RESUMEN
The outbreak of COVID-19 in 2020 brought significant challenges for Native Hawaiians (NH), Pacific Islanders (PI), and other communities of color worldwide. Rapidly increasing rates of infection and transmission of the virus in Native Hawaiian and Pacific Islander (NHPI) communities and incomplete or unavailable data signaled to Hawai'i's leaders that advocacy and action needed to take place to minimize the impact of COVID-19. The Native Hawaiian and Pacific Islander Response, Recovery, and Resilience team (NHPI 3R Team) emerged from an effort to lead and fill gaps in response to COVID-19. Through the swift, intentional, and collaborative work of the team and its partners, NHPI communities and the entities that serve them were better equipped to navigate the pandemic, improve health outcomes, and contribute to a reduction in the number of infections, a rise in vaccination uptake, and an increase in NH and PI representation on various levels of government agencies. As the world shifts its focus from COVID-19 to broader health topics, the NHPI 3R Team will continue to serve as a hub for the exchange of resources and a model of community-led work that can be used to tackle issues like COVID-19 and beyond.
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COVID-19 , Nativos de Hawái y Otras Islas del Pacífico , Humanos , COVID-19/epidemiología , COVID-19/prevención & control , Hawaii , Conducta Cooperativa , SARS-CoV-2 , Pandemias/prevención & controlRESUMEN
The COVID-19 pandemic was a public health emergency that required various public health policies and programs at the state and federal level to be established to protect the health and safety of the nation. These mainstream policies and programs proved to be inadequate in addressing the specific needs of Native Hawaiian and Pacific Islander (NHPI) communities as evidenced by the high case counts and low vaccination rates in these communities. In an effort to better understand and address the high case counts and low vaccination rates, a partnership was developed between the Hawai'i State Department of Health (HDOH), medical providers, and a network of NHPI-serving organizations. After the failure of Western approaches for data gathering, leaders of the partnership used an Indigenous qualitative interview method called Talanoa situated within a cultural safety framework to learn reasons for low vaccine uptake and identify NHPI-specific solutions. Findings suggest that the use of Talanoa and its ingrained cultural safety framework allowed us to gather richer data, identified solutions grounded in community, and assisted with building sustainable trusting partnerships.
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Servicios de Salud del Indígena , Nativos de Hawái y Otras Islas del Pacífico , Pandemias , Salud Pública , Humanos , Investigación Participativa Basada en la Comunidad , HawaiiRESUMEN
All UK H&I laboratories and transplant units operate under a single national kidney offering policy, but there have been variations in approach regarding when to undertake the pre-transplant crossmatch test. In order to minimize cold ischaemia times for deceased donor kidney transplantation we sought to find ways to be able to report a crossmatch result as early as possible in the donation process. A panel of experts in transplant surgery, nephrology, specialist nursing in organ donation and H&I (all relevant UK laboratories represented) assessed evidence and opinion concerning five factors that relate to the effectiveness of the crossmatch process, as follows: when the result should be ready for reporting; what level of donor HLA typing is needed; crossmatch sample type and availability; fairness and equity; risks and patient safety. Guidelines aimed at improving practice based on these issues are presented, and we expect that following these will allow H&I laboratories to contribute to reducing CIT in deceased donor kidney transplantation.
