IKZF1 gene deletions drive resistance to cytarabine in B-cell precursor acute lymphoblastic leukemia.

IKZF1-deletions occur in 10-15% of patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and predict a poor outcome. However, the impact of IKZF1-loss on sensitivity to drugs used in contemporary treatment protocols has remained underexplored. Here we show in experimental models and in patients that loss of IKZF1 promotes resistance to AraC, a key component of both upfront and relapsed treatment protocols. We attribute this resistance, in part, to diminished import and incorporation of cytarabine (AraC) due to reduced expression of the solute carrier hENT1. Moreover, we find elevated mRNA expression of Evi1, a known driver of therapy resistance in myeloid malignancies. Finally, a kinase directed CRISPR/Cas9-screen identified that inhibition of either mediator kinases CDK8/19 or casein kinase 2 can restore response to AraC. We conclude that this high-risk patient group could benefit from alternative antimetabolites, or targeted therapies that resensitize the cells to AraC.

Randomised clinical trial: First-line infliximab biosimilar is cost-effective compared to conventional treatment in paediatric Crohn's disease.

BACKGROUND: Data on cost-effectiveness of first-line infliximab in paediatric patients with Crohn's disease are limited. Since biologics are increasingly prescribed and accompanied by high costs, this knowledge gap needs to be addressed. AIM: To investigate the cost-effectiveness of first-line infliximab compared to conventional treatment in children with moderate-to-severe Crohn's disease. METHODS: We included patients from the Top-down Infliximab Study in Kids with Crohn's disease randomised controlled trial. Children with newly diagnosed moderate-to-severe Crohn's disease were treated with azathioprine maintenance and either five induction infliximab (biosimilar) infusions or conventional induction treatment (exclusive enteral nutrition or corticosteroids). Direct healthcare consumption and costs were obtained per patient until week 104. This included data on outpatient hospital visits, hospital admissions, drug costs, endoscopies and surgeries. The primary health outcome was the odds ratio of being in clinical remission (weighted paediatric Crohn's disease activity index<12.5) during 104 weeks. RESULTS: We included 89 patients (44 in the first-line infliximab group and 45 in the conventional treatment group). Mean direct healthcare costs per patient were €36,784 for first-line infliximab treatment and €36,874 for conventional treatment over 2 years (p = 0.981). The odds ratio of first-line infliximab versus conventional treatment to be in clinical remission over 104 weeks was 1.56 (95%CI 1.03-2.35, p = 0.036). CONCLUSIONS: First-line infliximab treatment resulted in higher odds of being in clinical remission without being more expensive, making it the dominant strategy over conventional treatment in the first 2 years after diagnosis in children with moderate-to-severe Crohn's disease. TRIAL REGISTRATION NUMBER: NCT02517684.

Evidence of diverse animal exploitation during the Middle Paleolithic at Ghar-e Boof (southern Zagros).

Although Middle Paleolithic (MP) hominin diets consisted mainly of ungulates, increasing evidence demonstrates that hominins at least occasionally consumed tortoises, birds, leporids, fish, and carnivores. Until now, the MP zooarchaeological record in the Zagros Mountains has been almost exclusively restricted to ungulates. The narrow range of hominin prey may reflect socioeconomic decisions and/or environmental constraints, but could also result from a research bias favoring the study of large prey, since archaeologists have undertaken no systematic taphonomic analyses of small game or carnivores in the region. Here, we report on the first comprehensive taphonomic analysis of an MP faunal assemblage from Ghar-e Boof (∼ 81-45 kyr), a Late Pleistocene site in the southern Zagros of Iran. Anthropogenic bone surface modifications point to hominins as the main agent of accumulation. Hominins preyed primarily on ungulates, particularly wild goat. However, we also found evidence for MP hominin exploitation of carnivores and tortoises at the site. Although small game represents only a minor portion of the diet, our results suggest that the hunting behavior of MP hominins in the Zagros was more diverse than previously thought, similar to what we find elsewhere in Eurasia.

