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CD39 (ENTPD1) is a key enzyme responsible for degradation of extracellular ATP and is upregulated in the tumor microenvironment (TME). Extracellular ATP accumulates in the TME from tissue damage and immunogenic cell death, potentially initiating proinflammatory responses that are reduced by the enzymatic activity of CD39. Degradation of ATP by CD39 and other ectonucleotidases (e.g., CD73) results in extracellular adenosine accumulation, constituting an important mechanism for tumor immune escape, angiogenesis induction, and metastasis. Thus, inhibiting CD39 enzymatic activity can inhibit tumor growth by converting a suppressive TME to a proinflammatory environment. SRF617 is an investigational, anti-CD39, fully human IgG4 Ab that binds to human CD39 with nanomolar affinity and potently inhibits its ATPase activity. In vitro functional assays using primary human immune cells demonstrate that inhibiting CD39 enhances T-cell proliferation, dendritic cell maturation/activation, and release of IL-1ß and IL-18 from macrophages. In vivo, SRF617 has significant single-agent antitumor activity in human cell line-derived xenograft models that express CD39. Pharmacodynamic studies demonstrate that target engagement of CD39 by SRF617 in the TME inhibits ATPase activity, inducing proinflammatory mechanistic changes in tumor-infiltrating leukocytes. Syngeneic tumor studies using human CD39 knock-in mice show that SRF617 can modulate CD39 levels on immune cells in vivo and can penetrate the TME of an orthotopic tumor, leading to increased CD8+ T-cell infiltration. Targeting CD39 is an attractive approach for treating cancer, and, as such, the properties of SRF617 make it an excellent drug development candidate.
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Imunoglobulina G , Ativação Linfocitária , Humanos , Animais , Camundongos , Anticorpos Monoclonais , Adenosina Trifosfatases , Trifosfato de AdenosinaRESUMO
The ectonucleotidases CD39 and CD73 catalyze extracellular ATP to immunosuppressive adenosine, and as such, represent potential cancer targets. We investigated biological impacts of CD39 and CD73 in pancreatic ductal adenocarcinoma (PDAC) by studying clinical samples and experimental mouse tumors. Stromal CD39 and tumoral CD73 expression significantly associated with worse survival in human PDAC samples and abolished the favorable prognostic impact associated with the presence of tumor-infiltrating CD8+ T cells. In mouse transplanted KPC tumors, both CD39 and CD73 on myeloid cells, as well as CD73 on tumor cells, promoted polarization of infiltrating myeloid cells towards an M2-like phenotype, which enhanced tumor growth. CD39 on tumor-specific CD8+ T cells and pancreatic stellate cells also suppressed IFNγ production by T cells. Although therapeutic inhibition of CD39 or CD73 alone significantly delayed tumor growth in vivo, targeting of both ectonucleotidases exhibited markedly superior antitumor activity. CD73 expression on human and mouse PDAC tumor cells also protected against DNA damage induced by gemcitabine and irradiation. Accordingly, large-scale pharmacogenomic analyses of human PDAC cell lines revealed significant associations between CD73 expression and gemcitabine chemoresistance. Strikingly, increased DNA damage in CD73-deficient tumor cells associated with activation of the cGAS-STING pathway. Moreover, cGAS expression in mouse KPC tumor cells was required for antitumor activity of the CD73 inhibitor AB680 in vivo. Our study, thus, illuminates molecular mechanisms whereby CD73 and CD39 seemingly cooperate to promote PDAC progression.
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Adenosina , Neoplasias Pancreáticas , Animais , Humanos , Camundongos , 5'-Nucleotidase/genética , 5'-Nucleotidase/metabolismo , Adenosina/metabolismo , Apirase , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular , Neoplasias PancreáticasRESUMO
Data sharing is required for research collaborations, but effective data transfer performance continues to be difficult to achieve. The NetSage Measurement and Analysis Framework can assist in understanding research data movement. It collects a broad set of monitoring data and builds performance Dashboards to visualize the data. Each Dashboard is specifically designed to address a well-defined analysis need of the stakeholders. This paper describes the design methodology, the resulting architecture, the development approach and lessons learned, and a set of discoveries that NetSage Dashboards made possible.
