Proteomic profiling reveals ACSS2 facilitating metabolic support in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by genomic aberrations in oncogenes, cytogenetic abnormalities, and an aberrant epigenetic landscape. Nearly 50% of AML cases will relapse with current treatment. A major source of therapy resistance is the interaction of mesenchymal stroma with leukemic cells resulting in therapeutic protection. We aimed to determine pro-survival/anti-apoptotic protein networks involved in the stroma protection of leukemic cells. Proteomic profiling of cultured primary AML (n = 14) with Hs5 stroma cell line uncovered an up-regulation of energy-favorable metabolic proteins. Next, we modulated stroma-induced drug resistance with an epigenetic drug library, resulting in reduced apoptosis with histone deacetylase inhibitor (HDACi) treatment versus other epigenetic modifying compounds. Quantitative phosphoproteomic probing of this effect further revealed a metabolic-enriched phosphoproteome including significant up-regulation of acetyl-coenzyme A synthetase (ACSS2, S30) in leukemia-stroma HDACi treated cocultures compared with untreated monocultures. Validating these findings, we show ACSS2 substrate, acetate, promotes leukemic proliferation, ACSS2 knockout in leukemia cells inhibits leukemic proliferation and ACSS2 knockout in the stroma impairs leukemic metabolic fitness. Finally, we identify ACSS1/ACSS2-high expression AML subtype correlating with poor overall survival. Collectively, this study uncovers the leukemia-stroma phosphoproteome emphasizing a role for ACSS2 in mediating AML growth and drug resistance.

Microscopic self-dynamics in liquid Ne-D_{2} mixtures: Quantum features and itinerant oscillators reexamined.

In this paper, we report the results of a centroid molecular dynamics (CMD) study of the canonical velocity autocorrelation functions (VACFs) in liquid Ne-D_{2} mixtures at a temperature of T=30K and in the full D_{2}-concentration range (0%≤x_{D_{2}}≤100%). This binary system was selected because of its moderate, although sizable, quantum effects which, as far as its equilibrium properties are concerned, are fully described by the path integral Monte Carlo (PIMC) simulations that have been also implemented. A comprehensive test of the VACF spectral moments carried out using three physical quantities (namely, mean kinetic energy, Einstein frequency, and mean-squared force) obtained from PIMC was performed revealing the potentialities, as well as the limitations, of the CMD approach to the single-particle dynamics in these low-T liquid mixtures. Additional physical information was extracted from the canonical VACFs by fitting their spectra via two distinct methods: the Levesque-Verlet model (LV, very flexible but highly heuristic) and the itinerant oscillator model (IO, based on the physical ground of a single particle rattling inside a short-lived diffusing pseudocage). Both provided good fits of the CMD outputs, with LV being always more adequate than IO in the case of the Ne VACFs, while, as for the D_{2} VACFs, the LV superiority is evident only at high x_{D_{2}} values. However, a peculiar and systematic effect was found after analyzing the IO-fitted parameters: the estimated pseudocage masses turned out to be at least one order of magnitude lower than the corresponding values inferred from the PIMC simulations. This outcome concerns both the Ne and the D_{2} rattling molecule and, as we also discovered, had already been observed (but promptly forgotten) in purely classical simulations of liquid Ar. The possible physical origins of this finding have been finally discussed in some detail, also in connection with the result of the more recent exponential expansion theory (EET), which manages to shed more light on the concept of single particles rattling inside short-lived pseudocages, ultimately demonstrating its untenability.

Molecular subgroups of T-cell acute lymphoblastic leukemia in adults treated according to pediatric-based GMALL protocols.

