Urine Extracellular Vesicle GATA2 mRNA Discriminates Biopsy Result in Men with Suspicion of Prostate Cancer.

PURPOSE: Prostate specific antigen has limited performance in detecting prostate cancer. The transcription factor GATA2 is expressed in aggressive prostate cancer. We analyzed the predictive value of urine extracellular vesicle GATA2 mRNA alone and in combination with a multigene panel to improve detection of prostate cancer and high risk disease. MATERIALS AND METHODS: GATA2 mRNA was analyzed in matched extracellular vesicles isolated from urines before and after prostatectomy (16) and paired urine and tissue prostatectomy samples (19). Extracellular vesicle GATA2 mRNA performance to distinguish prostate cancer and high grade disease was tested in training (52) and validation (165) cohorts. The predictive value of a multigene score including GATA2, PCA3 and TMPRSS2-ERG (GAPT-E) was tested in both cohorts. RESULTS: Confirming its prostate origin, urine extracellular vesicle GATA2 mRNA levels decreased significantly after prostatectomy and correlated with prostate cancer tissue GATA2 mRNA levels. In the training and validation cohort GATA2 discriminated prostate cancer (AUC 0.74 and 0.66) and high grade disease (AUC 0.78 and 0.65), respectively. Notably, the GAPT-E score improved discrimination of prostate cancer (AUC 0.84 and 0.72) and high grade cancer (AUC 0.85 and 0.71) in both cohorts when compared with each biomarker alone and PT-E (PCA3 and TMPRSS2-ERG). A GAPT-E score for high grade prostate cancer would avoid 92.1% of unnecessary prostate biopsies, compared to 61.9% when a PT-E score is used. CONCLUSIONS: Urine extracellular vesicle GATA2 mRNA analysis improves the detection of high risk prostate cancer and may reduce the number of unnecessary biopsies.

Stroke Disparities: Disaggregating Native Hawaiians from other Pacific Islanders.

OBJECTIVES: To compare the clinical characteristics of Native Hawaiians (NH) and other Pacific Islanders (PI) who are hospitalized with ischemic stroke. DESIGN: Retrospective, cross-sectional analysis of medical records. SETTING: Tertiary, Primary Stroke Center in Honolulu, Hawaii. PATIENTS: Consecutive patients with race/ethnicity identified as NH or PI who were hospitalized for ischemic stroke between January 2006 and December 2012. OUTCOME MEASURES: Age, sex, cardiovascular risk factors, intravenous tissue plasminogen activator (IV-tPA) utilization rate and hospital length of stay. RESULTS: A total of 561 patients (57% NH and 43% PI) were studied. PI were younger (59 ± 13 years vs 62 ± 14 years, P = .002), had higher prevalence of diabetes mellitus (58% vs 41%, P < .0001) and prosthetic valve (6% vs 2%, P = .007), lower prevalence of smoking (14% vs 21%, P = .03), lower HDL cholesterol (38 ± 11 mg/dL vs 41 ± 13 mg/dL, P = .004), and higher discharge diastolic blood pressure (79 ± 15 vs 76 mm Hg ± 14 mm Hg, P = .04) compared to NH. No difference was seen in other cardiovascular risk factors. The IV-tPA utilization rate (5% vs 6%, P = .48) and the hospital length of stay (10 ± 17 days vs 10 ± 49 days, P = .86) were not different between the two groups. CONCLUSION: Native Hawaiians and other Pacific Islanders with ischemic stroke have modestly different age of stroke presentation and burden of risk factors compared to each other. Disaggregating these two racial groups may be important to unmask any potential clinical differences in future studies.

Lipid Nanosystems Enhance the Bioavailability and the Therapeutic Efficacy of FTY720 in Acute Myeloid Leukemia.