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Trasplante de Riñón , Tipificación y Pruebas Cruzadas Sanguíneas , Isquemia Fría , Antígenos HLA , Prueba de Histocompatibilidad , Humanos , RiñónRESUMEN
Native Hawaiian and Pacific Islander populations have been disproportionately affected by COVID-19 (1-3). Native Hawaiian, Pacific Islander, and Asian populations vary in language; cultural practices; and social, economic, and environmental experiences, which can affect health outcomes (4).§ However, data from these populations are often aggregated in analyses. Although data aggregation is often used as an approach to increase sample size and statistical power when analyzing data from smaller population groups, it can limit the understanding of disparities among diverse Native Hawaiian, Pacific Islander, and Asian subpopulations¶ (4-7). To assess disparities in COVID-19 outcomes among Native Hawaiian, Pacific Islander, and Asian populations, a disaggregated, descriptive analysis, informed by recommendations from these communities,** was performed using race data from 21,005 COVID-19 cases and 449 COVID-19-associated deaths reported to the Hawaii State Department of Health (HDOH) during March 1, 2020-February 28, 2021. In Hawaii, COVID-19 incidence and mortality rates per 100,000 population were 1,477 and 32, respectively during this period. In analyses with race categories that were not mutually exclusive, including persons of one race alone or in combination with one or more races, Pacific Islander persons, who account for 5% of Hawaii's population, represented 22% of COVID-19 cases and deaths (COVID-19 incidence of 7,070 and mortality rate of 150). Native Hawaiian persons experienced an incidence of 1,181 and a mortality rate of 15. Among subcategories of Asian populations, the highest incidences were experienced by Filipino persons (1,247) and Vietnamese persons (1,200). Disaggregating Native Hawaiian, Pacific Islander, and Asian race data can aid in identifying racial disparities among specific subpopulations and highlights the importance of partnering with communities to develop culturally responsive outreach teams§§ and tailored public health interventions and vaccination campaigns to more effectively address health disparities.
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COVID-19/etnología , Disparidades en el Estado de Salud , Grupos Raciales/estadística & datos numéricos , COVID-19/mortalidad , Servicios de Salud Comunitaria/organización & administración , Interpretación Estadística de Datos , Hawaii/epidemiología , HumanosRESUMEN
OBJECTIVES: The Australian National Bowel Cancer Screening Program (NBCSP) offers free 2-yearly immunochemical faecal occult blood testing to individuals aged 50-74 years; national participation in 2015-2016 was 41%. In 2017, a 7-week television-led mass-media campaign to increase participation in the Australian state of Victoria was associated with a 1.31-fold increase in participation for 11 weeks. We aimed to evaluate the cost-effectiveness and health benefits of the 2017 campaign and scaled-up equivalent campaigns run over 4 years in Victoria and nationally. STUDY DESIGN: This study used microsimulation modelling. METHODS: A comprehensive microsimulation model of colorectal cancer (CRC), Policy1-Bowel, was used to simulate three scenarios. Scenario 1 simulated the 2017 campaign in Victoria; Scenarios 2 and 3 assumed that campaigns were run three times annually from 2019 to 2022 in Victoria and Australia-wide, respectively. Total campaign costs of AUD$1million, AUD$10million, and AUD$40million were assumed for Scenarios 1, 2, and 3, respectively. The incremental effects and costs of the campaign on the NBCSP were assessed. A governmental perspective was used. RESULTS: All campaign scenarios were predicted to be highly cost-effective, with cost-effectiveness ratios under AUD$4,800/life-year saved. The actual 2017 campaign in Victoria is estimated to prevent 319 CRC cases and 183 deaths over the following 40 years. A 4-year campaign would prevent 1,750 CRC cases and 987 deaths if conducted in Victoria, and 8,100 cases and 4,330 deaths if conducted Australia-wide. CONCLUSION: Mass-media participation campaigns could be highly cost-effective and maximise the potential life-saving impact of bowel screening. These results support ongoing investment in major bowel screening campaigns.
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Neoplasias Colorrectales/prevención & control , Detección Precoz del Cáncer/estadística & datos numéricos , Promoción de la Salud/economía , Medios de Comunicación de Masas , Anciano , Análisis Costo-Beneficio , Femenino , Humanos , Masculino , Persona de Mediana Edad , VictoriaRESUMEN
Aggressive dietary interventions may provide an accessible treatment option for children and adolescents with severe obesity who are not successful with traditional lifestyle behavioral interventions or do not want or qualify for weight loss surgery. One such intensive dietary option is the protein sparing modified fast (PSMF). The PSMF involves minimal carbohydrate intake to induce ketosis, while maintaining adequate or high protein intake to minimize catabolism. The PSMF, under medical supervision, can be an effective and safe intervention for children and adolescents, yet the PSMF diet is not regularly used in the treatment of pediatric severe obesity. This paper describes the rationale and design for a pilot study to evaluate the acceptability and effectiveness of a revised PSMF (rPSMF) implemented as a weight loss treatment option for children and adolescents with severe obesity in a pediatric tertiary care weight management clinic. The primary aim of the study is to evaluate the acceptability of the rPSMF as assessed by adherence, satisfaction with the intervention, and participation rate using quantitative and qualitative methods. The secondary aim is to investigate the effectiveness of the rPSMF on improving a) anthropometric measures (weight, body mass index [BMI], BMI z-score); b) metabolic measures (lipid profile, glycosylated hemoglobin, liver function tests); and c) quality of life. Results of this study will provide guidance for the standardization of a pediatric rPSMF protocol in a clinic setting, delineate which factors improve or hinder adherence and weight loss and provide preliminary data for a multicenter randomized controlled trial. CLINICALTRIALSGOV IDENTIFIER: NCT03899311.