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BACKGROUND/AIMS: The pathoetiology of functional dyspepsia remains unclear; one mechanism could be chemical gastropathy from chronic bile reflux. We aim to examine the association of bile reflux gastropathy with functional dyspepsia and identify predisposing factors. METHODS: In a retrospective study, patients with functional dyspepsia (Rome III) who completed symptom assessment, esophagogastroduodenoscopy, and biopsies were categorized into 3 groups; bile gastropathy (BG), non-bile gastropathy (NBG), and no gastropathy (NG). Demographics, symptoms, endoscopy, and motility data were compared between groups. Multivariate analysis identified clinical factors associated with BG. RESULTS: Of 262 patients (77.5% female), 90 had BG, 121 had NBG, and 51 had NG. Baseline demographics were similar, however, patients with BG reported significantly more severe abdominal pain than NBG or NG groups (P = 0.018). Gastric erythema was significantly more common in BG vs NBG groups (P < 0.001). Cholecystectomy was significantly associated (OR, 6.6; P = 0.003) with the presence of gastropathy in BG compared to NBG or NG group. Patients with cholecystectomy had significantly more severe abdominal pain (P < 0.05), gastric erythema (P < 0.03), and gastritis (P < 0.05), and were more likely to be prescribed narcotic medications (P < 0.004) than patients without cholecystectomy. CONCLUSION: s Bile reflux gastropathy is associated with functional dyspepsia and causes more severe symptoms. Cholecystectomy predisposes to BG and abnormal pain, and could contribute to the pathogenesis of functional dyspepsia.
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BACKGROUND: CD47 is a broadly expressed cell surface glycoprotein associated with immune evasion. Interaction with the inhibitory receptor signal regulatory protein alpha (SIRPα), primarily expressed on myeloid cells, normally serves to restrict effector function (eg, phagocytosis and immune cell homeostasis). CD47/SIRPα antagonists, commonly referred to as 'macrophage checkpoint' inhibitors, are being developed as cancer interventions. SRF231 is an investigational fully human IgG4 anti-CD47 antibody that is currently under evaluation in a phase 1 clinical trial. The development and preclinical characterization of SRF231 are reported here. METHODS: SRF231 was characterized in assays designed to probe CD47/SIRPα blocking potential and effects on red blood cell (RBC) phagocytosis and agglutination. Additionally, SRF231-mediated phagocytosis and cell death were assessed in macrophage:tumor cell in vitro coculture systems. Further mechanistic studies were conducted within these coculture systems to ascertain the dependency of SRF231-mediated antitumor activity on Fc receptor engagement vs CD47/SIRPα blockade. In vivo, SRF231 was evaluated in a variety of hematologic xenograft models, and the mechanism of antitumor activity was assessed using cytokine and macrophage infiltration analyses following SRF231 treatment. RESULTS: SRF231 binds CD47 and disrupts the CD47/SIRPα interaction without causing hemagglutination or RBC phagocytosis. SRF231 exerts antitumor activity in vitro through both phagocytosis and cell death in a manner dependent on the activating Fc-gamma receptor (FcγR), CD32a. Through its Fc domain, SRF231 engagement with macrophage-derived CD32a serves dual purposes by eliciting FcγR-mediated phagocytosis of cancer cells and acting as a scaffold to drive CD47-mediated death signaling into tumor cells. Robust antitumor activity occurs across multiple hematologic xenograft models either as a single agent or in combination with rituximab. In tumor-bearing mice, SRF231 increases tumor macrophage infiltration and induction of the macrophage cytokines, mouse chemoattractant protein 1 and macrophage inflammatory protein 1 alpha. Macrophage depletion results in diminished SRF231 antitumor activity, underscoring a mechanistic role for macrophage engagement by SRF231. CONCLUSION: SRF231 elicits antitumor activity via apoptosis and phagocytosis involving macrophage engagement in a manner dependent on the FcγR, CD32a.