The gut microbiome in bullous pemphigoid: implications of the gut-skin axis for disease susceptibility.

Bullous pemphigoid (BP) is an autoimmune blistering disease that primarily affects the elderly. An altered skin microbiota in BP was recently revealed. Accumulating evidence points toward a link between the gut microbiota and skin diseases; however, the gut microbiota composition of BP patients remains largely underexplored, with only one pilot study to date, with a very limited sample size and no functional profiling of gut microbiota. To thoroughly investigate the composition and function of the gut microbiota in BP patients, and explore possible links between skin conditions and gut microbiota, we here investigated the gut microbiota of 66 patients (81.8% firstly diagnosed) suffering from BP and 66 age-, sex-, and study center-matched controls (CL) with non-inflammatory skin diseases (132 total participants), using 16S rRNA gene and shotgun sequencing data. Decreased alpha-diversity and an overall altered gut microbial community is observed in BP patients. Similar trends are observed in subclassifications of BP patients, including first diagnoses and relapsed cases. Furthermore, we observe a set of BP disease-associated gut microbial features, including reduced Faecalibacterium prausnitzii and greater abundance of pathways related to gamma-aminobutyric acid (GABA) metabolism in BP patients. Interestingly, F. prausnitzii is a well-known microbiomarker of inflammatory diseases, which has been reported to be reduced in the gut microbiome of atopic dermatitis and psoriasis patients. Moreover, GABA plays multiple roles in maintaining skin health, including the inhibition of itching by acting as a neurotransmitter, attenuating skin lesions by balancing Th1 and Th2 levels, and maintaining skin elasticity by increasing the expression of type I collagen. These findings thus suggest that gut microbiota alterations present in BP may play a role in the disease, and certain key microbes and functions may contribute to the link between gut dysbiosis and BP disease activity. Further studies to investigate the underlying mechanisms of the gut-skin interaction are thus clearly warranted, which could aid in the development of potential therapeutic interventions.

Determining Minnesota bee species' distributions and phenologies with the help of participatory science.

The Minnesota Bee Atlas project contributed new information about bee distributions, phenologies, and community structure by mobilizing participatory science volunteers to document bees statewide. Volunteers submitted iNaturalist (©2016 California Academy of Sciences) photograph observations, monitored nest-traps for tunnel-nesting bees, and conducted roadside observational bumble bee surveys. By pairing research scientists and participatory science volunteers, we overcame geographic and temporal challenges to document the presence, phenologies, and abundances of species. Minnesota Bee Atlas project observations included new state records for Megachile inimica, Megachile frugalis, Megachile sculpturalis, Osmia georgica, Stelis permaculata, and Bombus nevadensis, nesting phenology for 17 species, a new documentation of bivoltinism for Megachile relativa in Minnesota, and over 500 observations of the endangered species Bombus affinis. We also expanded known ranges for 16 bee species compared with specimens available from the University of Minnesota (UMN) Insect Collection. Surveys with standardized effort across the state found ecological province associations for six tunnel-nesting species and lower bumble bee abundance in the Prairie Parkland ecological province than the Laurentian Mixed Forest or Eastern Broadleaf Forest ecological provinces, indicating potential benefit of a focus on bumble bee habitat management in the Prairie Parkland. Landcover analysis found associations for four tunnel-nesting species, as well as a possible association of B. affinis with developed areas. These data can inform management decisions affecting pollinator conservation and recovery of endangered species. By engaging over 2,500 project volunteers and other iNaturalist users, we also promoted conservation action for pollinators through our educational programs and interactions.

Persistent Brain Connectivity Changes in Healthy Volunteers Following Nitrous Oxide Inhalation.