RESUMEN
The intestinal epithelium must balance efficient absorption of nutrients with partitioning commensals and pathogens from the bodies' largest immune system. If this crucial barrier fails, inappropriate immune responses can result in inflammatory bowel disease or chronic infection. Enteroendocrine cells represent 1% of this epithelium and have classically been studied for their detection of nutrients and release of peptide hormones to mediate digestion. Intriguingly, enteroendocrine cells are the key sensors of microbial metabolites, can release cytokines in response to pathogen associated molecules and peptide hormone receptors are expressed on numerous intestinal immune cells; thus enteroendocrine cells are uniquely equipped to be crucial and novel orchestrators of intestinal inflammation. In this review, we introduce enteroendocrine chemosensory roles, summarize studies correlating enteroendocrine perturbations with intestinal inflammation and describe the mechanistic interactions by which enteroendocrine and mucosal immune cells interact during disease; highlighting this immunoendocrine axis as a key aspect of innate immunity.
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Células Enteroendocrinas/inmunología , Inflamación/inmunología , Mucosa Intestinal/inmunología , Animales , Citocinas/metabolismo , Digestión , Homeostasis/inmunología , Humanos , Inmunidad Mucosa , Moléculas de Patrón Molecular Asociado a Patógenos/inmunología , Hormonas Peptídicas/metabolismo , Vigilancia de GuardiaAsunto(s)
Exodesoxirribonucleasas/genética , Dedos/irrigación sanguínea , Isquemia/etiología , Fosfoproteínas/genética , Esclerodermia Limitada/genética , Dedos del Pie/irrigación sanguínea , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Humanos , Persona de Mediana Edad , Esclerodermia Limitada/complicaciones , Adulto JovenRESUMEN
Regulation of intestinal T-cell responses is crucial for immune homeostasis and prevention of inflammatory bowel disease (IBD). A vital cytokine in regulating intestinal T cells is transforming growth factor-ß (TGFß), which is secreted by cells as a latent complex that requires activation to function. However, how TGFß activation is regulated in the human intestine, and how such pathways are altered in IBD is completely unknown. Here we show that a key activator of TGFß, integrin αvß8, is highly expressed on human intestinal dendritic cells (DCs), specifically on the CD1c+ but not the CD141+ intestinal DC subset. Expression was significantly upregulated on intestinal DC from IBD patients, indicating that inflammatory signals may upregulate expression of this key TGFß-activating molecule. Indeed, we found that the Toll-like receptor 4 ligand lipopolysaccharide upregulates integrin αvß8 expression and TGFß activation by human DC. We also show that DC expression of integrin αvß8 enhanced induction of FOXP3 in CD4+ T cells, suggesting functional importance of integrin αvß8 expression by human DC. These results show that microbial signals enhance the TGFß-activating ability of human DC via regulation of integrin αvß8 expression, and that intestinal inflammation may drive this pathway in patients with IBD.
