Information needs of parents of children with congenital anomalies across Europe: a EUROlinkCAT survey.

BACKGROUND: Parents of children who have a congenital anomaly can experience significant worry about their child's health. Access to clear, helpful, and trustworthy information can provide a valuable source of support. In this study the aim was to explore the information needs of parents/carers of children with congenital anomalies across Europe. METHOD: A cross-sectional online survey was developed in nine languages to measure parents' information needs, including: (1) the 'helpfulness'/'trustworthiness' of information received from eight relevant sources, and (2) overall satisfaction with information received. Parents/carers of children (0-10 years) with cleft lip, spina bifida, congenital heart defect [CHD] requiring surgery, and/or Down syndrome were recruited online via relevant organisations in 10 European countries from March-July 2021. Quantitative analyses using multivariable logistic regressions were performed. RESULTS: One thousand seventy parents/carers of children with a cleft lip (n = 247), spina bifida (n = 118), CHD (n = 366), Down syndrome (n = 281), and Down syndrome with CHD (n = 58) were recruited in Poland (n = 476), the UK (n = 120), Germany (n = 97), the Netherlands/Belgium (n = 74), Croatia (n = 68), Italy (n = 59), other European countries (n = 92), and not specified/non-European countries (n = 84). Most participants were mothers (92%) and aged 31-40 years (71%). Participants were most likely to rate support groups (63%), patient organisations (60%), specialist doctors/nurses (58%), and social media (57%) as 'very helpful' information sources. 'Very trustworthy' ratings remained high for specialist doctors/nurses (61%), however, they declined for support groups (47%), patient organisations (48%), and social media (35%). Germany had the highest proportion of participants who were 'very satisfied' (44%, 95% CI = 34%-54%) with information, whereas this percentage was lowest in Croatia (11%, 95% CI = 3%-19%) and Poland (15%, 95% CI = 11%-18%). Parents of children with Down syndrome had significantly lower satisfaction ratings than parents of children with CHD; 13% (95% CI = 8%-18%) reported being 'very satisfied' compared to 28% (95% CI = 23%-33%) in the CHD group. CONCLUSIONS: Findings suggest that informal sources of information (e.g. support groups) are of value to parents, however, they are not deemed as trustworthy as specialist medical sources. Satisfaction ratings differed across countries and by anomaly, and were particularly low in Croatia and Poland, as well as for parents of children with Down syndrome, which warrants further investigation.

Remodeling and destabilization of chromosome 1 pericentromeric heterochromatin by SSX proteins.

Rearrangement of the 1q12 pericentromeric heterochromatin and subsequent amplification of the 1q arm is commonly associated with cancer development and progression and may result from epigenetic deregulation. In many premalignant and malignant cells, loss of 1q12 satellite DNA methylation causes the deposition of polycomb factors and formation of large polycomb aggregates referred to as polycomb bodies. Here, we show that SSX proteins can destabilize 1q12 pericentromeric heterochromatin in melanoma cells when it is present in the context of polycomb bodies. We found that SSX proteins deplete polycomb bodies and promote the unfolding and derepression of 1q12 heterochromatin during replication. This further leads to segregation abnormalities during anaphase and generation of micronuclei. The structural rearrangement of 1q12 pericentromeric heterochromatin triggered by SSX2 is associated with loss of polycomb factors, but is not mediated by diminished polycomb repression. Instead, our studies suggest a direct effect of SSX proteins facilitated though a DNA/chromatin binding, zinc finger-like domain and a KRAB-like domain that may recruit chromatin modifiers or activate satellite transcription. Our results demonstrate a novel mechanism for generation of 1q12-associated genomic instability in cancer cells.

The influence of assisted ventilation and recumbency on cardiorespiratory physiology in the anesthetized freshwater turtle Trachemys scripta scripta.