Background: Nitrous oxide holds promise in the treatment of major depressive disorder. Its psychotropic effects and NMDA receptor antagonism have led to comparisons with ketamine. Despite longstanding use, persistent effects of nitrous oxide on the brain have not been characterized. Methods: Sixteen healthy volunteers were recruited in a double-blind crossover study. In randomized order, individuals underwent a 1-hour inhalation of either 50% nitrous oxide/oxygen or air/oxygen mixtures. At least two 7.5-minute echo-planar resting-state functional magnetic resonance imaging scans were obtained before and at 2 and 24 hours after each inhalation (average 130 min/participant). Using the time series of preprocessed, motion artifact-scrubbed, and nuisance covariate-regressed imaging data, interregional signal correlations were measured and converted to T scores. Hierarchical clustering and linear mixed-effects models were employed. Results: Nitrous oxide inhalation produced changes in global brain connectivity that persisted in the occipital cortex at 2 and 24 hours postinhalation (p < .05, false discovery rate-corrected). Analysis of resting-state networks demonstrated robust strengthening of connectivity between regions of the visual network and those of the dorsal attention network, across 2 and 24 hours after inhalation (p < .05, false discovery rate-corrected). Weaker changes in connectivity were found between the visual cortex and regions of the frontoparietal and default mode networks. Parallel analyses following air/oxygen inhalation yielded no significant changes in functional connectivity. Conclusions: Nitrous oxide inhalation in healthy volunteers revealed persistent increases in global connectivity between regions of primary visual cortex and dorsal attention network. These findings suggest that nitrous oxide inhalation induces neurophysiological cortical changes that persist for at least 24 hours.

First direct evidence of lion hunting and the early use of a lion pelt by Neanderthals.

During the Upper Paleolithic, lions become an important theme in Paleolithic art and are more frequent in anthropogenic faunal assemblages. However, the relationship between hominins and lions in earlier periods is poorly known and primarily interpreted as interspecies competition. Here we present new evidence for Neanderthal-cave lion interactions during the Middle Paleolithic. We report new evidence of hunting lesions on the 48,000 old cave lion skeleton found at Siegsdorf (Germany) that attest to the earliest direct instance of a large predator kill in human history. A comparative analysis of a partial puncture to a rib suggests that the fatal stab was delivered with a wooden thrusting spear. We also present the discovery of distal lion phalanges at least 190,000 old from Einhornhöhle (Germany), representing the earliest example of the use of cave lion skin by Neanderthals in Central Europe. Our study provides novel evidence on a new dimension of Neanderthal behavioral complexity.

Relation between increasing attachment security and weight gain: a clinical study of adolescents and their parents at an outpatient ward.

PURPOSE: We wanted to evaluate the impact of a relational focus in the treatment of adolescent ED-patients and their parents at an intensive outpatient ward, based on attachment theory, combined with a family approach and psychodynamic principles. Our aim was to investigate the distribution of different attachment styles among the adolescent ED-patients and their parents, and to find out if they could change by the treatment. METHODS: Swedish adolescents (n = 33; 3 boys, 30 girls) and their parents (n = 60; 34 mothers, 26 fathers) participated. MEASURES: Attachment Style Questionnaire (ASQ), Body Mass Index (BMI) and Children's Global Assessment Scale (CGAS) before and after treatment. RESULTS: The adolescents were high on Need for Approval (ASQ4) of the Insecure/Anxious scale before treatment (in contrast to the parents). The patients had a significant decrease in ASQ4 after treatment, which correlated inversely to the increase in BMI but not to CGAS. The mothers showed features of the Secure/Confident style, fathers of the Insecure/Avoidant with elevated Relationships as Secondary (ASQ2). CONCLUSIONS: Treatment with a relational and a family focus has impact on attachment insecurity in adolescent ED-patients and outcomes in terms of BMI. It is important to engage the parents, who need to help the adolescents to separate at that developmental stage. A secure therapeutic context, which enables mentalizations and allows new relational experiences, is essential. The ASQ-instrument is useful in indicating how the treatment of ED-adolescents is proceeding. LEVEL OF EVIDENCE: Level IV: evidence obtained from multiple time series with the intervention.

Characterization and Pharmacokinetic Profile of Herbs and Spices' Phytochemicals over 24 h after Consumption in Overweight/Obese Adults.