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Linfocitos T CD4-Positivos/inmunología , Células Dendríticas/inmunología , Enfermedades Inflamatorias del Intestino/inmunología , Integrinas/metabolismo , Intestinos/inmunología , Adulto , Anciano , Antígenos CD1/metabolismo , Células Cultivadas , Femenino , Factores de Transcripción Forkhead/metabolismo , Glicoproteínas/metabolismo , Humanos , Lipopolisacáridos/inmunología , Masculino , Persona de Mediana Edad , Receptor Toll-Like 4/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Regulación hacia ArribaRESUMEN
BACKGROUND: When single-agent androgen deprivation therapy (ADT) is administered for locally advanced prostate cancer, men usually relapse within 1-2 years with more malignant castrate-resistant disease. The reason for this is currently unknown. We now hypothesise that an initial treatment response that increases tumour hypoxia drives selection of more malignant tumours. METHODS: The LNCaP prostate tumour xenografts were analysed for physiological (oxygen and vasculature) and genetic (PCR array) changes during longitudinal treatment with ADT (bicalutamide, 6 or 2 mg kg⻹ daily for 28 days). RESULTS: Bicalutamide caused an immediate (within 24 h) dose-dependent fall in oxygenation in LNCaP-luc prostate tumours with a nadir of ≤ 0.1% oxygen within 3-7 days; this was attributed to a significant loss of tumour microvessels (window chamber study). The hypoxic nadir persisted for 10-14 days. During the next 7 days, tumours regrew, oxygenation improved and the vasculature recovered; this was inhibited by the VEGF inhibitor B20.4.1.1. Gene expression over 28 days showed marked fluctuations consistent with the physiological changes. Accompanying the angiogenic burst (day 21) was a particularly striking increase in expression of genes associated with epithelial-to-mesenchymal transition (EMT). In particular, insulin-like growth factor 1 (IGF-1) showed increases in mRNA and protein expression. CONCLUSIONS: Hypoxic stress caused by ADT promotes EMT, providing a mechanism for the cause of malignant progression in prostate cancer.
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Antagonistas de Andrógenos/farmacología , Anilidas/farmacología , Hipoxia de la Célula/efectos de los fármacos , Nitrilos/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Compuestos de Tosilo/farmacología , Animales , Procesos de Crecimiento Celular , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Transición Epitelial-Mesenquimal/efectos de los fármacos , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Oxígeno/metabolismo , Neoplasias de la Próstata/irrigación sanguínea , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Family studies have provided overwhelming evidence for an underlying genetic component to psoriasis. Toll-like receptors (TLRs) are key transmembrane proteins in both the innate and adaptive immune responses which are known to be integral processes in psoriasis. Recent functional studies support this notion having suggested a role for TLR4 in the pathogenesis of psoriasis. Furthermore a missense polymorphism in the TLR4 gene has been associated with a number of autoimmune conditions, including Crohn diseases, making TLR4 a viable candidate gene for investigation. The aim of this study was to investigate polymorphisms across the TLR4 region with a high-density single nucleotide polymorphism (SNP) panel in a large cohort of patients with chronic plaque type psoriasis. Twenty SNPs were successfully genotyped using Sequenom iPLEX Gold platform in 2826 UK chronic plaque type psoriasis patients including subgroup data on presence of confirmed psoriatic arthritis (n = 1839) and early-onset psoriasis (n = 1466) was available. Allele frequencies for psoriasis patients were compared against imputed Wellcome Trust Case Control Consortium controls (n = 4861). Significant association was observed between a missense variant rs4986790 of TLR4 (Asp229Gly) and plaque type psoriasis (p = 2 × 10(-4)) which was also notable in those with psoriatic arthritis (p = 2 × 10(-4)) and early-onset psoriasis (p = 8 × 10(-4)). We present data suggestive of an association between a functional variant and an intronic variant of TLR4 and chronic plaque type psoriasis and psoriatic arthritis. However, validation of this association in independent cohorts will be necessary.