In contrast to B-cell precursor acute lymphoblastic leukemia (ALL), molecular subgroups are less well defined in T-lineage ALL. Comprehensive studies on molecular T-ALL subgroups have been predominantly performed in pediatric ALL patients. Currently, molecular characteristics are rarely considered for risk stratification. Herein, we present a homogenously treated cohort of 230 adult T-ALL patients characterized on transcriptome, and partly on DNA methylation and gene mutation level in correlation with clinical outcome. We identified nine molecular subgroups based on aberrant oncogene expression correlating to four distinct DNA methylation patterns. The subgroup distribution differed from reported pediatric T-ALL cohorts with higher frequencies of prognostic unfavorable subgroups like HOXA or LYL1/LMO2. A small subset (3%) of HOXA adult T-ALL patients revealed restricted expression of posterior HOX genes with aberrant activation of lncRNA HOTTIP. With respect to outcome, TLX1 (n = 44) and NKX2-1 (n = 4) had an exceptionally favorable 3-year overall survival (3y-OS) of 94%. Within thymic T-ALL, the non TLX1 patients had an inferior but still good prognosis. To our knowledge this is the largest cohort of adult T-ALL patients characterized by transcriptome sequencing with meaningful clinical follow-up. Risk classification based on molecular subgroups might emerge and contribute to improvements in outcome.

Developmental trajectories and cooperating genomic events define molecular subtypes of BCR::ABL1-positive ALL.

ABSTRACT: Distinct diagnostic entities within BCR::ABL1-positive acute lymphoblastic leukemia (ALL) are currently defined by the International Consensus Classification of myeloid neoplasms and acute leukemias (ICC): "lymphoid only", with BCR::ABL1 observed exclusively in lymphatic precursors, vs "multilineage", where BCR::ABL1 is also present in other hematopoietic lineages. Here, we analyzed transcriptomes of 327 BCR::ABL1-positive patients with ALL (age, 2-84 years; median, 46 years) and identified 2 main gene expression clusters reproducible across 4 independent patient cohorts. Fluorescence in situ hybridization analysis of fluorescence-activated cell-sorted hematopoietic compartments showed distinct BCR::ABL1 involvement in myeloid cells for these clusters (n = 18/18 vs n = 3/16 patients; P < .001), indicating that a multilineage or lymphoid BCR::ABL1 subtype can be inferred from gene expression. Further subclusters grouped samples according to cooperating genomic events (multilineage: HBS1L deletion or monosomy 7; lymphoid: IKZF1-/- or CDKN2A/PAX5 deletions/hyperdiploidy). A novel HSB1L transcript was highly specific for BCR::ABL1 multilineage cases independent of HBS1L genomic aberrations. Treatment on current German Multicenter Study Group for Adult ALL (GMALL) protocols resulted in comparable disease-free survival (DFS) for multilineage vs lymphoid cluster patients (3-year DFS: 70% vs 61%; P = .530; n = 91). However, the IKZF1-/- enriched lymphoid subcluster was associated with inferior DFS, whereas hyperdiploid cases showed a superior outcome. Thus, gene expression clusters define underlying developmental trajectories and distinct patterns of cooperating events in BCR::ABL1-positive ALL with prognostic relevance.

The Gene Expression Classifier ALLCatchR Identifies B-cell Precursor ALL Subtypes and Underlying Developmental Trajectories Across Age.

Current classifications (World Health Organization-HAEM5/ICC) define up to 26 molecular B-cell precursor acute lymphoblastic leukemia (BCP-ALL) disease subtypes by genomic driver aberrations and corresponding gene expression signatures. Identification of driver aberrations by transcriptome sequencing (RNA-Seq) is well established, while systematic approaches for gene expression analysis are less advanced. Therefore, we developed ALLCatchR, a machine learning-based classifier using RNA-Seq gene expression data to allocate BCP-ALL samples to all 21 gene expression-defined molecular subtypes. Trained on n = 1869 transcriptome profiles with established subtype definitions (4 cohorts; 55% pediatric / 45% adult), ALLCatchR allowed subtype allocation in 3 independent hold-out cohorts (n = 1018; 75% pediatric / 25% adult) with 95.7% accuracy (averaged sensitivity across subtypes: 91.1% / specificity: 99.8%). High-confidence predictions were achieved in 83.7% of samples with 98.9% accuracy. Only 1.2% of samples remained unclassified. ALLCatchR outperformed existing tools and identified novel driver candidates in previously unassigned samples. Additional modules provided predictions of samples blast counts, patient's sex, and immunophenotype, allowing the imputation in cases where these information are missing. We established a novel RNA-Seq reference of human B-lymphopoiesis using 7 FACS-sorted progenitor stages from healthy bone marrow donors. Implementation in ALLCatchR enabled projection of BCP-ALL samples to this trajectory. This identified shared proximity patterns of BCP-ALL subtypes to normal lymphopoiesis stages, extending immunophenotypic classifications with a novel framework for developmental comparisons of BCP-ALL. ALLCatchR enables RNA-Seq routine application for BCP-ALL diagnostics with systematic gene expression analysis for accurate subtype allocation and novel insights into underlying developmental trajectories.

