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1.
J Pharm Technol ; 35(3): 119-125, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34860981

RESUMO

Objective: To review the pharmacology, safety, and efficacy of andexanet alfa (andexanet), a recombinant modified human factor Xa protein for reversal of factor Xa inhibitors. Data Sources: English-language articles were obtained from MEDLINE (1966 to February 2019) using the following key words: andexanet, andexanet alfa, AndexXa, factor Xa, antidote, and reversal. Citations from selected articles were used to identify additional sources. Study Selection and Data Extraction: Available published articles reporting results of human studies of andexanet alfa were reviewed for inclusion. Prescribing information was used to obtain additional information regarding pharmacology, adverse events, contraindications, and precautions. Data Synthesis: Andexanet is a recombinant modified human factor Xa protein indicated for reversal of rivaroxaban and apixaban in patients with life-threatening or uncontrolled bleeding. Onset of action is rapid and sustained throughout bolus and infusion administration. Medication effects subside 1 to 3 hours postadministration. Andexanet is administered as a bolus followed by a 120-minute continuous infusion. Anti-factor Xa activity was reduced by 95% and 92% in apixaban and rivaroxaban groups, respectively, on infusion completion. Thrombin regeneration occurred within 2 to 5 minutes in up to 96% of patients. Minor infusion reactions and gastrointestinal upset were reported most. A black box warning for thrombotic events, cardiac arrest, ischemia, and sudden death should be noted. Conclusions: Andexanet is effective in reversing rivaroxaban and apixaban anticoagulation due to reduction of anti-factor Xa activity in healthy patients and those with acute major bleeds. Safety concerns, including thrombotic risks, exist and should be assessed against individual patient factors.

2.
Mol Carcinog ; 52 Suppl 1: E139-47, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23776098

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is an emerging epidemic with high prevalence in Western countries. Genome-wide association studies had reported that a variation in the patatin-like phospholipase domain containing 3 (PNPLA3) gene is associated with high susceptibility to NAFLD. However, the relationship between this variation and hepatocellular carcinoma (HCC) has not been well established. We investigated the impact of PNPLA3 genetic variation (rs738409: C>G) on HCC risk and prognosis in the United States by conducting a case-control study that included 257 newly diagnosed and pathologically confirmed Caucasian patients with HCC (cases) and 494 healthy controls. Multivariate logistics and Cox regression models were used to control for the confounding effects of HCC risk and prognostic factors. We observed higher risk of HCC for subjects with a homozygous GG genotype than for those with CC or CG genotypes, the adjusted odds ratio (OR) was 3.21 (95% confidence interval [CI], 1.68-6.41). We observed risk modification among individuals with diabetes mellitus (OR = 19.11; 95% CI, 5.13-71.20). The PNPLA3 GG genotype was significantly associated with underlying cirrhosis in HCC patients (OR = 2.48; 95% CI, 1.05-5.87). Moreover, GG allele represents an independent risk factor for death. The adjusted hazard ratio of the GG genotype was 2.11 (95% CI, 1.26-3.52) compared with CC and CG genotypes. PNPLA3 genetic variation (rs738409: C>G) may determine individual susceptibility to HCC development and poor prognosis. Further experimental investigations are necessary for thorough assessment of the hepatocarcinogenic role of PNPLA3.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/etiologia , Lipase/genética , Cirrose Hepática/etiologia , Neoplasias Hepáticas/etiologia , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Cirrose Hepática/mortalidade , Cirrose Hepática/patologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Reação em Cadeia da Polimerase , Prognóstico , Estudos Prospectivos , Fatores de Risco , Taxa de Sobrevida , Estados Unidos
3.
Nat Commun ; 6: 7419, 2015 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-26080861

RESUMO

Currently available human tumour cell line panels consist of a small number of lines in each lineage that generally fail to retain the phenotype of the original patient tumour. Here we develop a cell culture medium that enables us to routinely establish cell lines from diverse subtypes of human ovarian cancers with >95% efficiency. Importantly, the 25 new ovarian tumour cell lines described here retain the genomic landscape, histopathology and molecular features of the original tumours. Furthermore, the molecular profile and drug response of these cell lines correlate with distinct groups of primary tumours with different outcomes. Thus, tumour cell lines derived using this methodology represent a significantly improved platform to study human tumour pathophysiology and response to therapy.