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Antígeno CD47/metabolismo , Neoplasias/genética , Receptores de IgG/metabolismo , Animais , Humanos , Camundongos , Neoplasias/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: The American Cancer Society (ACS), the Centers for Disease Control and Prevention (CDC), the National Cancer Institute (NCI), and the North American Association of Central Cancer Registries (NAACCR) collaborate to provide annual updates on cancer occurrence and trends in the United States. METHODS: Incidence data were obtained from the CDC-funded and NCI-funded population-based cancer registry programs and compiled by NAACCR. Data on cancer deaths were obtained from the National Center for Health Statistics National Vital Statistics System. Trends in age-standardized incidence and death rates for all cancers combined and for the leading cancer types by sex, race, and ethnicity were estimated by joinpoint analysis and expressed as the annual percent change. Stage distribution and 5-year survival by stage at diagnosis were calculated for breast cancer, colon and rectum (colorectal) cancer, lung and bronchus cancer, and melanoma of the skin. RESULTS: Overall cancer incidence rates from 2008 to 2014 decreased by 2.2% per year among men but were stable among women. Overall cancer death rates from 1999 to 2015 decreased by 1.8% per year among men and by 1.4% per year among women. Among men, incidence rates during the most recent 5-year period (2010-2014) decreased for 7 of the 17 most common cancer types, and death rates (2011-2015) decreased for 11 of the 18 most common types. Among women, incidence rates declined for 7 of the 18 most common cancers, and death rates declined for 14 of the 20 most common cancers. Death rates decreased for cancer sites, including lung and bronchus (men and women), colorectal (men and women), female breast, and prostate. Death rates increased for cancers of the liver (men and women); pancreas (men and women); brain and other nervous system (men and women); oral cavity and pharynx (men only); soft tissue, including heart (men only); nonmelanoma skin (men only); and uterus. Incidence and death rates were higher among men than among women for all racial and ethnic groups. For all cancer sites combined, black men and white women had the highest incidence rates compared with other racial groups, and black men and black women had the highest death rates compared with other racial groups. Non-Hispanic men and women had higher incidence and mortality rates than those of Hispanic ethnicity. Five-year survival for cases diagnosed from 2007 through 2013 ranged from 100% (stage I) to 26.5% (stage IV) for female breast cancer, from 88.1% (stage I) to 12.6% (stage IV) for colorectal cancer, from 55.1% (stage I) to 4.2% (stage IV) for lung and bronchus cancer, and from 99.5% (stage I) to 16% (stage IV) for melanoma of the skin. Among children, overall cancer incidence rates increased by 0.8% per year from 2010 to 2014, and overall cancer death rates decreased by 1.5% per year from 2011 to 2015. CONCLUSIONS: For all cancer sites combined, cancer incidence rates decreased among men but were stable among women. Overall, there continue to be significant declines in cancer death rates among both men and women. Differences in rates and trends by race and ethnic group remain. Progress in reducing cancer mortality has not occurred for all sites. Examining stage distribution and 5-year survival by stage highlights the potential benefits associated with early detection and treatment. Cancer 2018;124:2785-2800. © 2018 American Cancer Society.
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Causas de Morte/tendências , Censos , Neoplasias/epidemiologia , Programa de SEER/estatística & dados numéricos , American Cancer Society , Feminino , Humanos , Incidência , Masculino , National Cancer Institute (U.S.)/estatística & dados numéricos , Estadiamento de Neoplasias , Neoplasias/patologia , Serviços Preventivos de Saúde/estatística & dados numéricos , Fatores Sexuais , Análise de Sobrevida , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Temporal trends in prostate cancer incidence and death rates have been attributed to changing patterns of screening and improved treatment (mortality only), among other factors. This study evaluated contemporary national-level trends and their relations with prostate-specific antigen (PSA) testing prevalence and explored trends in incidence according to disease characteristics with stage-specific, delay-adjusted rates. METHODS: Joinpoint regression was used to examine changes in delay-adjusted prostate cancer incidence rates from population-based US cancer registries from 2000 to 2014 by age categories, race, and disease characteristics, including stage, PSA, Gleason score, and clinical extension. In addition, the analysis included trends for prostate cancer mortality between 1975 and 2015 by race and the estimation of PSA testing prevalence between 1987 and 2005. The annual percent change was calculated for periods defined by significant trend change points. RESULTS: For all age groups, overall prostate cancer incidence rates declined approximately 6.5% per year from 2007. However, the incidence of distant-stage disease increased from 2010 to 2014. The incidence of disease according to higher PSA levels or Gleason scores at diagnosis did not increase. After years of significant decline (from 1993 to 2013), the overall prostate cancer mortality trend stabilized from 2013 to 2015. CONCLUSIONS: After a decline in PSA test usage, there has been an increased burden of late-stage disease, and the decline in prostate cancer mortality has leveled off. Cancer 2018;124:2801-2814. © 2018 American Cancer Society.