The use of assisted ventilation is required in anesthetized reptiles as their respiratory drive is lost at surgical depths of anesthesia. The minute volume of the assisted ventilation influences arterial blood gases and acid-base regulation. Meanwhile, the ventilatory pattern may also affect hemodynamics in chelonians, which, given their large capacity for cardiac shunts, may impact the efficacy of the ventilation in terms of gas exchange. Hence, there is a need for primary information on the influence of assisted ventilation on chelonian physiology, and we, therefore, performed a randomized study into the effects of recumbency and maximum airway pressure on pressure-cycled ventilation in nine female Trachemys scripta scripta. Pronounced effects of ventilation pressure on arterial PCO2 and pH regardless of recumbency were revealed, whilst dorsal recumbency led to a larger Arterial-alveolar (A-a) O2 difference, suggesting compromised pulmonary gas exchange. Plasma [Na+] and [K+] balance was also significantly correlated with maximum airway pressure. Computed tomography (CT) scanning at a range of end-inspiratory pressures and ventral and dorsal recumbencies in eight T. scripta scripta showed that lung volumes increase with maximum ventilatory pressure, while recumbency did not influence volume at pressures above 5 cmH2O. Static compliance of the lungs was influenced by recumbency at neutral pressures. In conclusion, dorsal recumbency reduces pulmonary efficacy during positive pressure ventilation and tends to lower lung volume when ventilation is not provided. However, lung volumes and function - even in dorsal recumbency - can be adequately supported by assisted ventilation, and an end inspiratory pressure of 10 cmH2O at 4 breaths min-1 provided the most physiologically appropriate ventilation of anesthetized T. scripta scripta.

The kinetics of glucagon action on the liver during insulin-induced hypoglycemia.

Glucagon's effect on hepatic glucose production (HGP), under hyperglycemic conditions, is time dependent such that after an initial burst of HGP, it slowly wanes. It is not known whether this is also the case under hypoglycemic conditions, where an increase in HGP is essential. This question was addressed using adrenalectomized dogs to avoid the confounding effects of other counterregulatory hormones. During the study, infusions of epinephrine and cortisol were given to maintain basal levels. Somatostatin and insulin (800 µU·kg-1·min-1) were infused to induce hypoglycemia. After 30 min, glucagon was infused at a basal rate (1 ng·kg-1·min-1, baGGN group, n = 5 dogs) or a rate eightfold basal (8 ng·kg-1·min-1, hiGGN group, n = 5 dogs) for 4 h. Glucose was infused to match the arterial glucose levels between groups (≈50 mg/dL). Our data showed that glucagon has a biphasic effect on the liver despite hypoglycemia. Hyperglucagonemia stimulated a rapid, transient peak in HGP (4-fold basal production) over ~60 min, which was followed by a slow reduction in HGP to a rate 1.5-fold basal. During the last 2 h of the experiment, hiGGN stimulated glucose production at a rate fivefold greater than baGGN (2.5 vs. 0.5 mg·kg-1·min-1, respectively), indicating a sustained effect of the hormone. Of note, the hypoglycemia-induced rises in norepinephrine and glycerol were smaller in hiGGN compared with the baGGN group despite identical hypoglycemia. This finding suggests that there is reciprocity between glucagon and the sympathetic nervous system such that when glucagon is increased, the sympathetic nervous response to hypoglycemia is downregulated.

The anatomy of single cell mass cytometry data.

Mass cytometry enables the measurement of up to 50 features on single cell. This has catalyzed a shift toward multidimensional data analysis methods, rather than the manual gating strategies as traditionally for in flow cytometry data. This shift means that data scientists are involved in the analysis process to an increasing degree. As the data is analyzed in a more unbiased fashion, where noisy or uninformative observations are not easily excluded, a deeper knowledge of the origin, noise, and modalities of the data is therefore needed to embark on useful data analysis. In this primer, we introduce the idiosyncrasies of mass cytometry data with a focus on the technical properties of how data generated with the CyTOF® system, and the characteristics of protein expression in the cells of the hematopoietic continuum, specifically targeted toward data scientists. We also provide a comprehensive online repository of scripts, tutorials, and example data. © 2018 International Society for Advancement of Cytometry.