SCOPE: This study aims to characterize the phytochemicals in commonly consumed herbs/spices (H/S) in the United States and their pharmacokinetic profile (PK) over 24 h in humans after consumption. METHOD AND RESULTS: The clinical trial is a randomized, single-blinded, four-arm, 24 h, multi-sampling, single-center crossover design (Clincaltrials.gov NCT03926442) conducted in obese/overweight adults (n = 24, aged 37 ± 3 years, BMI = 28.4 ± 0.6 kg m-2 ). Study subjects consume a high-fat high-carbohydrate meal with salt and pepper (control) or the control meal with 6 g of three different H/S mixtures (Italian herb: rosemary, basil, thyme, oregano, and parsley in the same ratio; cinnamon; and pumpkin pie spice containing cinnamon, ginger, nutmeg, and allspice, the ratio is unknown). Three H/S mixtures are analyzed and 79 phytochemicals are tentatively identified and quantified. Following H/S consumption, 47 metabolites are tentatively identified and quantified in plasma samples. The PK data suggest that some metabolites appear in blood as early as 0.5 h while others can extend up to 24 h. CONCLUSION: Phytochemicals from H/S include in a meal are absorbed and undergo phase I and phase II metabolism and/or catabolized to phenolic acids peaking at different times.

A Combination of Acetate, Propionate, and Butyrate Increases Glucose Uptake in C2C12 Myotubes.

BACKGROUND: Dietary fibers are subjected to saccharolytic fermentation by the gut microbiota, leading to the production of short chain fatty acids (SCFAs). SCFAs act as signaling molecules to different cells in the human body including skeletal muscle cells. The ability of SCFAs to induce multiple signaling pathways, involving nuclear erythroid 2-related factor 2 (Nrf2), may contribute to the redox balance, and thereby may be involved in glucose homeostasis. The aim of this study is to investigate whether SCFAs increase glucose uptake by upregulating the endogenous antioxidant glutathione (GSH) in C2C12 myotubes. METHODS: C2C12 myotubes were exposed to 1, 5, or 20 mM of single (acetate, propionate, or butyrate) or mixtures of SCFAs for 24 h. Cytotoxicity, glucose uptake, and intracellular GSH levels were measured. RESULTS: 20 mM of mixture but not separate SCFAs induced cytotoxicity. Exposure to a mixture of SCFAs at 5 mM increased glucose uptake in myotubes, while 20 mM of propionate, butyrate, and mixtures decreased glucose uptake. Exposure to single SCFAs increased GSH levels in myotubes; however, SCFAs did not prevent the menadione-induced decrease in glucose uptake in myotubes. CONCLUSIONS: The effect of SCFAs on modulating glucose uptake in myotubes is not associated with the effect on endogenous GSH levels.

Application of postmortem imaging modalities in cases of sudden death due to cardiovascular diseases-current achievements and limitations from a pathology perspective : Endorsed by the Association for European Cardiovascular Pathology and by the International Society of Forensic Radiology and Imaging.

Postmortem imaging (PMI) is increasingly used in postmortem practice and is considered a potential alternative to a conventional autopsy, particularly in case of sudden cardiac deaths (SCD). In 2017, the Association for European Cardiovascular Pathology (AECVP) published guidelines on how to perform an autopsy in such cases, which is still considered the gold standard, but the diagnostic value of PMI herein was not analyzed in detail. At present, significant progress has been made in the PMI diagnosis of acute ischemic heart disease, the most important cause of SCD, while the introduction of postmortem CT angiography (PMCTA) has improved the visualization of several parameters of coronary artery pathology that can support a diagnosis of SCD. Postmortem magnetic resonance (PMMR) allows the detection of acute myocardial injury-related edema. However, PMI has limitations when compared to clinical imaging, which severely impacts the postmortem diagnosis of myocardial injuries (ischemic versus non-ischemic), the age-dating of coronary occlusion (acute versus old), other potentially SCD-related cardiac lesions (e.g., the distinctive morphologies of cardiomyopathies), aortic diseases underlying dissection or rupture, or pulmonary embolism. In these instances, PMI cannot replace a histopathological examination for a final diagnosis. Emerging minimally invasive techniques at PMI such as image-guided biopsies of the myocardium or the aorta, provide promising results that warrant further investigations. The rapid developments in the field of postmortem imaging imply that the diagnosis of sudden death due to cardiovascular diseases will soon require detailed knowledge of both postmortem radiology and of pathology.

