All-trans retinoic acid skews monocyte differentiation into interleukin-12-secreting dendritic-like cells

All-trans retinoic acid (ATRA) and retinoid derivatives are essential agents for multiple biological processes. Numerous immune system dysfunctions can occur in the case of retinoid deficiency. Because of the central role of dendritic cells (DCs) in controlling immunity and the wide effects of retinoids on the immune system homeostasis, we investigated the ability of ATRA to influence the differentiation of DCs from circulating peripheral blood monocytes. Human peripheral blood monocytes were cultured with granulocyte-macrophage colony-stimulating factor (GM-CSF) and various concentrations of ATRA. Differentiated cells were assayed for their morphology, phenotype, antigen uptake, allostimulatory capacity and cytokine secretion profile. ATRA (10(-12) mol/l) and GM-CSF drove the differentiation of monocytes into dendritic-like cells (ATRA-DC). ATRA-DCs exhibited DC morphology, had a phenotype of immature DCs, with the expression of CD1a, and upregulation of adhesion and co-stimulatory molecules. ATRA-DCs could induce a proliferative response in naive CD4+ T cells. Although ATRA-DCs retained their antigen-capture capacity, they secreted interleukin (IL)-12p70 without the need for any maturation agent. In addition, ATRA-DCs could drive T cells towards an IL-12-dependent T-helper cell type 1 response with secretion of interferon-gamma. DCs appear to be potential targets for ATRA, giving new insights into the immunomodulatory function of retinoids, with implications potentially related to immunotherapy.     

Respiratory syncytial virus infections in pediatric transplant recipients: A Canadian Paediatric Surveillance Program study

The incidence and spectrum of severity of RSV infections in SOT or HSCT recipients is not known. From September 2010 through August 2013, pediatricians were surveyed monthly by the CPSP for SOT or HSCT recipients with RSV infection within two yr post‐transplant. There were 24 completed case report forms that fit the inclusion criteria (10 HSCT and 14 SOT recipients). Six of 24 cases (25%) remained outpatients, and 11 (46%) were managed on an inpatient ward, while seven (29%) required intensive care of which five required mechanical ventilation and two died of RSV infection. Ten of 23 cases (43%) were nosocomial with these data not recorded for one case. Many transplant recipients recover uneventfully from RSV infection in the first two yr post‐transplant. However, severe disease and death also occur. Larger studies are required to establish risk factors for poor outcomes. Prevention of nosocomial RSV should be a priority in transplant recipients.     

Array CGH analysis identifies two distinct subgroups of primary angiosarcoma of bone

Molecular genetic studies on vascular tumors are rare. Recently, possible involvement of MYC and KDR has been documented in a subset of angiosarcomas of soft tissue. We performed a cytogenetic analysis of primary angiosarcomas of bone (n = 13) and soft tissue (n = 5) using high density array‐comparative genomic hybridization (array‐CGH). Regions of interest were validated by fluorescence in situ hybridization (FISH). Antibodies for candidate genes (SKI, MYC, KDR, and MAPK9) were selected and immunohistochemistry was performed. Six angiosarcomas of bone and four angiosarcomas of soft tissue showed chromosomal losses, gains, and high level amplifications. Cluster analysis identified two groups: a group with a complex genetic profile and a group with only few genetic aberrations. Five regions of interest were selected, which were located at chromosome bands 1p36.23, 2q32‐34, 5q35, 8q24, and 17q21.32‐24.2. Interphase FISH confirmed the high‐level amplifications. Immunohistochemical analysis showed high expression of MYC (16/60), MAPK9 (63/69), and SKI (52/62). There were no differences between the two groups with regards to location, immunohistochemical expression nor survival. In summary, we identified two subgroups of angiosarcoma: those with few or no gross aberrations and those which show numerous genetic aberrations consisting of chromosomal losses, gains and high level amplifications or complex aberrations. The most common finding was amplification of 2q and 17q in both angiosarcoma of bone and soft tissue, suggesting overlap in tumorigenesis irrespective of their location. We show MYC amplification in primary angiosarcoma indicating this is not entirely specific for radiation‐induced angiosarcoma. © 2014 Wiley Periodicals, Inc.     

Noise-Induced Variability of Immuno-PET with Zirconium-89-Labeled Antibodies: an Analysis Based on Count-Reduced Clinical Images

Purpose

Positron emission tomography (PET) with Zirconium-89 (Zr-89)-labeled antibodies can be used for in vivo quantification of antibody uptake. Knowledge about measurement variability is required to ensure correct interpretation. However, no clinical studies have been reported on measurement variability of Zr-89 immuno-PET. As variability due to low signal-to-noise is part of the total measurement variability, the aim of this study was to assess noise-induced variability of Zr-89 -immuno-PET using count-reduced clinical images.

Procedures

Data were acquired from three previously reported clinical studies with [⁸⁹Zr]antiCD20 (74 MBq, n?=?7), [⁸⁹Zr]antiEGFR (37 MBq, n?=?7), and [⁸⁹Zr]antiCD44 (37 MBq, n?=?13), with imaging obtained 1 to 6 days post injection (D0–D6). Volumes of interest (VOIs) were manually delineated for liver, spleen, kidney, lung, brain, and tumor. For blood pool and bone marrow, fixed-size VOIs were used. Original PET list mode data were split and reconstructed, resulting in two count-reduced images at 50 % of the original injected dose (e.g., 37 MBq_74inj).Repeatability coefficients (RC) were obtained from Bland-Altman analysis on standardized uptake values (SUV) derived from VOIs applied to these images.