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Polimorfismo de Nucleótido Simple , Psoriasis/genética , Receptor Toll-Like 4/genética , Edad de Inicio , Artritis Psoriásica/epidemiología , Artritis Psoriásica/genética , Estudios de Casos y Controles , Enfermedad Crónica , Estudios de Cohortes , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Intrones/genética , Masculino , Mutación Missense , Psoriasis/epidemiología , Reino Unido/epidemiologíaRESUMEN
Realizing the full therapeutic potential of mesenchymal stromal/stem cells (MSCs) awaits improved understanding of mechanisms controlling their fate. Using MSCs cultured as spheroids to recapitulate a three-dimensional cellular environment, we show that perturbing the mesenchymal regulators, platelet-derived growth factor (PDGF) receptors or fibronectin, reverts MSCs toward mesodermal progenitors with endothelial potential that can potently induce neovascularization in vivo. MSCs within untreated spheroids retain their mesenchymal spindle shape with abundant smooth muscle α-actin filaments and fibronectin-rich matrix. Inhibiting PDGF receptors or depleting fibronectin induces rounding and depletes smooth muscle α-actin expression; these cells have characteristics of mesenchymoangioblasts, with enhanced expression of mesendoderm and endoderm transcription factors, prominent upregulation of E-cadherin, and Janus kinase signaling-dependent expression of Oct4A and Nanog. PDGF receptor-inhibited spheroids also upregulate endothelial markers platelet endothelial cell adhesion molecule 1 and vascular endothelial-cadherin and secrete many angiogenic factors, and in vivo they potently stimulate neovascularization, and their MSCs integrate within functional blood vessels that are perfused by the circulation. Thus, MSC potency and vascular induction are regulated by perturbing mesenchymal fate.
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Células Endoteliales/citología , Fibronectinas/metabolismo , Células Madre Mesenquimatosas/metabolismo , Mesodermo/citología , Receptores del Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Adulto , Inductores de la Angiogénesis/metabolismo , Animales , Colágeno/farmacología , Combinación de Medicamentos , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Femenino , Fibronectinas/deficiencia , Perfilación de la Expresión Génica , Proteínas de Homeodominio/metabolismo , Humanos , Laminina/farmacología , Masculino , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Proteína Homeótica Nanog , Neovascularización Fisiológica/efectos de los fármacos , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Proteoglicanos/farmacología , Receptores del Factor de Crecimiento Derivado de Plaquetas/metabolismo , Transducción de Señal/efectos de los fármacos , Esferoides Celulares/citología , Esferoides Celulares/efectos de los fármacos , Esferoides Celulares/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Adulto JovenRESUMEN
Interleukin-6 (IL-6) is an important pro-inflammatory cytokine involved in many autoimmune and inflammatory diseases. We have shown previously that a region from -5307 to -5202 bp upstream of the IL-6 transcriptional start site is responsible for basal IL-6 gene expression, and that there were DNA-binding proteins involved from electrophoretic mobility shift assay (EMSA) and transient expression experiments. Here we have combined surface plasmon resonance technology with mass spectrometry analysis and have identified nuclear proteins bound to this region. HNRNPA1 and HNRNPA2B1 were found consistently. EMSA supershift and chromatin immunoprecipitation assays confirmed the involvement of HNRNPA1, but not of HNRNPA2B1. Knocking down the HNRNPA1 expression by small interfering RNA resulted in reduced IL-6 transcriptional activity as assessed from transfection experiments using reporter constructs, mRNA and protein measurements. Overexpression of HNRNPA1 cDNA increased IL-6 mRNA expression. This regulation was dependent on the presence of the sequence from -5307 to -5202 bp of the IL-6 gene. Thus, HNRNPA1 is a novel transcriptional regulator of IL-6 expression, acting via the 5'-flanking sequence of the gene.
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Región de Flanqueo 5' , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/metabolismo , Interleucina-6/genética , Transcripción Genética , Regulación hacia Arriba , Células HeLa , Ribonucleoproteína Nuclear Heterogénea A1 , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/genética , Humanos , Unión Proteica , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
The aim of this study was to explore the role of vitamin D in rheumatoid arthritis (RA) pathogenesis by investigating the enrichment of vitamin D response elements (VDREs) in confirmed RA susceptibility loci and testing variants associated with vitamin D levels for association with RA. Bioinformatically, VDRE genomic positions were overlaid with non-HLA (human leukocyte antigen)-confirmed RA susceptibility regions. The number of VDREs at RA loci was compared to a randomly selected set of genomic loci to calculate an average relative risk (RR). Single-nucleotide polymorphisms (SNPs) in the DHCR7/NADSYN1 (nicotinamide adenine dinucleotide synthase 1) and CYP2R1 loci, previously associated with circulating vitamin D levels, were tested in UK RA cases (n=3870) and controls (n=8430). Significant enrichment of VDREs was seen at RA loci (P=9.23 × 10(-8)) when regions were defined either by gene (RR 5.50) or position (RR 5.86). SNPs in the DHCR7/NADSYN1 locus showed evidence of positive association with RA, rs4944076 (P=0.008, odds ratio (OR) 1.14, 95% confidence interval (CI) 1.03-1.24). The significant enrichment of VDREs at RA-associated loci and the modest association of variants in loci-controlling levels of circulating vitamin D supports the hypothesis that vitamin D has a role in the development of RA.
