Prostaglandin E2 stimulates cAMP signaling and resensitizes human leukemia cells to glucocorticoid-induced cell death.

Glucocorticoid (GC) resistance remains a clinical challenge in pediatric acute lymphoblastic leukemia where response to GC is a reliable prognostic indicator. To identify GC resistance pathways, we conducted a genome-wide, survival-based, short hairpin RNA screen in murine T-cell acute lymphoblastic leukemia (T-ALL) cells. Genes identified in the screen interfere with cyclic adenosine monophosphate (cAMP) signaling and are underexpressed in GC-resistant or relapsed ALL patients. Silencing of the cAMP-activating Gnas gene interfered with GC-induced gene expression, resulting in dexamethasone resistance in vitro and in vivo. We demonstrate that cAMP signaling synergizes with dexamethasone to enhance cell death in GC-resistant human T-ALL cells. We find the E prostanoid receptor 4 expressed in T-ALL samples and demonstrate that prostaglandin E2 (PGE2) increases intracellular cAMP, potentiates GC-induced gene expression, and sensitizes human T-ALL samples to dexamethasone in vitro and in vivo. These findings identify PGE2 as a target for GC resensitization in relapsed pediatric T-ALL.

Household-smoking bans are associated with reduced nicotine exposure, increased smoking abstinence, and improved birth outcomes among pregnant women enrolled in smoking-cessation treatment.

Data indicate household-smoking bans aid cessation and reduce secondhand smoke exposure. This study assessed prevalence of antepartum (AP) and postpartum (PP) household-smoking bans and associations with nicotine exposure, abstinence, and birth weight among pregnant women. The current study is a secondary analysis of clinical trials examining the efficacy of financial incentives for smoking-cessation among pregnant women (N = 284). Participants were current smokers at the start of prenatal care and followed from ∼10 weeks gestational age through 24 weeks PP. Household-smoking rules and biochemically verified urinary cotinine were measured repeatedly. Nicotine exposure and birth weight were analyzed using analysis of covariance. Association with abstinence was analyzed using backward elimination logistic regressions. Prevalence of household-smoking bans increased from ∼ 45% to 55% AP and then increased to ∼80% PP. Women with a ban exhibited lower nicotine exposure in early and late pregnancy compared to smokers without a ban. Women with a ban at baseline or who adopted a ban early in treatment were more likely to be abstinent at late pregnancy and 24 weeks PP compared to women without a ban. There was a dose-response relationship between combined exposure (i.e., smoking and ban status) and infant birth weight, with infants of women who quit and reported a ban having the highest adjusted mean birth weight (3426 ± 63 g), while infants of women who continued smoking without a ban having the lowest (3153 ± 37 g). These results provide an empirical rationale for prospectively investigating whether adopting a household-smoking ban can reduce fetal exposure among pregnant smokers. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Smartphone-based financial incentives to promote smoking cessation during pregnancy: A pilot study.

Cigarette smoking during pregnancy increases risk for pregnancy complications, growth restriction, and other adverse health outcomes. The most effective intervention for reducing smoking during pregnancy is financial incentives contingent on biochemically-verified smoking abstinence. The present study examined the efficacy of a smartphone-based intervention whereby smoking monitoring and incentive delivery occurred remotely using a mobile app. If efficacious, this remote intervention would allow pregnant women residing in geographically remote areas to benefit from incentives-based cessation interventions. Sixty U.S. pregnant smokers were recruited between May 2018 to May 2019 via obstetrical clinics, Women, Infants, and Children (WIC) offices, and Facebook. Participants were assigned sequentially to one of two treatments: best practices alone (N = 30) or best practices plus financial incentives (N = 30). Outcomes were analyzed using repeated measures analysis based on generalized estimating equations (GEE). Seven-day point prevalence abstinence rates were greater in the incentives versus best practices arms early- (46.7% vs 20.0%, OR = 3.50, 95%CI = 1.11,11.02) and late-antepartum (36.7% vs 13.3%, OR = 3.76, 95%CI = 1.04,13.65), and four- (36.7% vs 10.0%, OR = 5.21, 95%CI = 1.28,21.24) and eight-weeks postpartum (40.0% vs 6.7%, OR = 9.33, 95%CI = 1.87,46.68), although not at the 12- (23.3% vs 10.0%, OR = 2.74, 95%CI = 0.63,11.82) or 24-week (20.0% vs 6.7%, OR = 3.50, 95%CI = 0.65,18.98) postpartum assessments likely due to this pilot study being underpowered for discerning differences at the later assessments, especially 24-weeks postpartum which was three months after treatment completion. These results support the efficacy of this remote, incentives-based intervention for pregnant smokers. Further research evaluating its efficacy and cost-effectiveness in a well-powered, randomized controlled trial appears warranted.