Role of the single-particle dynamics in the transverse current autocorrelation function of a liquid metal.

A recent simulation study of the transverse current autocorrelation of the Lennard-Jones fluid [Guarini et al., Phys. Rev. E 107, 014139 (2023)] revealed that this function can be perfectly described within the exponential expansion theory [Barocchi et al., Phys. Rev. E 85, 022102 (2012)]. However, above a certain wavevector Q, not only transverse collective excitations were found to propagate in the fluid, but a second oscillatory component of unclear origin (therefore called X) must be considered to fully account for the time dependence of the correlation function. Here, we present an extended investigation of the transverse current autocorrelation of liquid Au as obtained by ab initio molecular dynamics in the very wide range of wavevectors 5.7 ≤ Q ≤ 32.8 nm-1 in order to also follow the behavior of the X component, if present, at large Q values. A joint analysis of the transverse current spectrum and its self-portion indicates that the second oscillatory component arises from the longitudinal dynamics, as suggested by its close resemblance with the previously determined component accounting for the longitudinal part of the density of states. We conclude that such a mode, albeit featuring a merely transverse property, fingerprints the effect of longitudinal collective excitations on single-particle dynamics, rather than arising from a possible coupling between transverse and longitudinal acoustic waves.

Onset of collective excitations in the transverse dynamics of simple fluids.

A thorough analysis of the transverse current autocorrelation function obtained by molecular dynamics simulations of a dense Lennard-Jones fluid reveals that even such a simple system is characterized by a varied dynamical behavior with changing length scale. By using the exponential expansion theory, we provide a full account of the time correlation at wavevectors Q between the upper boundary of the hydrodynamic region and Q_{p}/2, with Q_{p} being the position of the main peak of the static structure factor. In the Q range studied, we identify and accurately locate the wavevector at which shear wave propagation starts to take place, and show clearly how this phenomenon may be represented by a damped harmonic oscillator changing, in a continuous way, from an overdamped to an underdamped condition. The decomposition into exponential modes allows one to convincingly establish not only the crossover related to the onset of transverse waves but, surprisingly, also the existence of a second pair of modes equivalent to another oscillator that undergoes, at higher Q values, a similarly smooth over to underdamped transition.

FAT1 expression in T-cell acute lymphoblastic leukemia (T-ALL) modulates proliferation and WNT signaling.

FAT atypical cadherin 1 (FAT1), a transmembrane protein, is frequently mutated in various cancer types and has been described as context-dependent tumor suppressor or oncogene. The FAT1 gene is mutated in 12-16% of T-cell acute leukemia (T-ALL) and aberrantly expressed in about 54% of T-ALL cases contrasted with absent expression in normal T-cells. Here, we characterized FAT1 expression and profiled the methylation status from T-ALL patients. In our T-ALL cohort, 53% of patient samples were FAT1 positive (FAT1pos) compared to only 16% FAT1 positivity in early T-ALL patient samples. Aberrant expression of FAT1 was strongly associated with FAT1 promotor hypomethylation, yet a subset, mainly consisting of TLX1-driven T-ALL patient samples showed methylation-independent high FAT1 expression. Genes correlating with FAT1 expression revealed enrichment in WNT signaling genes representing the most enriched single pathway. FAT1 knockdown or knockout led to impaired proliferation and downregulation of WNT pathway target genes (CCND1, MYC, LEF1), while FAT1 overexpressing conveyed a proliferative advantage. To conclude, we characterized a subtype pattern of FAT1 gene expression in adult T-ALL patients correlating with promotor methylation status. FAT1 dependent proliferation and WNT signaling discloses an impact on deeper understanding of T-ALL leukemogenesis as a fundament for prospective therapeutic strategies.