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Efeitos Psicossociais da Doença , Mortalidade/tendências , Neoplasias da Próstata/epidemiologia , Comitês Consultivos/normas , Distribuição por Idade , Idoso , Detecção Precoce de Câncer/normas , Detecção Precoce de Câncer/estatística & dados numéricos , Humanos , Incidência , Masculino , Programas de Rastreamento/normas , Programas de Rastreamento/estatística & dados numéricos , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prevalência , Serviços Preventivos de Saúde/normas , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/patologia , Programa de SEER/estatística & dados numéricos , Estados Unidos/epidemiologiaRESUMO
Background: The American Cancer Society (ACS), the Centers for Disease Control and Prevention (CDC), the National Cancer Institute (NCI), and the North American Association of Central Cancer Registries (NAACCR) collaborate to provide annual updates on cancer occurrence and trends in the United States. This Annual Report highlights survival rates. Data were from the CDC- and NCI-funded population-based cancer registry programs and compiled by NAACCR. Trends in age-standardized incidence and death rates for all cancers combined and for the leading cancer types by sex were estimated by joinpoint analysis and expressed as annual percent change. We used relative survival ratios and adjusted relative risk of death after a diagnosis of cancer (hazard ratios [HRs]) using Cox regression model to examine changes or differences in survival over time and by sociodemographic factors. Results: Overall cancer death rates from 2010 to 2014 decreased by 1.8% (95% confidence interval [CI] = -1.8 to -1.8) per year in men, by 1.4% (95% CI = -1.4 to -1.3) per year in women, and by 1.6% (95% CI = -2.0 to -1.3) per year in children. Death rates decreased for 11 of the 16 most common cancer types in men and for 13 of the 18 most common cancer types in women, including lung, colorectal, female breast, and prostate, whereas death rates increased for liver (men and women), pancreas (men), brain (men), and uterine cancers. In contrast, overall incidence rates from 2009 to 2013 decreased by 2.3% (95% CI = -3.1 to -1.4) per year in men but stabilized in women. For several but not all cancer types, survival statistically significantly improved over time for both early and late-stage diseases. Between 1975 and 1977, and 2006 and 2012, for example, five-year relative survival for distant-stage disease statistically significantly increased from 18.7% (95% CI = 16.9% to 20.6%) to 33.6% (95% CI = 32.2% to 35.0%) for female breast cancer but not for liver cancer (from 1.1%, 95% CI = 0.3% to 2.9%, to 2.3%, 95% CI = 1.6% to 3.2%). Survival varied by race/ethnicity and state. For example, the adjusted relative risk of death for all cancers combined was 33% (HR = 1.33, 95% CI = 1.32 to 1.34) higher in non-Hispanic blacks and 51% (HR = 1.51, 95% CI = 1.46 to 1.56) higher in non-Hispanic American Indian/Alaska Native compared with non-Hispanic whites. Conclusions: Cancer death rates continue to decrease in the United States. However, progress in reducing death rates and improving survival is limited for several cancer types, underscoring the need for intensified efforts to discover new strategies for prevention, early detection, and treatment and to apply proven preventive measures broadly and equitably.
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Neoplasias/epidemiologia , American Cancer Society , Centers for Disease Control and Prevention, U.S. , Estudos Transversais , Feminino , Humanos , Incidência , Masculino , Neoplasias/etnologia , Neoplasias/mortalidade , Modelos de Riscos Proporcionais , Sistema de Registros , Programa de SEER , Fatores Sexuais , Taxa de Sobrevida , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Annual updates on cancer occurrence and trends in the United States are provided through an ongoing collaboration among the American Cancer Society (ACS), the Centers for Disease Control and Prevention (CDC), the National Cancer Institute (NCI), and the North American Association of Central Cancer Registries (NAACCR). This annual report highlights the increasing burden of liver and intrahepatic bile duct (liver) cancers. METHODS: Cancer incidence data were obtained from the CDC, NCI, and NAACCR; data about cancer deaths were obtained from the CDC's National Center for Health Statistics (NCHS). Annual percent changes in incidence and death rates (age-adjusted to the 2000 US Standard Population) for all cancers combined and for the leading cancers among men and women were estimated by joinpoint analysis of long-term trends (incidence for 1992-2012 and mortality for 1975-2012) and short-term trends (2008-2012). In-depth analysis of liver cancer incidence included an age-period-cohort analysis and an incidence-based estimation of person-years of life lost because of the disease. By using NCHS multiple causes of death data, hepatitis C virus (HCV) and liver cancer-associated death rates were examined from 1999 through 2013. RESULTS: Among men and women of all major racial and ethnic groups, death rates continued to decline for all cancers combined and for most cancer sites; the overall cancer death rate (for both sexes combined) decreased by 1.5% per year from 2003 to 2012. Overall, incidence rates decreased among men and remained stable among women from 2003 to 2012. Among both men and women, deaths from liver cancer increased at the highest rate of all cancer sites, and liver cancer incidence rates increased sharply, second only to thyroid cancer. Men had more than twice the incidence rate of liver cancer than women, and rates increased with age for both sexes. Among non-Hispanic (NH) white, NH black, and Hispanic men and women, liver cancer incidence rates were higher for persons born after the 1938 to 1947 birth cohort. In contrast, there was a minimal birth cohort effect for NH Asian and Pacific Islanders (APIs). NH black men and Hispanic men had the lowest median age at death (60 and 62 years, respectively) and the highest average person-years of life lost per death (21 and 20 years, respectively) from liver cancer. HCV and liver cancer-associated death rates were highest among decedents who were born during 1945 through 1965. CONCLUSIONS: Overall, cancer incidence and mortality declined among men; and, although cancer incidence was stable among women, mortality declined. The burden of liver cancer is growing and is not equally distributed throughout the population. Efforts to vaccinate populations that are vulnerable to hepatitis B virus (HBV) infection and to identify and treat those living with HCV or HBV infection, metabolic conditions, alcoholic liver disease, or other causes of cirrhosis can be effective in reducing the incidence and mortality of liver cancer. Cancer 2016;122:1312-1337. © 2016 American Cancer Society.