Early evidence for bear exploitation during MIS 9 from the site of Schöningen 12 (Germany).

A cutmarked bear metatarsal and phalanx from the German open-air sites of Schöningen 12 II-1 and 12 B, respectively, correlated with the interglacial optimum of MIS 9 (ca. 320 ka), provide early evidence for the exploitation of bear skins. Archaeological sites with evidence of bear exploitation from the Lower Paleolithic are rare, with only Boxgrove (United Kingdom) and Bilzingsleben (Germany) yielding cutmarked bear bones indicating skinning. We interpret these finds as evidence for bear hunting and primary access since bear skins are best extracted shortly after the animal's death. The very thin cutmarks found on the Schöningen specimens indicate delicate butchering and show similarities in butchery patterns to bears from other Paleolithic sites. The Eurasian Lower Paleolithic record does not show any evidence for the exploitation of bear meat; only Middle Paleolithic sites, such as Biache-Saint-Vaast (France; ca. 175 ka) and Taubach (Germany; ca. 120 ka), yield evidence for the exploitation of both skin and meat from bear carcasses. Bear skins have high insulating properties and might have played a role in the adaptations of Middle Pleistocene hominins to the cold and harsh winter conditions of Northwestern Europe.

Effects of context and discrepancy when reading multiple documents.

On a daily basis, most people read about issues of interest from a diversity of sources. Moreover, the information they encounter frequently encompass discrepancies, ranging from minor inconsistencies to straight contradictions. Readers may construct coherent representations from discrepant contents by linking contents to their respective sources and connecting the sources with agree-disagree or other types of connectives. Across research studies, however, college-level readers' attention to sources has been found to vary according to individual, text and task dimensions. The present study tested the assumption that readers' strategies depend both on the discrepancy of the information and on the context in which the task is framed. Moreover, beliefs about science were included as potential moderator of context effects. One hundred and sixty university students were tasked to read about a series of social-scientific issues. The task was framed in either a university context or a personal context scenario. For each topic, the participants read two short texts which provided either consistent or discrepant information, and then they wrote a short overview essay. The university context had a significant impact on indicators related to a documents model representation (e.g., text switches, number of adversative connectors in the essay) and standards for presentation (e.g., time on the essay/task page, formal features of the essay). The data support a context-dependent view of reading comprehension, whereby both reading behavior and outcomes are primarily a function of the standards and goals set by the reader. Supplementary Information: The online version contains supplementary material available at 10.1007/s11145-022-10321-2.

Characterization of the skin microbiota in bullous pemphigoid patients and controls reveals novel microbial indicators of disease.

INTRODUCTION: Bullous pemphigoid (BP) is the most common autoimmune blistering disease. It predominately afflicts the elderly and is significantly associated with increased mortality. The observation of age-dependent changes in the skin microbiota as well as its involvement in other inflammatory skin disorders suggests that skin microbiota may play a role in the emergence of BP blistering. We hypothesize that changes in microbial diversity associated with BP might occur before the emergence of disease lesions, and thus could represent an early indicator of blistering risk. OBJECTIVES: The present study aims to investigate potential relationships between skin microbiota and BP and elaborate on important changes in microbial diversity associated with blistering in BP. METHODS: The study consisted of an extensive sampling effort of the skin microbiota in patients with BP and age- and sex-matched controls to analyze whether intra-individual, body site, and/or geographical variation correlate with changes in skin microbial composition in BP and/or blistering status. RESULTS: We find significant differences in the skin microbiota of patients with BP compared to that of controls, and moreover that disease status rather than skin biogeography (body site) governs skin microbiota composition in patients with BP. Our data reveal a discernible transition between normal skin and the skin surrounding BP lesions, which is characterized by a loss of protective microbiota and an increase in sequences matching Staphylococcus aureus, a known inflammation-promoting species. Notably, Staphylococcus aureus is ubiquitously associated with BP disease status, regardless of the presence of blisters. CONCLUSION: The present study suggests Staphylococcus aureus may be a key taxon associated with BP disease status. Importantly, we however find contrasting patterns in the relative abundances of Staphylococcus hominis and Staphylococcus aureus reliably discriminate between patients with BP and matched controls. This may serve as valuable information for assessing blistering risk and treatment outcomes in a clinical setting.

