• CpG(A)-siRNA oligonucleotides allow for targeting genes specifically in human TLR9 ϩ immune cells and blood cancer cells.• Tumoricidal and immunostimulatory properties of CpG(A)-STAT3 siRNA provide a novel therapeutic opportunity for hematologic malignancies.STAT3 operates in both cancer cells and tumor-associated immune cells to promote cancer progression. As a transcription factor, it is a highly desirable but difficult target for pharmacologic inhibition. We have recently shown that the TLR9 agonists CpG oligonucleotides can be used for targeted siRNA delivery to mouse immune cells. In the present study, we demonstrate that a similar strategy allows for targeted gene silencing in both normal and malignant human TLR9 ؉ hematopoietic cells in vivo. We have developed new human cell-specific CpG(A) - IntroductionThe proliferation and survival of the majority of hematologic cancers depends on constitutive activity of STAT transcription factors. 1,2 The first evidence linking STAT activity with human blood cancer was derived from studies on multiple myeloma (MM). Permanent activity of STAT3 observed in myeloma cells was critical for their survival because of up-regulation of antiapoptotic BCL-X L protein. 3 Later reports identified constitutive activation of STAT3 not only in myeloma but also in other hematologic malignancies, with the highest frequency in B-cell lymphoma (BCL) and acute myeloid leukemia (AML) patient blasts. 1,4,5 The presence of activated STAT3 in leukemic blasts was associated with decreased disease-free survival of AML patients. 4 As a point of convergence for downstream signaling from cytokine and growth factor receptors, STAT3 plays a critical role in mediating cross-talk within the tumor microenvironment, which promotes tumor immune tolerance, vascularization, and metastasis. 6 Because STAT3 operates in both cancer cells and nonmalignant tumorassociated cells, it represents a highly desirable target for cancer therapy. 6 These important findings instigated numerous attempts to develop STAT3 inhibitors; however, pharmacologic inhibition of a protein lacking enzymatic activity is challenging. 4,7 An additional complication is the close structural similarity between oncogenic STAT3 and functionally distinct STAT1, a transcriptional factor critical for generation of antitumor immunity by IFNs. 8,9 The tyrosine kinase inhibitors upstream from STAT3, such as JAK, SRC, c-KIT, and FLT3 in leukemia, gained attention as promising blood cancer therapeutics. 4 However, the effect of small-molecule drugs, including FLT3 inhibitors, in most clinical trials was short-lived. 10,11 Other conventional treatment regimens for hematologic malignancies are limited by the high toxicity to normal tissues, development of drug resistance, and low disease-free survival rates. For personal use only. on May 11, 2018. by guest www.bloodjournal.org FromThe emergence of therapeutic strategies based on RNA interference (RNAi) created a unique opportunity to silence any diseaserelated target gene. 13,14 The major obstacle ...

Correspondence to: Yong Liu, ikd8@cdc.gov. Conflict of interestThe authors declare that they have no conflict of interest.Part of the manuscript was presented in 28th Annual BRFSS Conference on March 19-23, 2011 in Atlanta, GA. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptPurpose-Our study assesses the relationships between self-reported adverse childhood experiences (ACEs) (including sexual, physical, or verbal abuse, along with household dysfunction including parental separation or divorce, domestic violence, mental illness, substance abuse, or incarcerated household member) and unemployment status in five US states in 2009.Methods-We examined these relationships using the 2009 Behavioral Risk Factor Surveillance System survey data from 17,469 respondents (aged 18-64 years) who resided in five states, completed the ACE Questionnaire, and provided socio-demographic and social support information. We also assessed the mediation of these relationships by respondents' educational attainment, marital status, and social support.Results-About two-third of respondents reported having had at least one ACEs, while 15.1 % of men and 19.3 % of women reported having had ≥4 ACEs. Among both men and women, the unemployment rate in 2009 was significantly higher among those who reported having had any ACE than among those who reported no ACEs (p < 0.05). Educational attainment, marital status, and social support mediated the relationship between ACEs and unemployment, particularly among women.Conclusions-ACEs appear to be associated with increased risk for unemployment among men and women. Further studies may be needed to better understand how education, marital status, and social support mediate the association between multiple ACEs and unemployment.

U.S. adult binge drinkers consume about 17.5 billion total binge drinks annually, or about 470 binge drinks/binge drinker. Monitoring total binge drinks can help characterize disparities in binge drinking and help plan and evaluate effective prevention strategies.