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Neoplasias/epidemiologia , Distribuição por Idade , American Cancer Society , Causas de Morte/tendências , Centers for Disease Control and Prevention, U.S. , Etnicidade/estatística & dados numéricos , Feminino , Humanos , Incidência , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/etnologia , Masculino , National Cancer Institute (U.S.) , Neoplasias/etnologia , Grupos Raciais/estatística & dados numéricos , Sistema de Registros/estatística & dados numéricos , Distribuição por Sexo , Fatores Sexuais , Fatores de Tempo , Estados Unidos/epidemiologia , Estados Unidos/etnologiaRESUMO
Hyperactivity of microglia and loss of functional circuitry is a common feature of many neurological disorders including those induced or exacerbated by inflammation. Herein, we investigate the response of microglia and changes in hippocampal dendritic postsynaptic spines by dendritic polyglycerol sulfate (dPGS) treatment. Mouse microglia and organotypic hippocampal slices were exposed to dPGS and an inflammogen (lipopolysaccharides). Measurements of intracellular fluorescence and confocal microscopic analyses revealed that dPGS is avidly internalized by microglia but not CA1 pyramidal neurons. Concentration and time-dependent response studies consistently showed no obvious toxicity of dPGS. The adverse effects induced by proinflammogen LPS exposure were reduced and dendritic spine morphology was normalized with the addition of dPGS. This was accompanied by a significant reduction in nitrite and proinflammatory cytokines (TNF-α and IL-6) from hyperactive microglia suggesting normalized circuitry function with dPGS treatment. Collectively, these results suggest that dPGS acts anti-inflammatory, inhibits inflammation-induced degenerative changes in microglia phenotype and rescues dendritic spine morphology.
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Região CA1 Hipocampal/metabolismo , Espinhas Dendríticas/metabolismo , Glicerol/farmacologia , Microglia/metabolismo , Polímeros/farmacologia , Células Piramidais/metabolismo , Animais , Linhagem Celular , Espinhas Dendríticas/patologia , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Interleucina-6/metabolismo , Lipopolissacarídeos/toxicidade , Camundongos , Camundongos Transgênicos , Microglia/patologia , Doenças do Sistema Nervoso/induzido quimicamente , Doenças do Sistema Nervoso/metabolismo , Doenças do Sistema Nervoso/patologia , Células Piramidais/patologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: The American Cancer Society (ACS), Centers for Disease Control and Prevention (CDC), National Cancer Institute (NCI), and North American Association of Central Cancer Registries (NAACCR) collaborate annually to produce updated, national cancer statistics. This Annual Report includes a focus on breast cancer incidence by subtype using new, national-level data. METHODS: Population-based cancer trends and breast cancer incidence by molecular subtype were calculated. Breast cancer subtypes were classified using tumor biomarkers for hormone receptor (HR) and human growth factor-neu receptor (HER2) expression. RESULTS: Overall cancer incidence decreased for men by 1.8% annually from 2007 to 2011 [corrected]. Rates for women were stable from 1998 to 2011. Within these trends there was racial/ethnic variation, and some sites have increasing rates. Among children, incidence rates continued to increase by 0.8% per year over the past decade while, like adults, mortality declined. HR+/HER2- breast cancers, the subtype with the best prognosis, were the most common for all races/ethnicities with highest rates among non-Hispanic white women, local stage cases, and low poverty areas (92.7, 63.51, and 98.69 per 100000 non-Hispanic white women, respectively). HR+/HER2- breast cancer incidence rates were strongly, positively correlated with mammography use, particularly for non-Hispanic white women (Pearson 0.57, two-sided P < .001). Triple-negative breast cancers, the subtype with the worst prognosis, were highest among non-Hispanic black women (27.2 per 100000 non-Hispanic black women), which is reflected in high rates in southeastern states. CONCLUSIONS: Progress continues in reducing the burden of cancer in the United States. There are unique racial/ethnic-specific incidence patterns for breast cancer subtypes; likely because of both biologic and social risk factors, including variation in mammography use. Breast cancer subtype analysis confirms the capacity of cancer registries to adjust national collection standards to produce clinically relevant data based on evolving medical knowledge.