SSX2 is a novel DNA-binding protein that antagonizes polycomb group body formation and gene repression.

Polycomb group (PcG) complexes regulate cellular identity through epigenetic programming of chromatin. Here, we show that SSX2, a germline-specific protein ectopically expressed in melanoma and other types of human cancers, is a chromatin-associated protein that antagonizes BMI1 and EZH2 PcG body formation and derepresses PcG target genes. SSX2 further negatively regulates the level of the PcG-associated histone mark H3K27me3 in melanoma cells, and there is a clear inverse correlation between SSX2/3 expression and H3K27me3 in spermatogenesis. However, SSX2 does not affect the overall composition and stability of PcG complexes, and there is no direct concordance between SSX2 and BMI1/H3K27me3 presence at regulated genes. This suggests that SSX2 antagonizes PcG function through an indirect mechanism, such as modulation of chromatin structure. SSX2 binds double-stranded DNA in a sequence non-specific manner in agreement with the observed widespread association with chromatin. Our results implicate SSX2 in regulation of chromatin structure and function.

Influence of soil structure on contaminant leaching from injected slurry.

Animal manure application to agricultural land provides beneficial organic matter and nutrients but can spread harmful contaminants to the environment. Contamination of fresh produce, surface water and shallow groundwater with the manure-borne pollutants can be a critical concern. Leaching and persistence of nitrogen, microorganisms (bacteriophage, E. coli, and Enterococcus) and a group of steroid hormone (estrogens) were investigated after injection of swine slurry into either intact (structured) or disturbed (homogeneous repacked) soil. The slurry was injected into hexaplicate soil columns at a rate of 50 t ha-1 and followed with four irrigation events: 3.5-h period at 10 mm h-1 after 1, 2, 3, and 4 weeks. The disturbed columns delayed the leaching of a conservative tracer and microorganisms in the first irrigation event compared to the intact columns due to the effect of disturbed macropore flow paths. The slurry constituents that ended up in or near the macropore flow paths of the intact soil were presumably washed out relatively quickly in the first event. For the last three events the intact soil leached fewer microorganisms than the disturbed soil due to the bypassing effect of water through the macropore flow path in the intact soil. Estrogen leached from the intact soil in the first event only, but for the disturbed soil it was detected in the leachates of last two events also. Leaching from the later events was attributed to higher colloid transport from the disturbed soils. In contrast, NO3-N leaching from the intact soil was higher for all events except the first event, probably due to a lower nitrification rate in the disturbed soil. A week after the last irrigation event, the redistribution of all slurry constituents except NO3-N in most of the sections of the soil column was higher for the disturbed soil. Total recovery of E. coli was significantly higher from the disturbed soil and total leaching of mineral nitrogen was significantly lower from the disturbed soil. Results demonstrate how manure-borne constituents injected into undisturbed soil columns respond more as expected in the field, in terms of leaching and persistence, than do the same constituents injected into typically constructed columns of disturbed soil.

Cognitive impairment in testicular cancer survivors 2 to 7 years after treatment.

PURPOSE: The aim of the present study was to determine the prevalence of cognitive impairment (CI) in a group of testicular (TC) survivors by comparing their neuropsychological test scores with normative data and to assess their performance in specific cognitive domains. METHODS: Seventy-two TC survivors were evaluated 2 to 7 years post-treatment with a neuropsychological test battery that assessed multiple cognitive domains-attention and working memory, processing speed, verbal fluency, learning and memory, and executive functioning. Test scores were compared with normative data, and CI status was calculated for each participant. RESULTS: In group-level analyses, survivors exhibited significantly impaired scores on a majority (9/12) of the neuropsychological outcomes (p < 0.01). In individual-level analyses, 62.5 % of the survivors were classified as having CI, significantly exceeding the expected normative frequency of 25 % (binomial test: p < 0.001). In particular, CI was observed in multiple outcomes related to verbal learning and memory (29 to 33 % of participants), visual learning and memory (14-28 %), processing speed (8-24 %), executive functioning (17 %), and attention and working memory (4-15 %). No association was found between treatment modality (surgery ± chemotherapy) and CI. CONCLUSIONS: The prevalence of CI in TC survivors was unexpectedly high, with survivors performing significantly worse than expected on a majority of the neuropsychological outcomes. While the findings are preliminary in nature, they still have important implications for the diagnosis and treatment of CI in TC survivors.