Assuntos
Carcinoma/patologia , Linhagem Celular Tumoral , Neoplasias Ovarianas/patologia , Cisplatino , Meios de Cultura , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Perfilação da Expressão Gênica , Xenoenxertos , Humanos , Paclitaxel , Fenótipo
4.
Head Neck ; 36(1): 15-21, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23633104

RESUMO

BACKGROUND: Sinonasal undifferentiated carcinoma (SNUC) remains a poorly characterized malignancy at both the clinical and molecular level, and, consequently, the optimal treatment strategy remains undefined. METHODS: We used a mass spectroscopy-based approach (Sequenom) to evaluate 95 hallmark single nucleotide variations (SNVs) within 12 oncogenes or tumor suppressor genes (AKT, BRAF, CDK4, Beta-catenin, epidermal growth factor receptor [EGFR], FBXW7, JAK2, c-KIT, KRAS, PDGFR, PI3K, and vascular endothelial growth factor [VEGF]) in 13 histologically confirmed SNUC cases. RESULTS: None of the samples demonstrated activating mutations in any of the 95 SNVs. CONCLUSION: Select clinically relevant activating genomic mutations were not identified in the 13 patient samples. However, polymorphisms were noted within the promoter region of VEGF. These may merit future studies as predictive biomarkers for treatment response or overall survival. Additionally, future studies focusing on larger tumor sets and utilizing whole genome or exome sequencing may help define genetic aberrations in SNUC that can be clinically targeted with available or emerging biological agents.


Assuntos
Carcinoma/genética , Carcinoma/patologia , Genes Supressores de Tumor , Predisposição Genética para Doença , Neoplasias do Seio Maxilar/genética , Neoplasias do Seio Maxilar/patologia , Neoplasias dos Seios Paranasais/genética , Neoplasias dos Seios Paranasais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia por Agulha , Carcinoma/terapia , DNA de Neoplasias/genética , Feminino , Genótipo , Humanos , Imuno-Histoquímica , Masculino , Espectrometria de Massas , Neoplasias do Seio Maxilar/terapia , Microscopia Eletrônica de Transmissão , Pessoa de Meia-Idade , Neoplasias dos Seios Paranasais/terapia , Polimorfismo de Nucleotídeo Único , Prognóstico
5.
J Cancer Res Clin Oncol ; 138(3): 377-85, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22146979

RESUMO

PURPOSE: The phosphatidylinositol 3-kinase (PI3K)/PTEN/AKT/mTOR and Ras/Raf/MEK/ERK pathways have been implicated in endometrial tumorigenesis. In this candidate pathway analysis, we investigated associations between genetic variations in these two pathways and both risk and clinical outcomes of endometrial cancer. METHODS: We genotyped a total of 48 potentially functional SNPs in 11 key genes (AKT1, AKT2, AKT3, BRAF, FRAP1, KRAS, PDPK1, PIK3CA, PIK3CB, PIK3R1, and PTEN) with the Sequenom genotyping platform in 115 endometrial cancer patients and 230 cancer-free women to evaluate their associations with risk, survival, and recurrence of endometrial cancer. RESULTS: We found the following: (1) PIK3CA rs6443624 and rs9838411 variants either borderline or significantly decreased risk of endometrial cancer in a dominant model (adjusted odds ratio [OR], 0.62; 95% CI, 0.39-1.00 and 0.59; 95% CI, 0.36-0.95, respectively). Furthermore, there was a statistically significant multiplicative interaction (P (int) = 0.036) between these two loci in risk of endometrial cancer. In contrast, the AKT1 rs2498801 genotype significantly increased risk of endometrial cancer (adjusted OR, 1.94; 95% CI, 1.02-3.67 in a recessive model). (2) In Cox regression analyses, three SNPs (PIK3R1 rs1862162, AKT2 rs892119, and PIK3CA rs2699887) showed significant associations with survival of endometrial cancer patients. (3) KRAS rs7312175 and PIK3CA rs6443624 had significant effects on recurrence of endometrial cancer individually and combined in a locus-dosage manner (adjusted P (trend) = 0.003). CONCLUSION: These results suggest that common genetic variations in these pathways may modulate risk and clinical outcomes of endometrial cancer. Further replication and functional studies are needed to confirm these findings.


