eradication of MSIhigh or reduction of MSS tumors in mice. CONCLUSIONS: These results support a paradigm-shifting concept that expands the utility of PARP inhibitor and encourage testing metronomic dosing of PARP inhibitor to enhance the efficacy of checkpoint inhibitor-based immunotherapies in cancer.


Assuntos
Colite/complicações , Neoplasias do Colo/tratamento farmacológico , Inibidores de Checkpoint Imunológico/administração & dosagem , Ftalazinas/administração & dosagem , Piperazinas/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Administração Metronômica , Animais , Azoximetano/efeitos adversos , Linhagem Celular Tumoral , Colite/induzido quimicamente , Neoplasias do Colo/etiologia , Sulfato de Dextrana/efeitos adversos , Sinergismo Farmacológico , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Camundongos , Células Supressoras Mieloides/metabolismo , Ftalazinas/farmacologia , Piperazinas/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Oncogene ; 37(33): 4534-4545, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29743595

RESUMO

Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of several human cancers such as Kaposi's sarcoma (KS), which represents the most common AIDS-associated malignancy that lacks effective treatment options. Despite its clear role in AIDS malignancies, the fact that only a small set of KSHV-infected patients will eventually develop these tumors implies that additional co-factors are required for the development of KSHV-related cancers. In the current study, we demonstrate for the first time that KSHV de novo infection or viral latent proteins are able to transactivate human endogenous retrovirus K (HERV-K) through a variety of cellular signaling pathways and transcriptional factors. Moreover, we found that HERV-K transactivation, particularly activation of its encoded oncogenic NP9 protein, plays an important role in KSHV pathogenesis and tumorigenesis in vitro and in vivo. Our data provide innovative insights into the mechanisms of HERV-K transactivation contributing to viral oncogenesis, which may represent a promising target for KS treatment.


Assuntos
Retrovirus Endógenos/genética , Sarcoma de Kaposi/genética , Sarcoma de Kaposi/virologia , Ativação Transcricional/genética , Adulto , Idoso , Carcinogênese/genética , Linhagem Celular , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Pessoa de Meia-Idade , Transdução de Sinais/genética , Fatores de Transcrição/genética , Proteínas Virais/genética , Adulto Jovem
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