Effect of Livestock Slurry Ozonation and Separation on pH, Particles, and Phosphate.

Applying slurry to arable land as fertilizer increases the risk of phosphorus (P) runoff and thereby increases the risk of eutrophication. Solid-liquid separation can reduce the excess application of P, and this study focused on the use of ozonation as an alternative chemical pretreatment for separation to improve P separation efficiency. Sow and cattle slurries were separated by screw press and flocculation+filtration. The screw press and flocculation liquid fractions and raw slurries were treated with no ozone or with low-, medium-, or high-ozone doses and then separated by centrifugation. The pH, particle size distribution, dry matter, and dissolved phosphate (PO) concentrations were measured. For separations without ozonation, pH increased by 0.15 to 0.87 pH units, and correlation analysis showed that the dissolved PO concentration decreased with increasing pH and particle removal efficiency. During ozonation, pH increased, and a shift in particle size distribution in the liquid fraction combined with an improved dry matter separation indicated particle aggregation. Ozonation thus affected the parameters found to affect dissolved PO separation, and at the highest ozone dose, dissolved PO separation efficiency increased by 7 to 81%. An ozonation pretreatment may therefore promote removal of dissolved PO from the liquid fraction during separation.

The use of complementary and alternative medicine after the completion of hospital treatment for colorectal cancer: findings from a questionnaire study in Denmark.

BACKGROUND: Little is known about the use of complementary and alternative medicine (CAM) for colorectal cancer, despite the high incidence of colorectal cancer and the frequency of CAM use for cancer-related symptoms. This is the first Danish study to examine the use of CAM by individuals who completed hospital treatment for colorectal cancer. METHODS: In 2011-12, a pragmatic trial on energy healing as rehabilitation after colorectal cancer was conducted in Denmark with participants who had completed cancer-related hospital treatment within the past 18 months prior to study inclusion. As part of the trial, participants (n = 247) completed a questionnaire on the use, motivations, pathways and perceived benefits of CAM. Socio-demographic information was obtained via the Danish National Patient Registry and self-report. Descriptive statistics were generated, using SPSS, version 18, and logistic regression analysis was carried out. RESULTS: Of 247 individuals, 49.4% used some form of CAM in the past month. Nearly half of the CAM users (49.2%) used natural medicines and/or dietary supplements only; 32% consulted an alternative therapist; 18.9% used both. Those who consulted alternative therapists were most commonly women (OR: 3.36; p = .002; CI: 1.54-7.33) with high educational levels (OR: 2.77; p = 0.010; CI: 1.28-6.01); more women than men used natural medicines and/or dietary supplements (OR: 1.83; p = .047; CI: 1.01-3.30) independent of educational levels. A majority commenced CAM on their own initiative; CAM was predominantly used to achieve better physical wellbeing. Beneficial effects were reported particularly in relation to physical health; few harmful effects were reported. Of those using CAM, 51.5% did not disclose its use to their physician; 8.5% of participants reported to have been asked by their physician about CAM use. CONCLUSION: The use of CAM following completion of hospital treatment for colorectal cancer seems widespread in Denmark. The identified extensive CAM use suggests a need for more reliable and diverse information about CAM for both patients and biomedical providers, and improved communication about its use in the clinical context.

Changes in Pulmonary Vascular Resistance and Obstruction Score Following Acute Pulmonary Embolism in Pigs.