Using the Cigarette Purchase Task to examine the relative reinforcing value of cigarettes among mothers with versus without opioid dependence.

The Cigarette Purchase Task (CPT), in which participants estimate the number of cigarettes they would smoke across increasing cigarette prices, measures the relative reinforcing value of cigarettes. Although opioid-dependent individuals are particularly vulnerable to tobacco addiction, more research is needed to elucidate whether and to what extent their motivation to smoke differs from not-opioid-dependent smokers controlling for potential sociodemographic differences. Participants were 173 women (65 opioid-dependent) in an ongoing clinical trial for smoking cessation. Baseline CPT responses were compared between opioid-dependent and not-opioid-dependent women using five demand indices: Demand Intensity; Omax; Pmax; Breakpoint (BP); and α, and two latent factors: Amplitude and Persistence. Final regression models adjusted for sociodemographic characteristics differing between the two groups. Opioid-dependent women had greater demand Intensity (i.e., number of cigarettes they would smoke if they were free) than not-opioid dependent women in the adjusted model, F(1, 156) = 6.93, p = .016. No other demand indices differed significantly. Regarding latent factors, demand Amplitude (i.e., volumetric consumption), but not Persistence (i.e., price insensitivity), was greater for opioid-dependent women in the adjusted model, F(1, 146) = 4.04, p = .046. These results further demonstrate that the CPT is a highly sensitive task that can illuminate potentially important individual and population differences in the relative reinforcing value of smoking. Greater demand Intensity and Amplitude differentiated smokers with comorbid opioid dependence; thus, decreasing smoking prevalence among opioid-dependent populations may require policies and interventions that can decrease cigarette demand Intensity and Amplitude. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Impact of electronic nicotine delivery systems and other respondent characteristics on tobacco use transitions among a U.S. national sample of women of reproductive age.

BACKGROUND: Identifying predictors of tobacco use patterns that differ in harm among reproductive-aged women may inform efforts to protect women and children against adverse health impacts of tobacco use. METHODS: Changes in tobacco use patterns were examined among women (18-49 years) who completed Wave 1 (W1) and Wave 2 (W2), or W2 and Wave 3 (W3) of the U.S. Population Assessment of Tobacco and Health (PATH, 2013-2016) study, and were using cigarettes, filtered cigars and/or cigarillos in the first wave over which data were included for that respondent (Time 1; T1). We examined the proportion of respondents whose tobacco use transitions from T1 to Time 2 (T2) were harm-maintaining (continued using combusted tobacco), harm-reducing (transitioned to electronic nicotine delivery systems (ENDS), or harm-eliminating (quit tobacco). Multinomial logistic regressions (with harm-maintaining as the baseline category) were conducted to examine associations between ENDS use, demographic, and psychosocial characteristics with each transition. RESULTS: A majority of women (83 %) exhibited harm-maintaining transitions, followed by harm-eliminating (14.7 %) and harm-reducing (2.3 %) transitions. Use of ENDS at T1 was associated with increased odds of harm reduction and decreased odds of harm elimination. Younger women were more likely to make both harm-reducing and harm-eliminating transitions. Increased educational attainment, identifying as Black or Hispanic, increased psychiatric symptoms, and pregnancy were associated with harm elimination, whereas living at or above poverty was associated with harm reduction. CONCLUSIONS: Study results contribute new information on the impact of ENDS, sociodemographic characteristics, psychiatric symptoms, and pregnancy on tobacco use transitions among reproductive-aged women.

Leveraging technology to address the problem of cigarette smoking among women of reproductive age.

Women of reproductive age and particularly pregnant women underutilize evidence-based smoking cessation services such as counseling and quit lines. Mobile health (mHealth) may constitute an unexplored and innovative avenue for providing smoking cessation support to a population that is otherwise difficult to reach with evidence-based interventions. Female respondents aged 18-44 years (N = 10,023) were drawn from the first wave of the Population Assessment of Tobacco and Health (PATH) study (2013-2014). We examined prevalence of use of various digital forms of communication (e.g., social media, text messaging, smartphone ownership) among non-pregnant women of reproductive age, pregnant women, and among smokers versus non-smokers within these groups. Multiple logistic regression modeling was conducted to identify correlates of using each digital form adjusting for smoking status, pregnancy, and demographic characteristics. Over two thirds of women overall and within subgroups of non-pregnant and pregnant smokers reported using social media, owning a cell phone, owning a smartphone, downloading apps, and sending/receiving text messages. Current smokers and those with lower educational attainment generally had lower odds of using each digital form relative to non-smokers and those with higher educational attainment, the exception being that smokers had higher odds of using social media relative to non-smokers. The high prevalence of using various digital forms among both non-pregnant smokers of reproductive age and pregnant smokers suggests that leveraging technology to expand access to prevention, education, and treatment resources may reduce smoking-attributable adverse health effects among reproductive-aged women and their offspring.