A Quality Improvement Project to Decrease CLABSIs in Non-ICU Settings.

BACKGROUND AND OBJECTIVES: Central line-associated bloodstream infections (CLABSIs) are a common, preventable healthcare-associated infection. In our 3-hospital health system, CLABSI rates in non-intensive care unit (ICU) settings were above the internal target rate of zero. A robust quality improvement (QI) project to reduce non-ICU CLABSIs was undertaken by a team of Doctor of Nursing Practice (DNP)-prepared nurse leaders enrolled in a post-DNP Quality Implementation Scholars program and 2 QI experts. Based on a review of the literature and local root cause analyses, the QI team implemented the evidence-based practice of using 2% chlorhexidine gluconate (CHG) cloths for daily bathing for non-ICU patients with a central line. METHODS: A pre-post-design was used for this QI study. CHG bathing was implemented using multifaceted educational strategies that included an e-learning module, printed educational materials, educational outreach, engagement of unit-based CLABSI champions, and an electronic reminder in the electronic health record. Generalized linear mixed-effects models were used to assess the change in CLABSI rates before and after implementation of CHG bathing. CLABSI rates were also tracked using statistical process control (SPC) charts to monitor stability over time. CHG bathing documentation compliance was audited as a process measure. These audit data were provided to unit-based leadership (nurse managers and clinical team leaders) on a monthly basis. A Qualtrics survey was also disseminated to nursing leadership to evaluate their satisfaction with the CHG bathing implementation processes. RESULTS: Thirty-four non-ICU settings participated in the QI study, including general medical/surgical units and specialty areas (oncology, neurosciences, cardiac, orthopedic, and pediatrics). While the change in CLABSI rates after the intervention was not statistically significant ( b = -0.35, P = .15), there was a clinically significant CLABSI rate reduction of 22.8%. Monitoring the SPC charts demonstrated that CLABSI rates remained stable after the intervention at all 3 hospitals as well as the health system. CHG bathing documentation compliance increased system-wide from 77% (January 2020) to 94% (February 2021). Overall, nurse leaders were satisfied with the CHG bathing implementation process. CONCLUSIONS: To sustain this practice change in non-ICU settings, booster sessions will be completed at least on an annual basis. This study provides further support for using CHG cloths for daily patient bathing in the non-ICU setting.

Adolescent sleep duration: associations with social-cognitive determinants and the mediating role of sleep hygiene practices.

Insufficient sleep duration among adolescents is a widespread public health problem. Gaining better insight into social-cognitive determinants associated with adolescent sleep duration is necessary for developing effective preventive interventions to support healthy sleep. This study aimed to explore whether social-cognitive determinants regarding sufficient sleep duration were associated with sleep duration, and if these associations were mediated by collective sleep hygiene practices. Furthermore, we examined these associations for social-cognitive determinants related to not using media before bedtime and doing relaxing activities and considered whether these associations were mediated by specific sleep hygiene practices. Data were collected amongst second- and third-grade adolescents from 10 Dutch high schools. A total of 878 adolescents (mean [SD] age 13.3 [0.71] years) completed data on sleep duration, social-cognitive determinants of the Theory of Planned Behaviour (i.e., attitude, subjective norms from parents, subjective norms from peers, perceived behavioural control, intention), and sleep hygiene practices. Single- and multivariable path models were constructed and mediation by sleep hygiene practices was analysed by Monte Carlo simulation. All social-cognitive determinants except for subjective norms from peers were associated with longer sleep duration (p < 0.01). Sleep hygiene practices mediated all associations between social-cognitive determinants and sleep duration (mediation ranging from 16% to 72%). Although some of the significant associations and mediation disappeared in the multivariable model, behavioural arousal was the strongest mediator, but collective sleep hygiene practices and cognitive/emotional arousal also explained parts of the associations. The findings indicate that social-cognitive factors should not be overlooked when targeting adolescent sleep duration.