OBJECTIVES: To investigate the contribution of mechanical obstruction and pulmonary vasoconstriction to pulmonary vascular resistance (PVR) in acute pulmonary embolism (PE) in pigs. DESIGN: Controlled, animal study. SETTING: Tertiary university hospital, animal research laboratory. SUBJECTS: Female Danish slaughter pigs (n = 12, ~60 kg). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: PE was induced by infusion of autologous blood clots in pigs. CT pulmonary angiograms were performed at baseline, after PE (first experimental day [PEd0]) and the following 2 days (second experimental day [PEd1] and third experimental day [PEd2]), and clot burden quantified by a modified Qanadli Obstruction Score. Hemodynamics were evaluated with left and right heart catheterization and systemic invasive pressures each day before, under, and after treatment with the pulmonary vasodilators sildenafil (0.1 mg/kg) and oxygen (Fio2 40%). PE increased PVR (baseline vs. PEd0: 178 ± 54 vs. 526 ± 160 dynes; p < 0.0001) and obstruction score (baseline vs. PEd0: 0% vs. 45% ± 13%; p < 0.0001). PVR decreased toward baseline at day 1 (baseline vs. PEd1: 178 ± 54 vs. 219 ± 48; p = 0.16) and day 2 (baseline vs. PEd2: 178 ± 54 vs. 201 ± 50; p = 0.51). Obstruction score decreased only slightly at day 1 (PEd0 vs. PEd1: 45% ± 12% vs. 43% ± 14%; p = 0.04) and remained elevated throughout the study (PEd1 vs. PEd2: 43% ± 14% vs. 42% ± 17%; p = 0.74). Sildenafil and oxygen in combination decreased PVR at day 0 (-284 ± 154 dynes; p = 0.0064) but had no effects at day 1 (-8 ± 27 dynes; p = 0.4827) or day 2 (-18 ± 32 dynes; p = 0.0923). CONCLUSIONS: Pulmonary vasoconstriction, and not mechanical obstruction, was the predominant cause of increased PVR in acute PE in pigs. PVR rapidly declined over the first 2 days after onset despite a persistent mechanical obstruction of the pulmonary circulation from emboli. The findings suggest that treatment with pulmonary vasodilators might only be effective in the acute phase of PE thereby limiting the window for such therapy.

Single-cell sequencing unveils extensive intratumoral heterogeneity of cancer/testis antigen expression in melanoma and lung cancer.

Cancer/testis antigens (CTAs) are widely expressed in melanoma and lung cancer, emerging as promising targets for vaccination strategies and T-cell-based therapies in these malignancies. Despite recognizing the essential impact of intratumoral heterogeneity on clinical responses to immunotherapy, our understanding of intratumoral heterogeneity in CTA expression has remained limited. We employed single-cell mRNA sequencing to delineate the CTA expression profiles of cancer cells in clinically derived melanoma and lung cancer samples. Our findings reveal a high degree of intratumoral transcriptional heterogeneity in CTA expression. In melanoma, every cell expressed at least one CTA. However, most individual CTAs, including the widely used therapeutic targets NY-ESO-1 and MAGE, were confined to subpopulations of cells and were uncoordinated in their expression, resulting in mosaics of cancer cells with diverse CTA profiles. Coordinated expression was observed, however, mainly among highly structurally and evolutionarily related CTA genes. Importantly, a minor subset of CTAs, including PRAME and several members of the GAGE and MAGE-A families, were homogenously expressed in melanomas, highlighting their potential as therapeutic targets. Extensive heterogeneity in CTA expression was also observed in lung cancer. However, the frequency of CTA-positive cancer cells was notably lower and homogenously expressed CTAs were only identified in one of five tumors in this cancer type. Our findings underscore the need for careful CTA target selection in immunotherapy development and clinical testing and offer a rational framework for identifying the most promising candidates.

Building flexible and robust analysis frameworks for molecular subtyping of cancers.