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Biomarcadores Tumorais/análise , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Detecção Precoce de Câncer , Mamografia/tendências , Pobreza , Grupos Raciais/estatística & dados numéricos , Adulto , Negro ou Afro-Americano/estatística & dados numéricos , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/química , Neoplasias da Mama/etnologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Neoplasias da Mama Masculina/epidemiologia , Neoplasias da Mama Masculina/patologia , Fatores de Confusão Epidemiológicos , Detecção Precoce de Câncer/métodos , Detecção Precoce de Câncer/estatística & dados numéricos , Etnicidade/estatística & dados numéricos , Feminino , Hispânico ou Latino/estatística & dados numéricos , Humanos , Incidência , Masculino , Mamografia/estatística & dados numéricos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Receptor ErbB-2/análise , Receptores de Estrogênio/análise , Receptores de Progesterona/análise , Sistema de Registros , Estados Unidos/epidemiologia , População Branca/estatística & dados numéricosRESUMO
Workplace exposure to engineered nanoparticles (ENPs) is a potential health and environmental hazard. This paper reports a novel approach for tracking hazardous airborne ENPs by applying online poly (amic) acid membranes (PAA) with offline electrochemical detection. Test aerosol (Fe2O3, TiO2 and ZnO) nanoparticles were produced using the Harvard (Versatile Engineered Generation System) VENGES system. The particle morphology, size and elemental composition were determined using SEM, XRD and EDS. The PAA membrane electrodes used to capture the airborne ENPs were either stand-alone or with electron-beam gold-coated paper substrates. Cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) were used to conceptually illustrate that exposure levels of industry-relevant classes of airborne nanoparticles could be captured and electrochemically detected at PAA membranes filter electrodes. CV parameters showed that PAA catalyzed the reduction of Fe2O3 to Fe(2+) with a size-dependent shift in reduction potential (E(0)). Using the proportionality of peak current to concentration, the amount of Fe2O3 was found to be 4.15×10(-17)mol/cm(3) PAA electrodes. Using EIS, the maximum phase angle (Φmax) and the interfacial charge transfer resistance (Rct) increased significantly using 100µg and 1000µg of TiO2 and ZnO respectively. The observed increase in Φmax and Rct at increasing concentration is consistent with the addition of an insulating layer of material on the electrode surface. The integrated VENGES/PAA filter sensor system has the potential to be used as a portable monitoring system.
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Poluentes Ambientais/química , Nanopartículas/química , Polímeros/química , Aerossóis , Eletroquímica , Filtração , Membranas Artificiais , Microscopia Eletrônica de Varredura , Tamanho da PartículaRESUMO
Rare examples of homodinuclear zwitterionic Pd(II) and Pt(II) complexes with bridging, two-coordinate P{cyclo-CH(2)N(R)CHN(R)CH(2)} ligands (R = 4-FC(6)H(4)CH(2), C(6)H(5)CH(2)) have been characterized by single-crystal X-ray diffraction using synchrotron radiation. Short N-C distances and enlarged N-C-N bond angles support electron delocalization in the central N-C-N backbone.