Examining the relationship between pregnancy and quitting use of tobacco products in a U.S. national sample of women of reproductive age.

This study examined quit rates longitudinally for cigarettes, e-cigarettes, hookah, cigars, and all tobacco products in a U.S. national sample of women aged 18-44 who completed both Wave 1 (W1) and Wave 2 (W2) of the Population Assessment of Tobacco and Health (PATH, 2013-2014, 2014-2015) study (N = 7814). Quit rates were examined among women who transitioned into pregnancy across survey waves, and among a comparable sample of non-pregnant women to provide contextual information about quitting among the broader population of reproductive-aged women. Multiple logistic regression modeling was used to estimate the associations of pregnancy and quitting adjusting for other demographic and psychosocial characteristics. Quit rates among women who were pregnant in W2 were highest for hookah (98.3%), followed by cigars (88.0%), e-cigarettes (81.3%), and lowest for tobacco cigarettes (53.4%). Slightly more than half (58.7%) of women reported quitting use all tobacco products while pregnant. Pregnancy was independently associated with increased odds of quitting hookah (AOR = 52.9, 95%CI = 3.4, 830.2), e-cigarettes (AOR = 21.0, 95%CI = 2.6, 170.3), all tobacco products (AOR = 9.6, 95%CI = 6.4, 14.5), and cigarettes (AOR = 6.5, 95%CI = 4.2, 10.1), although not cigars. Relative to other demographic and psychosocial characteristics, pregnancy was the strongest predictor of quitting use of each tobacco product. While these data indicate that pregnancy has strong, independent associations with quitting a variety of commercially available tobacco products, the comparatively lower quit rates for cigarettes versus other tobacco products underscores the long-standing need for more intensive, multipronged clinical and regulatory interventions to reduce cigarette use among reproductive-aged women.

Frontline Science: Splenic progenitors aid in maintaining high neutrophil numbers at sites of sterile chronic inflammation.

Neutrophils are constantly generated from hematopoietic stem and progenitor cells in the bone marrow to maintain high numbers in circulation. A considerable number of neutrophils and their progenitors have been shown to be present in the spleen too; however, their exact role in this organ remains unclear. Herein, we sought to study the function of splenic neutrophils and their progenitors using a mouse model for sterile, peritoneal inflammation. In this microcapsule device implantation model, we show chronic neutrophil presence at implant sites, with recruitment from circulation as the primary mechanism for their prevalence in the peritoneal exudate. Furthermore, we demonstrate that progenitor populations in the spleen play a key role in maintaining elevated neutrophil numbers. Our results provide new insight into the role for splenic neutrophils and their progenitors and establish a model to study neutrophil function during sterile inflammation.

Combinatorial hydrogel library enables identification of materials that mitigate the foreign body response in primates.

The foreign body response is an immune-mediated reaction that can lead to the failure of implanted medical devices and discomfort for the recipient. There is a critical need for biomaterials that overcome this key challenge in the development of medical devices. Here we use a combinatorial approach for covalent chemical modification to generate a large library of variants of one of the most widely used hydrogel biomaterials, alginate. We evaluated the materials in vivo and identified three triazole-containing analogs that substantially reduce foreign body reactions in both rodents and, for at least 6 months, in non-human primates. The distribution of the triazole modification creates a unique hydrogel surface that inhibits recognition by macrophages and fibrous deposition. In addition to the utility of the compounds reported here, our approach may enable the discovery of other materials that mitigate the foreign body response.

Extracellular matrix remodeling following myocardial infarction influences the therapeutic potential of mesenchymal stem cells.