Molecular subtyping is essential to infer tumor aggressiveness and predict prognosis. In practice, tumor profiling requires in-depth knowledge of bioinformatics tools involved in the processing and analysis of the generated data. Additionally, data incompatibility (e.g., microarray versus RNA sequencing data) and technical and uncharacterized biological variance between training and test data can pose challenges in classifying individual samples. In this article, we provide a roadmap for implementing bioinformatics frameworks for molecular profiling of human cancers in a clinical diagnostic setting. We describe a framework for integrating several methods for quality control, normalization, batch correction, classification and reporting, and develop a use case of the framework in breast cancer.

Use of complementary and alternative medicine (CAM) and changes in depressive symptoms from 3 to 15 months after surgery for primary breast cancer: results from a nationwide cohort study.

Background This large population-based prospective study explored the associations between use of complementary and alternative medicine (CAM) and prevalence and changes in depressive symptoms from 3 to 15 months after surgery for primary breast cancer. Methods In an ongoing nationwide cohort study, depressive symptoms and the use of ten different types of CAM since time of diagnosis were assessed by questionnaire at 3 (N = 3233) and 15 months post-surgery (N = 2833). Clinical and socio-demopraphic variables were obtained from the Danish Breast Cancer Cooperative Group (DBCG) and national longitudinal registries. Results At 3 months post-surgery, 40.2 % reported having used CAM since the diagnosis, and in the time from 3 to 15 months after surgery, 49.9 % had used CAM. Compared with non-users, CAM users experienced more depressive symptoms at both 3 and 15 months follow-up when adjusting for several possible confounders. In a fully adjusted model, including all CAM variables and adjusting for depressive symptoms at 3 months, use of dietary/vitamin supplements was the only independent, statistically significant risk factor for experiencing more depressive symptoms at 15 months (RM = 1.10; 95 % CI 1.02-1.19, P = 0.014). Conclusion Cross-sectionally, CAM use was associated with higher levels of depressive symptoms at both time-points. Prospectively, users of dietary or vitamin supplements at 3 months after surgery reported higher levels of depressive symptoms than non-users 1 year later. Possible explanations could be an increased vulnerability for depressive symptoms among women using CAM or adverse effects of dietary or vitamin supplements.

In God and CAM we trust. Religious faith and use of complementary and alternative medicine (CAM) in a nationwide cohort of women treated for early breast cancer.

Turning to faith in God or a higher spiritual power is a common way of coping with life-threatening disease such as cancer. Little, however, is known about religious faith among cancer patients in secular societies. The present study aimed at exploring the prevalence of religious faith among Danish breast cancer patients and at identifying whether socio-demographic, pre-cancer health status, clinical, and health behavior characteristics, including their use of complementary and alternative medicine (CAM), were associated with their degree of faith. Information on faith in God or a higher spiritual power and use of CAM was provided by a nationwide sample of 3,128 recurrence-free Danish women who had received surgery for early-stage breast cancer 15-16 months earlier. Socio-demographic, clinical, and health status variables were obtained from national longitudinal registries, and health behaviors had been assessed at 3-4 months post-surgery. Of the women, 47.3% reported a high degree of faith (unambiguous believers), 35.9% some degree of faith (ambiguous believers), while the remaining 16.8% were non-believers. Unambiguous believers were more likely than ambiguous believers to experience their faith as having a positive impact on their disease and their disease-related quality-of-life. When compared to non-believers, unambiguous believers were also older, had poorer physical function, and were more frequent users of CAM, and more inclined to believe that their use of CAM would have a beneficial influence on their cancer. Disease- and treatment-related variables were unrelated to faith. While overall religious faith appears equally prevalent among Danish and US breast cancer patients, the majority of Danish breast cancer patients experienced ambiguous faith, whereas the majority of US patients have been found to express unambiguous faith. Our results suggest that future studies may benefit from exploring the role of faith for health behaviors, adherence to conventional treatment, and impact upon quality of life.

Midwife Educators' perceptions of the efficacy of the Objective Structured clinical assessment of life-saving interventions - a qualitative interview study in Bangladesh.