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INTRODUCTION: Several states with large Hispanic populations have historically served as the source for US Hispanic cancer incidence rates, with aggregation of data across all states limited by different methodologies to identify Hispanic persons. Now with data available for more than 85% of the US Hispanic population, state rates suggest regional diversity in their Hispanic cancer profiles. METHOD: We tested an approach of using a surrogate indicator of county residential homogeneity for Hispanic groups based on the 2000 US Census. The indicator used the counts of specific Hispanic residents compared to the total Hispanic population in the county to define counties with homogenous Hispanic populations. From these data, we aggregated counties into homogeneity categories for each Hispanic group and defined thresholds and rules for allocating Hispanic persons to a specific Hispanic group. RESULTS: We found that it was possible to use county demographic data in many counties to meaningfully attribute a specific Hispanic ethnicity to incident cancer cases based on homogeneity thresholds. Cancer rates for the US Hispanic population describe a profile of high rates of cancers of the liver, gallbladder, cervix (in female), stomach, and lower rates of the cancers of the lung, female breast, and prostate compared with the non-Hispanic white population. In general, rates among US Mexicans are lower than the US Hispanic rates, while rates for Puerto Ricans and Cubans are higher than the US Hispanic rates. Additional variations among the three Hispanic groups were also evident. CONCLUSION: The approach yielded reasonable and useful information to explore etiologic differences among the populations, as well as to develop relevant cancer control interventions. However, direct identification of specific Hispanic ethnicity in medical records and annual Census estimates of these populations would be preferable if they ever became available.
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Hispânico ou Latino , Neoplasias/etnologia , Vigilância da População/métodos , Demografia , Feminino , Humanos , Incidência , Masculino , Estados Unidos/etnologiaRESUMO
New cationic trialkylphosphines [P(CH(2)NH(2)R){CH(2)N(R)CH(2)N(R)CH(2)}](+) (R = C(6)H(5)CH(2), a; 4-FC(6)H(4)CH(2), b), as their Cl(-) (1a, 1b), SbF(6)(-) (2a, 2b), and PF(6)(-) (3a, 3b) salts, are described. The phosphine framework is conformationally locked, in the solid state, through pairs of intramolecular N-H...N hydrogen bonds which are maintained in the Ru(II) and Rh(III) complexes 4 and 5. Phosphines 1a-3b can be considered as charged variants of the well-known PTA ligand.
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Base induced P,N-chelation, C-C coupling and methylene C-H deprotonation affords an unusual fluorene containing square-planar Pt(II) complex Pt(kappa4-P2N2-Ph2PCH=NNCC12H8)2 which has been isolated and structurally characterised.
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The authors developed the Record Uniqueness (RU) software program to assess electronic data files for risk of confidentiality breach based on unique combinations of key variables. The underlying methodology utilized by the RU program generates a frequency distribution for every variable selected for analysis and for all combinations of the variables selected. In addition, the program provides the regression coefficient that designates the relative contribution of each variable to the unique records on the data file. The authors used RU to evaluate a North American Association of Central Cancer Registries research data set with 4.67 million cases from 34 population-based cancer registries for 1995-2001. To illustrate the process and utility of RU, they describe the evaluation process of the confidentiality risk of adding a county-based socioeconomic measure to the research file. The RU method enables one to be assured of record confidentiality, provides flexibility to adjust record uniqueness thresholds for different users or purposes of data release, and facilitates good stewardship of confidential data balanced with maximum use and release of information for research. RU is a useful data tool that can quantify the risk of confidentiality breach of electronic health databases, including reidentifiability of cases through triangulation of information or linkage with other electronic databases.
Assuntos
Confidencialidade , Registro Médico Coordenado/normas , Sistemas Computadorizados de Registros Médicos/normas , Neoplasias/epidemiologia , Sistemas de Identificação de Pacientes/normas , Software , Humanos , Incidência , Sistema de Registros , Análise de Regressão , Fatores Socioeconômicos , Estados Unidos/epidemiologiaRESUMO
Therapeutic induction of angiogenesis is a potential treatment for chronic ischemia. Heparan sulfate proteoglycans are known to play an important role by their interactions with proangiogenic growth factors such as vascular endothelial growth factor (VEGF). Low molecular weight fucoidan (LMWF), a sulfated polysaccharide from brown seaweeds that mimic some biological activities of heparin, has been shown recently to promote revascularization in rat critical hindlimb ischemia. In this report, we first used cultured human endothelial cells (ECs) to investigate the possible ability of LMWF to enhance the actions of VEGF(165). Data showed that LMWF greatly enhances EC tube formation in growth factor reduced matrigel. LMWF is a strong enhancer of VEGF(165)-induced EC chemotaxis, but not proliferation. In addition, LMWF has no effect on VEGF(121)-induced EC migration, a VEGF isoform that does not bind to heparan sulfate proteoglycans. Then, with binding studies using (125)I-VEGF(165), we observed that LMWF enhances the binding of VEGF(165) to recombinant VEGFR-2 and Neuropilin-1 (NRP1), but not to VEGFR-1. Surface plasmon resonance analysis showed that LMWF binds with high affinity to VEGF(165) (1.2 nm) and its receptors (5-20 nm), but not to VEGF(121). Pre-injection of LMWF on immobilized receptors shows that VEGF(165) has the highest affinity for VEGFR-2 and NRP1, as compared with VEGFR-1. Overall, the effects of LMWF were much more pronounced than those of LMW heparin. These findings suggested an efficient mechanism of action of LMWF by promoting VEGF(165) binding to VEGFR-2 and NRP1 on ECs that could help in stimulating therapeutic revascularization.