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Amida Sintasas/genética , Artritis Reumatoide/genética , Colestanotriol 26-Monooxigenasa/genética , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/genética , Polimorfismo de Nucleótido Simple , Elementos de Respuesta/genética , Artritis Reumatoide/sangre , Familia 2 del Citocromo P450 , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Humanos , Modelos Logísticos , Oportunidad Relativa , Factores de Riesgo , Vitamina D/sangreRESUMEN
BACKGROUND: Phenotypically diverse autoimmune conditions share common genetic susceptibility loci and underlying molecular pathways. OBJECTIVES: By systematically searching for single nucleotide polymorphisms (SNPs) associated with another autoimmune disease, rheumatoid arthritis (RA), we aimed to elucidate novel genetic markers of psoriasis. METHODS: We investigated 18 SNPs, previously confirmed as being associated with RA, in a U.K. cohort of 623 patients with early-onset psoriasis (presenting before age 40 years), comparing them with 2662 control subjects. RESULTS: Our findings confirm the association of early-onset psoriasis with REL (rs13031237, P=0·0027). The minor allele of REL had opposing effects upon susceptibility to disease in patients with psoriasis and RA. CONCLUSION: Similar exploration of additional autoimmune loci and fine mapping of such regions may provide further insight into the genetics and molecular pathophysiology of psoriasis.
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Artritis Reumatoide/genética , Genes rel/genética , Polimorfismo de Nucleótido Simple/genética , Psoriasis/genética , Adulto , Marcadores Genéticos/genética , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Factores de RiesgoRESUMEN
BACKGROUND: We have previously shown that hypoxia selects for more invasive, apoptosis-resistant LNCaP prostate cancer cells, with upregulation of the osteogenic transcription factor RUNX2 and the anti-apoptotic factor Bcl-2 detected in the hypoxia-selected cells. Following this observation, we questioned through what biological mechanism this occurs. METHODS: We examined the effect of hypoxia on RUNX2 expression and the role of RUNX2 in the regulation of Bcl-2 and apoptosis resistance in prostate cancer. RESULTS: Hypoxia increased RUNX2 expression in vitro, and bicalutamide-treated LNCaP tumours in mice (previously shown to have increased tumour hypoxia) exhibited increased RUNX2 expression. In addition, RUNX2-overexpressing LNCaP cells showed increased cell viability, following bicalutamide and docetaxel treatment, which was inhibited by RUNX2 siRNA; a range of assays demonstrated that this was due to resistance to apoptosis. RUNX2 expression was associated with increased Bcl-2 levels, and regulation of Bcl-2 by RUNX2 was confirmed through chromatin immunoprecipitation (ChIP) binding and reporter assays. Moreover, a Q-PCR array identified other apoptosis-associated genes upregulated in the RUNX2-overexpressing LNCaP cells. CONCLUSION: This study establishes a contributing mechanism for progression of prostate cancer cells to a more apoptosis-resistant and thus malignant phenotype, whereby increased expression of RUNX2 modulates the expression of apoptosis-associated factors, specifically Bcl-2.