Defective Desmosomal Adhesion Causes Arrhythmogenic Cardiomyopathy by Involving an Integrin-αVß6/TGF-ß Signaling Cascade.

BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is characterized by progressive loss of cardiomyocytes with fibrofatty tissue replacement, systolic dysfunction, and life-threatening arrhythmias. A substantial proportion of ACM is caused by mutations in genes of the desmosomal cell-cell adhesion complex, but the underlying mechanisms are not well understood. In the current study, we investigated the relevance of defective desmosomal adhesion for ACM development and progression. METHODS: We mutated the binding site of DSG2 (desmoglein-2), a crucial desmosomal adhesion molecule in cardiomyocytes. This DSG2-W2A mutation abrogates the tryptophan swap, a central interaction mechanism of DSG2 on the basis of structural data. Impaired adhesive function of DSG2-W2A was confirmed by cell-cell dissociation assays and force spectroscopy measurements by atomic force microscopy. The DSG2-W2A knock-in mouse model was analyzed by echocardiography, ECG, and histologic and biomolecular techniques including RNA sequencing and transmission electron and superresolution microscopy. The results were compared with ACM patient samples, and their relevance was confirmed in vivo and in cardiac slice cultures by inhibitor studies applying the small molecule EMD527040 or an inhibitory integrin-αVß6 antibody. RESULTS: The DSG2-W2A mutation impaired binding on molecular level and compromised intercellular adhesive function. Mice bearing this mutation develop a severe cardiac phenotype recalling the characteristics of ACM, including cardiac fibrosis, impaired systolic function, and arrhythmia. A comparison of the transcriptome of mutant mice with ACM patient data suggested deregulated integrin-αVß6 and subsequent transforming growth factor-ß signaling as driver of cardiac fibrosis. Blocking integrin-αVß6 led to reduced expression of profibrotic markers and reduced fibrosis formation in mutant animals in vivo. CONCLUSIONS: We show that disruption of desmosomal adhesion is sufficient to induce a phenotype that fulfils the clinical criteria to establish the diagnosis of ACM, confirming the dysfunctional adhesion hypothesis. Deregulation of integrin-αVß6 and transforming growth factor-ß signaling was identified as a central step toward fibrosis. A pilot in vivo drug test revealed this pathway as a promising target to ameliorate fibrosis. This highlights the value of this model to discern mechanisms of cardiac fibrosis and to identify and test novel treatment options for ACM.

Reversal of IKZF1-induced glucocorticoid resistance by dual targeting of AKT and ERK signaling pathways.

Although long-term survival in pediatric acute lymphoblastic leukemia (ALL) currently exceeds 90%, some subgroups, defined by specific genomic aberrations, respond poorly to treatment. We previously reported that leukemias harboring deletions or mutations affecting the B-cell transcription factor IKZF1 exhibit a tumor cell intrinsic resistance to glucocorticoids (GCs), one of the cornerstone drugs used in the treatment of ALL. Here, we identified increased activation of both AKT and ERK signaling pathways as drivers of GC resistance in IKZF1-deficient leukemic cells. Indeed, combined pharmacological inhibition of AKT and ERK signaling effectively reversed GC resistance in IKZF1-deficient leukemias. As inhibitors for both pathways are under clinical investigation, their combined use may enhance the efficacy of prednisolone-based therapy in this high-risk patient group.