Protein phosphatase 2A (PP2A) is a serin-threonin phosphatase that regulates many proteins critical for malignant cell behavior; therefore, PP2A is considered to be a human tumor suppressor. In this study, we assessed the pharmacokinetic profile and the antileukemic effects of the PP2A activator FTY720, free or encapsulated in lipid nanoparticles, in in vitro and in vivo models of acute myeloid leukemia. FTY720 lipid nanoparticles presented diameters around 210 nm, with an encapsulation efficiency up to 75% and significantly increased FTY720 oral bioavailability. In addition, FTY720 restores PP2A phosphatase activity and decreases phosphorylation of PP2A and its targets Akt, ERK1/2 and STAT5, all implicated in the pathogenesis of acute myeloid leukemia. Moreover, FTY720 exerts an additive anti-leukemic effect in combination with drugs used in standard induction therapy. Importantly, FTY720 lipid nanoparticles were more efficient at inducing cell growth arrest and apoptosis than FTY720 solution. Finally, oral administration of FTY720 lipid nanoparticles to mice every three days was as effective in reducing acute myeloid leukemia xenograft tumor growth as daily oral administration of FTY720. These results provide the first evidence for the potential use of FTY720 lipid nanoparticles as an oral therapeutic agent in acute myeloid leukemia.

Importance of genetics in acute myeloid leukemia.

Acute myeloid leukemia (AML) comprises a biologically and clinically heterogeneous group of aggressive disorders that occur as a consequence of a wide variety of genetic and epigenetic abnormalities in hematopoietic progenitors. Despite significant advances in the understanding of the biology of AML, most patients will die from relapsed disease. Whole-genome studies have identified novel recurrent gene mutations with prognostic impact in AML; furthermore, it is likely that in the near future genome-wide sequencing will become a routine for newly diagnosed patients with AML. Therefore, future clinical trials should aim to identify genetically defined high-risk patients, and further research is necessary to identify effective agents and develop new individualized therapeutic strategies for the treatment of this deadly disease.

p27Kip1 represses transcription by direct interaction with p130/E2F4 at the promoters of target genes.

The cyclin-cdk (cyclin-dependent kinase) inhibitor p27Kip1 (p27) has a crucial negative role on cell cycle progression. In addition to its classical role as a cyclin-cdk inhibitor, it also performs cyclin-cdk-independent functions as the regulation of cytoskeleton rearrangements and cell motility. p27 deficiency has been associated with tumor aggressiveness and poor clinical outcome, although the mechanisms underlying this participation still remain elusive. We report here a new cellular function of p27 as a transcriptional regulator in association with p130/E2F4 complexes that could be relevant for tumorigenesis. We observed that p27 associates with specific promoters of genes involved in important cellular functions as processing and splicing of RNA, mitochondrial organization and respiration, translation and cell cycle. On these promoters p27 co-localizes with p130, E2F4 and co-repressors as histone deacetylases (HDACs) and mSIN3A. p27 co-immunoprecipitates with these proteins and by affinity chromatography, we demonstrated a direct interaction of p27 with p130 and E2F4 through its carboxyl-half. We have also shown that p130 recruits p27 on the promoters, and there p27 is needed for the subsequent recruitment of HDACs and mSIN3A. Expression microarrays and luciferase assays revealed that p27 behaves as transcriptional repressor of these p27-target genes (p27-TGs). Finally, in human tumors, we established a correlation with overexpression of p27-TGs and poor survival. Thus, this new function of p27 as a transcriptional repressor could have a role in the major aggressiveness of tumors with low levels of p27.

Geographical maldistribution of native Hawaiian and other Pacific Islander physicians in Hawai'i.

BACKGROUND: Native Hawaiians and other Pacific Islanders (NHOPI) have high prevalence of overweight status, obesity, and hypertension, as well as high rates of asthma and cancer mortality. Some barriers to health care delivery for this population are a physician shortage in Hawai'i and a geographical maldistribution of actively practicing physicians. This study examines the distribution of NHOPI physicians compared to the NHOPI population in Hawai'i through Geographical Information System choropleth mapping. METHODS: The maps and results were gathered and constructed from Census Tract data from the US Department of Commerce, the Census Bureau, the Physician Workforce Assessment, and the 'Ahahui o na Kauka reports. RESULTS: With the exception of East Honolulu, all areas of Hawai'i show drastic disparities in the ratio of NHOPI physicians to NHOPI populations as compared to the ratio of total physicians to the total population. DISCUSSION: Given the NHOPI physician shortage and their geographical maldistribution, this study underscores the importance of increasing the number of NHOPI medical school applicants, graduates, residents, and physicians in permanent active practices in rural areas and the neighbor islands. Current institutional and academic programs, such as the John A. Burns School of Medicine, Imi Ho'ola, and the Native Hawaiian Center of Excellence, are contributing to resolving some of the health disparities and should consider expanding their efforts.