Assuntos
Células Endoteliais/efeitos dos fármacos , Células Endoteliais/fisiologia , Neuropilina-1/metabolismo , Polissacarídeos/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Células Cultivadas , Humanos , Peso Molecular , Neovascularização Fisiológica/efeitos dos fármacos , Neuropilina-1/genética , Polissacarídeos/química , Ligação Proteica , Ratos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologia , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genéticaRESUMO
Adiponutrin and a related protein, adipocyte triglyceride lipase (ATGL; also known as Desnutrin), were recently described as adipocyte-specific proteins with lipid hydrolase activity. Using bioinformatics, we identified three additional Adiponutrin family members (GS2, GS2-Like, and PNPLA1). Here, we report on the expression, regulation, and activity of GS2 and GS2-Like compared with Adiponutrin and Desnutrin/ATGL. GS2-Like is expressed and regulated in a manner similar to Adiponutrin; however, the absolute levels of mRNA are significantly lower than those of Adiponutrin or Desnutrin/ATGL. GS2 transcripts were identified only in humans and are highly expressed in adipose as well as other tissues. All four proteins show lipase activity in vitro, which is dependent on the presence of the active site serine for Adiponutrin, Desnutrin/ATGL, and GS2. Overexpression of Desnutrin/ATGL, GS2, and GS2-Like, but not Adiponutrin, decreases intracellular triglyceride levels. This is consistent with a function for Desnutrin/ATGL, GS2, and GS2-Like in lipolysis, but not for Adiponutrin. Consistent with previously reported data, Desnutrin/ATGL is upregulated by fasting in adipose tissue, whereas Adiponutrin is downregulated. Additionally, Adiponutrin and GS2-Like, but not Desnutrin/ATGL, are strongly induced in the liver of ob/ob mice. Our data support distinct functions for Adiponutrin and Desnutrin/ATGL and raise the possibility that GS2 may contribute significantly to lipolysis in human adipose tissue.
Assuntos
Regulação Enzimológica da Expressão Gênica , Proteínas de Membrana/biossíntese , Proteínas de Membrana/química , Triglicerídeos/metabolismo , Adipócitos/metabolismo , Tecido Adiposo/enzimologia , Motivos de Aminoácidos , Sequência de Aminoácidos , Animais , Sítios de Ligação , Northern Blotting , Biologia Computacional/métodos , Regulação da Expressão Gênica , Vetores Genéticos , Humanos , Imunoprecipitação , Lipase/metabolismo , Lipólise , Masculino , Cadeias de Markov , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Dados de Sequência Molecular , Mutação , Ácido Oleico/química , Filogenia , Estrutura Terciária de Proteína , RNA/metabolismo , RNA Mensageiro/metabolismo , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Esterol Esterase/metabolismo , Transfecção , Regulação para CimaRESUMO
Uterine fibroids (leiomyomas) are a major women's health problem. Currently, the standard for treatment remains hysterectomy, since no other treatment modalities can reduce both symptoms and recurrence. As leiomyomas are benign neoplasias of smooth muscle cells, we sought to understand the regulation of uterine smooth muscle cell mitogenesis by CCN5, a growth arrest-specific gene in vascular smooth muscle cells which is induced and maintained by heparin treatment. Using autologous human myometrial and leiomyoma smooth muscle cells, we demonstrate that the proliferation and motility of both cell types are inhibited by the overexpression of CCN5. Surprisingly, we show that even though CCN5 is induced by heparin in vascular smooth muscle cells, treatment with heparin does not induce CCN5 expression in human uterine smooth muscle cells. Furthermore, we examine CCN5 mRNA expression in 10 autologous pairs of human myometrial and leiomyoma tissues and determine that CCN5 is down-regulated in 100% of the leiomyoma tissues analysed when compared to their normal myometrial counterparts. Thus, our data strongly suggest that CCN5 may exert an important function in maintaining the normal uterine phenotype and that loss of the anti-proliferative protein CCN5 from normal myometrium may account, at least in part, for tumorigenesis.