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Anilidas/farmacología , Apoptosis/efectos de los fármacos , Hipoxia de la Célula/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Nitrilos/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-bcl-2/genética , Compuestos de Tosilo/farmacología , Animales , Antineoplásicos/farmacología , Apoptosis/genética , Hipoxia de la Célula/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Docetaxel , Humanos , Masculino , Ratones , Ratones SCID , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Proteínas Proto-Oncogénicas c-bcl-2/biosíntesis , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Taxoides/farmacología , Células Tumorales Cultivadas , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND AND PURPOSE: Existing epidemiological studies of Myasthenia Gravis have generally examined small populations. Few national studies have been conducted, and published incidence and prevalence rates vary widely. We report one of the largest national studies of Myasthenia Gravis, and the first incidence and prevalence rates for Australia. METHODS: Prescriptions for Pyridostigmine Bromide in 2009 were utilized from a national prescribing database to estimate incidence and the prevalence of symptomatic and treated disease. Crude rates were age-standardized to the WHO world population. We compared standardized rates to recent national studies from Norway and Taiwan. RESULTS: In 2009, there were 2574 prevalent cases of symptomatic and treated Myasthenia Gravis, corresponding to an annual crude prevalence rate of 117.1 per 1 million residents. There were 545 incident cases, yielding a crude incidence rate of 24.9 per 1 million residents. The crude incidence in women and men was estimated to be 27.9 and 21.9 per 1 million, respectively. Prevalence and incidence rates were higher in women than men between the ages of 15 and 64 years, and were higher in men than women in those older than 65 years. Rates peaked between the ages of 74 and 84 years, declining thereafter. Standardized incidence was higher in Australia than Norway, but similar to Taiwan (P-values = 0.007 and 1.00, respectively). CONCLUSIONS: This first Australian epidemiological study of symptomatic Myasthenia Gravis is one of the largest population-based studies ever reported and supports higher incidence rates for Myasthenia Gravis. Myasthenia Gravis disproportionately affected younger females and older males.
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Miastenia Gravis/epidemiología , Adolescente , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Australia/epidemiología , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Distribución por Sexo , Adulto JovenRESUMEN
Whole-genome association studies in rheumatoid arthritis have identified single-nucleotide polymorphisms (SNPs) predisposing to disease with moderate risk. We aimed to investigate the role of these markers in predicting methotrexate (MTX) response, measured by continuation on MTX monotherapy in patients with recent onset inflammatory polyarthritis (IP). In all, 19 SNPs were genotyped in 736 patients treated with MTX following registration, or not more than 3 months before registration, to the Norfolk Arthritis Register. The association of SNPs with MTX continuation by year 1 and by year 2 was investigated using Cox proportional hazard regression models. A SNP within the OLIG3/TNFAIP3 locus (rs6920220) was associated with being less likely to maintain MTX monotherapy at year 1, hazards ratio (HR) 1.73 (1.18, 2.52) and year 2, HR 1.49 (1.11, 2.00); correlating with an increased in adverse events. Weak evidence for an effect at the PTPN22 locus was also observed. These findings require replication in other large datasets.
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Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Proteínas de Unión al ADN/genética , Marcadores Genéticos , Péptidos y Proteínas de Señalización Intracelular/genética , Metotrexato/uso terapéutico , Proteínas Nucleares/genética , Anciano , Estudios de Cohortes , Humanos , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Sistema de Registros , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfaRESUMEN
BACKGROUND: The ABCD(2) stroke risk score is recommended in national guidelines for stratifying care in transient ischaemic attack (TIA) patients, based on its prediction of early stroke risk. We had become concerned about the score accuracy and its clinical value in modern TIA cohorts. METHODS: We identified emergency department-diagnosed TIA at two hospitals over 3 years (2004-2006). Cases were followed for stroke occurrence and ABCD(2) scores were determined from expert record review. Sensitivity, specificity and positive predictive values (PPV) of moderate-high ABCD(2) scores were determined. RESULTS: There were 827 indexed TIA diagnoses and record review was possible in 95.4%. Admitted patients had lower 30-day stroke risk (n = 0) than discharged patients (n = 7; 3.1%) (P < 0.0001). There was no significant difference in proportion of strokes between those with a low or moderate-high ABCD(2) score at 30 (1.2 vs 0.8%), 90 (2.0 vs 1.9%) and 365 days (2.4 vs 2.4%) respectively. At 30 days the sensitivity, specificity and PPV of a moderate-high score were 57% (95% confidence interval (CI) 25.0-84.2), 32.2% (95% CI 29.1-35.6) and 0.75% (95% CI 0.29-1.91) respectively. CONCLUSIONS: Early stroke risk was low after an emergency diagnosis of TIA and significantly lower in admitted patients. Moderate-high ABCD(2) scores did not predict early stroke risk. We suggest local validation of ABCD(2) before its clinical use and a review of its place in national guidelines.