INTRODUCTION: Although stem cell therapy is a promising treatment for myocardial infarction, the minimal functional improvements observed clinically limit its widespread application. A need exists to maximize the therapeutic potential of these stem cells by first understanding what factors within the infarct microenvironment affect their ability to regenerate the necrotic tissue. In this study, we assessed both differentiation capacity and paracrine signaling as a function of extracellular matrix remodeling after myocardial infarction. METHODS: Mechanical and compositional changes to the decellularized infarcted myocardium were characterized to understand how the extracellular environment, specifically, was altered as a function of time after coronary artery ligation in Sprague-Dawley rats. These alterations were first modeled in a polyacrylamide gel system to understand how the variables of composition and stiffness drive mesenchymal stem cell differentiation towards a cardiac lineage. Finally, the paracrine secretome was characterized as a function of matrix remodeling through gene and protein expression and conditioned media studies. RESULTS: The decellularized infarct tissue revealed significant alterations in both the mechanical and compositional properties of the ECM with remodeling following infarction. This altered microenvironment dynamically regulates the potential for early cardiac differentiation. Whereas Nkx2.5 expression is limited in the presence of chronic remodeled matrix of increased stiffness, GATA4 expression is enhanced. In addition, the remodeled matrix promotes the expression of several proangiogenic, prosurvival, antifibrotic, and immunomodulatory growth factors. In particular, an increase in HGF and SDF1 expression and secretion by mesenchymal stem cells can rescue oxidatively stressed cardiomyocytes in vitro. CONCLUSIONS: This study demonstrated that decellularization of diseased tissue allows for the exclusive analysis of the remodeled matrix and its ability to influence significantly the cellular phenotype. Characterization of cell fate as a function of myocardial remodeling following infarction is critical in developing the ideal strategy for cell implantation to maximize tissue regeneration and to ultimately reduce the prevalence and severity of heart failure.

Down-regulation of MHC II in mesenchymal stem cells at high IFN-gamma can be partly explained by cytoplasmic retention of CIITA.

Mesenchymal stem cells (MSCs) are located in postnatal bone marrow, show plasticity, are linked to various bone marrow disorders, exhibit phagocytosis, exert Ag-presenting properties (APC), and are immune suppressive. Unlike professional APCs, MSCs respond bimodally to IFN-gamma in MHC-II expression, with expression at 10 U/ml and baseline, and down-regulation at 100 U/ml. The effects at high IFN-gamma could not be explained by down-regulation of its receptor, IFN-gammaRI. In this study, we report on the mechanisms by which IFN-gamma regulates MHC-II expression in MSCs. Gel shift assay and Western blot analyses showed dose-dependent increases in activated STAT-1, indicating responsiveness by IFN-gammaRI. Western blots showed decreased intracellular MHC-II, which could not be explained by decreased transcription of the master regulator CIITA, based on RT-PCR and in situ immunofluorescence. Reporter gene assays with PIII and PIV CIITA promoters indicate constitutive expression of PIII in MSCs and a switch to PIV by IFN-gamma, indicating the presence of factors for effect promoter responses. We explained decreased MHC-II at the level of transcription because CIITA protein was observed in the cytosol and not in nuclei at high IFN-gamma level. The proline/serine/threonine region of CIITA showed significant decrease in phosphorylation at high IFN-gamma levels. An understanding of the bimodal effects could provide insights on bone marrow homeostasis, which could be extrapolated to MSC dysfunction in hematological disorders.

Antigen-presenting property of mesenchymal stem cells occurs during a narrow window at low levels of interferon-gamma.

Mesenchymal stem cells (MSCs) are mostly found around the vasculature system of the adult bone marrow (BM). They function as immune suppressors, express MHC-II, are phagocytic, and support T-cell cytotoxicity. We hypothesize that these contradictory properties of MSCs are important for BM homeostasis and occur partly through antigen presentation (antigen-presenting cells [APCs]) within a narrow window. Indeed, we have verified APC functions of MSCs to recall antigens, Candida albicans and Tetanus toxoid. The target cells have been identified to be CD4(+) T cells. APC assays with IFNgamma-knockdown MSCs and with anti-IFNgamma receptor confirmed that MHC-II expression requires autocrine stimulation by IFNgamma. During APC functions, as IFNgamma levels become elevated, there was a concomitant decrease in MHC-II on MSCs. This observation was correlated with flow cytometry studies showing a gradual decrease in MHC-II expression as IFNgamma levels were increased. The reduced levels of MHC-II correlated with losses in their allogeneic potential, as indicated in mixed lymphocyte reaction. In summary, endogenous and low levels of IFNgamma are required for MHC-II expression on MSCs, and for APC functions. APC functions occur during a narrow window before IFNgamma levels are increased. The study has implications for BM protection against infection and exacerbated inflammatory responses.