Assuntos
Neoplasias do Endométrio/genética , Fosfatidilinositol 3-Quinases/genética , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais , Idoso , Estudos de Casos e Controles , Classe I de Fosfatidilinositol 3-Quinases , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/mortalidade , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/terapia , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Pessoa de Meia-Idade , Razão de Chances , PTEN Fosfo-Hidrolase/genética , Projetos Piloto , Modelos de Riscos Proporcionais , Proteínas Proto-Oncogênicas p21(ras)/genética , Medição de Risco , Fatores de Risco , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/genética , Resultado do Tratamento , Quinases raf/genética
6.
Int J Pharm Compd ; 14(1): 48-53, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-23965370

RESUMO

Over the past century, as the dynamic of pharmacy practice has evolved, there has been continual ebb and flow in the practice of compounding. However, the basic art and science remain the same. Mirroring these practice trends, education in the components of compounding and curricular requirements in many Doctor of Pharmacy programs has also experienced many changes. At the University Of Washington School Of Pharmacy, students receive basic instruction in the science and techniques of compounding during their first professional year, but little further. To accommodate an increasing interest in the art, science, and practice of compounding in community pharmacy, the University Of Washington School Of Pharmacy created a unique elective in advanced compounding skills. This intensive course operates over a weekend at a successful community compounding pharmacy located in central Washington State. The course is primarily taught by the pharmacy owner and other pharmacists with compounding expertise. This article describes the evolution, assessment, and future potential of this advanced compounding elective at the University Of Washington School Of Pharmacy.

7.
Nat Genet ; 41(9): 991-5, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19648920

RESUMO

We conducted a genome-wide association study on 969 bladder cancer cases and 957 controls from Texas. For fast-track validation, we evaluated 60 SNPs in three additional US populations and validated the top SNP in nine European populations. A missense variant (rs2294008) in the PSCA gene showed consistent association with bladder cancer in US and European populations. Combining all subjects (6,667 cases, 39,590 controls), the overall P-value was 2.14 x 10(-10) and the allelic odds ratio was 1.15 (95% confidence interval 1.10-1.20). rs2294008 alters the start codon and is predicted to cause truncation of nine amino acids from the N-terminal signal sequence of the primary PSCA translation product. In vitro reporter gene assay showed that the variant allele significantly reduced promoter activity. Resequencing of the PSCA genomic region showed that rs2294008 is the only common missense SNP in PSCA. Our data identify rs2294008 as a new bladder cancer susceptibility locus.


Assuntos
Antígenos de Neoplasias/genética , Predisposição Genética para Doença , Variação Genética , Glicoproteínas de Membrana/genética , Proteínas de Neoplasias/genética , Neoplasias da Bexiga Urinária/genética , Alelos , Antígenos de Neoplasias/imunologia , Estudos de Casos e Controles , Mapeamento Cromossômico , Cromossomos Humanos Par 8 , Proteínas Ligadas por GPI , Frequência do Gene , Genes Reporter , Estudo de Associação Genômica Ampla , Haplótipos , Heterozigoto , Homozigoto , Humanos , Desequilíbrio de Ligação , Modelos Logísticos , Masculino , Análise Multivariada , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Reprodutibilidade dos Testes , Neoplasias da Bexiga Urinária/imunologia
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