INTRODUCTION: Objective Structured Clinical Assessment (OSCA) is a way of evaluating students or clinicians in how they are carrying out their duties. The aim of this study was to examine how midwifery educators in Bangladesh perceived using OSCA as an assessment device in midwifery education for student performance in life-saving midwifery interventions. METHOD: Individual interviews were conducted with 47 academic midwives and clinical midwives using purposive sampling at 38 education institutions in Bangladesh. Content analysis inspired by Elo and Kyngas was used to analyze the data. RESULTS: The ability of students to perform effectively in the OSCA-evaluated simulation of life-saving skills was related to the educators' understanding of the concept of midwifery. The overarching main category of this study showed that for midwifery educators to be able to effectually teach professional, evidence-based midwifery, they need to be able to synthesize the delivery of practical and theoretical skills with pedagogical skills and knowledge. To implement the OSCA tool more effectively, midwifery educators need to understand the underpinning principles of midwifery values and philosophy including leadership, ownership, responsibility, and personal engagement. CONCLUSION: There is potential to improve the efficacy of using OSCA to deliver the teaching of life-saving skills. Team sessions with midwives and physicians aiming to practice teamwork and role divisions in life-saving interventions are recommended.

DNA methyltransferase inhibition promotes recruitment of myeloid-derived suppressor cells to the tumor microenvironment through induction of tumor cell-intrinsic interleukin-1.

DNA methyltransferase (DNMT) inhibitors are used for treatment of certain hematological malignancies and exert anti-cancer activity through diverse mechanisms, including reexpression of tumor suppressor genes and anti-viral responses triggered by expression of endogenous retroviruses. Despite advances in the pharmacokinetic properties of DNMT inhibitors, the efficacy of these drugs in solid cancers remains low. Here, we show in cell lines and clinical and experimental tumors across multiple cancer types that DNMT inhibition induces the expression of interleukin-1 (IL-1), a cytokine with proinflammatory and protumorigenic properties. Specifically, this tumor-intrinsic IL-1 expression modulates the chemokine landscape of tumors and leads to the recruitment of monocytic myeloid-derived suppressor cells to the tumor microenvironment, processes that can be blocked by IL-1 antagonists. Molecular analysis demonstrates complex patterns of IL-1 and interferon activation and crosstalk in response to DNMT inhibition, which depend on the integrity of IRF- and NF-κB-mediated antiviral pathways and may determine the outcome of DNMT-inhibitor treatment. Together, our results show that DNMT inhibitors may negatively affect the microenvironment of a large subset of tumors and suggest that co-treatment with IL-1 antagonists may be a favorable combination for these patients.

Dasatinib overcomes glucocorticoid resistance in B-cell acute lymphoblastic leukemia.

Resistance to glucocorticoids (GC) is associated with an increased risk of relapse in B-cell progenitor acute lymphoblastic leukemia (BCP-ALL). Performing transcriptomic and single-cell proteomic studies in healthy B-cell progenitors, we herein identify coordination between the glucocorticoid receptor pathway with B-cell developmental pathways. Healthy pro-B cells most highly express the glucocorticoid receptor, and this developmental expression is conserved in primary BCP-ALL cells from patients at diagnosis and relapse. In-vitro and in vivo glucocorticoid treatment of primary BCP-ALL cells demonstrate that the interplay between B-cell development and the glucocorticoid pathways is crucial for GC resistance in leukemic cells. Gene set enrichment analysis in BCP-ALL cell lines surviving GC treatment show enrichment of B cell receptor signaling pathways. In addition, primary BCP-ALL cells surviving GC treatment in vitro and in vivo demonstrate a late pre-B cell phenotype with activation of PI3K/mTOR and CREB signaling. Dasatinib, a multi-kinase inhibitor, most effectively targets this active signaling in GC-resistant cells, and when combined with glucocorticoids, results in increased cell death in vitro and decreased leukemic burden and prolonged survival in an in vivo xenograft model. Targeting the active signaling through the addition of dasatinib may represent a therapeutic approach to overcome GC resistance in BCP-ALL.