Results

The RC for the combined manually delineated organs for [⁸⁹Zr] antiCD20 (37 MBq_74inj) increased from D0 to D6 and was less than 6 % at all time points. Blood pool and bone marrow had higher RC, up to 43 % for 37 MBq_74inj at D6. For tumor, the RC was up to 42 % for [⁸⁹Zr]antiCD20 (37 MBq_74inj). For [⁸⁹Zr]antiCD20, (18 MBq_74inj), [⁸⁹Zr]antiEGFR (18 MBq_37inj), and [⁸⁹Zr]antiCD44 (18 MBq_37inj), measurement variability was independent of the investigated antibody.

Conclusions

Based on this study, noise-induced variability results in a RC for Zr-89-immuno-PET (37 MBq) around 6 % for manually delineated organs combined, increasing up to 43 % at D6 for blood pool and bone marrow, assuming similar biodistribution of antibodies. The signal-to-noise ratio leads to tumor RC up to 42 %.

     

Adverse Birth Outcomes in Colorado: Assessing the Impact of a Statewide Initiative to Prevent Unintended Pregnancy

Objectives. We assessed whether living in counties with Title X clinics and increased use of long-acting reversible contraception (LARC) in Colorado are associated with decreased risk of adverse birth outcomes.Methods. We linked Title X clinic counties to the Colorado birth data set by using the mother’s county of residence. We compared low birth weight (LBW) and preterm birth (PTB) in 2008 and 2012, in counties with and without Title X clinics. We compared the relationship between LARC use and the incidence of LBW or PTB in 2012 for women living in counties with Title X clinics.Results. For women living in counties with Title X clinics, the odds of PTB were significantly lower in 2012 compared with 2008 (odds ratio = 0.85; 95% confidence interval = 0.81, 0.89; interaction P = .02). For women living in Title X clinic counties in 2012, a higher proportion of LARC use (> 12.4%) was significantly associated with decreased risk of PTB (P = .02) compared with a low proportion of LARC use (≤ 4.96%).Conclusions. Improved access to family planning services and increased use of LARC are associated with lower risk of PTB.Unintended pregnancy is a significant public health issue in the United States. According to the most recent published estimates, 51% of pregnancies in the United States were unintended, and 60% of unintended pregnancies resulted in a live birth.1 Unintended pregnancies are associated with increased risk of adverse pregnancy outcomes, such as preterm birth (PTB) and delivery of low–birth weight (LBW) infants.2–8 In a large systematic review, Shah et al. reported increased odds of PTB (odds ratio [OR] = 1.31; 95% confidence interval [CI] = 1.09, 1.58) and LBW (OR = 1.36; 95% CI = 1.25, 1.48) among unintended pregnancies ending in live birth compared with intended pregnancies.2 The link between unintended pregnancy and poor birth outcomes is likely multifaceted, and may be associated with maternal socioeconomic risk factors, inadequate prenatal care, and preconceptual and prenatal maternal behavioral risk factors such as smoking and alcohol use.9–11 As part of the national effort to improve overall public health, increasing the proportion of pregnancies that are intended and decreasing the rates of PTB and LBW deliveries are all objectives of the Healthy People 2020 initiative.12In 2008, 37% of live births in Colorado resulted from unintended pregnancies according to the Pregnancy Risk Assessment Monitoring System.13 To address this issue, the Colorado Initiative to Reduce Unintended Pregnancy (Colorado Initiative) was developed and enacted in 2009 with the generous support of an anonymous donor.14 As part of the effort, the Colorado Family Planning Initiative was implemented through the Colorado Department of Public Health and Environment. Two of the primary goals of the initiative were (1) increasing the number of women accessing family planning services and (2) increasing the adoption of long-acting reversible contraceptive (LARC) methods such as intrauterine devices and contraceptive implants.14 Long-acting reversible contraceptive methods are safe and highly effective forms of contraception that have been shown to reduce rates of unintended pregnancy.15–18To help achieve these objectives, the Colorado Initiative provided funding to 28 Title X–funded agencies across the state of Colorado from 2009 to 2013, serving 37 of 64 Colorado counties. Those 37 counties were home to 95% of the state’s low-income population (defined as individuals with incomes at or below 150% of the federal poverty level).14 The locations of Colorado Title X clinics are shown in Figure 1. This distribution of resources in Colorado is important, in light of the known disparities of unintended pregnancy rates for women on the basis of socioeconomic status, age, race/ethnicity, and level of education.1Open in a separate windowFIGURE 1—Counties and locations of Title X clinics: Colorado, 2008 and 2012.The funding for the Colorado Initiative specifically supported the provision of intrauterine devices and contraceptive implants to women seeking care at Title X clinics, training for providers and staff on the counseling and provision of LARC methods, and technical assistance to Title X agencies related to increasing the use of these methods.14 Many of the Title X clinics across the state successfully executed the primary objectives of the Colorado Initiative, resulting in a rise in the total number of clients accessing family planning services per year from 46 201 to 64 148 and the proportion of women choosing LARC methods out of all women using contraception at Title X clinics from 0.8% to 8.6% from 2008 to 2012 (G. Klinger, Colorado Department of Public Health and Environment, e-mail communication, April 1, 2014).Although LARC use is on the rise in the United States, there is little in the published literature demonstrating an association between the use of LARC methods and rates of adverse birth outcomes.19 Given the scale of the Colorado Initiative, there is a unique opportunity to evaluate this possible association. As a result of improved use of family planning services in general and LARC use in particular, we hypothesized the following: (1) there will be a significant decrease in LBW and PTB in Colorado from 2008 to 2012; (2) for women living in Colorado counties in 2012 compared with 2008, LBW and PTB will differ by whether there is a Title X clinic in that woman’s county of residence; and (3) for women living in Colorado counties with Title X clinics in 2012, there will be a significant inverse association between LARC use at Title X clinics and LBW and PTB.