Isocitrate dehydrogenase 1 mutation drives leukemogenesis by PDGFRA activation due to insulator disruption in acute myeloid leukemia (AML).

Acute myeloid leukemia (AML) is characterized by complex molecular alterations and driver mutations. Elderly patients show increased frequencies of IDH mutations with high chemoresistance and relapse rates despite recent therapeutic advances. Besides being associated with global promoter hypermethylation, IDH1 mutation facilitated changes in 3D DNA-conformation by CTCF-anchor methylation and upregulated oncogene expression in glioma, correlating with poor prognosis. Here, we investigated the role of IDH1 p.R132H mutation in altering 3D DNA-architecture and subsequent oncogene activation in AML. Using public RNA-Seq data, we identified upregulation of tyrosine kinase PDGFRA in IDH1-mutant patients, correlating with poor prognosis. DNA methylation analysis identified CpG hypermethylation within a CTCF-anchor upstream of PDGFRA in IDH1-mutant patients. Increased PDGFRA expression, PDGFRA-CTCF methylation and decreased CTCF binding were confirmed in AML CRISPR cells with heterozygous IDH1 p.R132H mutation and upon exogenous 2-HG treatment. IDH1-mutant cells showed higher sensitivity to tyrosine kinase inhibitor dasatinib, which was supported by reduced blast count in a patient with refractory IDH1-mutant AML after dasatinib treatment. Our data illustrate that IDH1 p.R132H mutation leads to CTCF hypermethylation, disrupting DNA-looping and insulation of PDGFRA, resulting in PDGFRA upregulation in IDH1-mutant AML. Treatment with dasatinib may offer a novel treatment strategy for IDH1-mutant AML.

The State and the Citizen: Overview of a complex relationship from a paradigmatic perspective.

Notwithstanding the huge literature on state studies, both definition and method have always been subject of intense debate. This debate is still open and equally intense despite two millennia of philosophical and methodological attempts to define what the state is, to describe how the state works, and why does it work. As times, geopolitical contexts, and human action have shaped the historical and conceptual trajectory of polity studies, the theories as well as methodologies have increasingly emphasized focus on individuals, (political) cultures, power, and relationships both between individuals and between individuals and the state. With time, the study of these types of relationships have revealed the complexity of the state, and the dynamics of its change. Though economy and political economy theories of the twentieth century gradually diminished the central role of the state in economy in favor of the free market and individual and company small as well as big entrepreneurship, the increased focus on individuals and individual (inter)action(s) has paradoxically turned into a revival of the state, a reinforcement of its role, as latest neo-statism trends reveal. It was the COVID-19 global pandemics to highlight what people think and expect from the state in the volatile European and global political context of our time. Not only that isolation and social distance conditions have deepened and strengthened the perception of the state as the source of their security and receptor of their highest level of trust but have also revealed that the state studies are about to reach again a turning point in the philosophical thinking about society and polity.

Hierarchy and diffusion of organizational forms.

In this paper we first of all summarize and rationalize current typologies of organizational forms, arranging available classifications in a hierarchy of increasing generality. The ensuing structure parallels the classification of living beings into classes of increasing generality such as species, genus, family, order, and so on. Subsequently, we analyze the structure of communications that favored the diffusion of each organizational form. We isolate a few stylized communication structures, pointing to the presence of several sources endowed with global connections as the most efficient diffusion mode. The empirical research that is being carried out on single organizations is close to observing their T-patterns, whereas nothing comparable is in sight for organizational forms as yet. However, at least in some cases, we dare to formulate tentative hypotheses on certain features that the ensuing T-patterns-of-patterns might exhibit.

Microscopic collective dynamics in liquid neon-deuterium mixtures: Inelastic neutron scattering and quantum simulations.

In this paper a combined neutron scattering and quantum simulation study of the collective dynamics in liquid Ne-D_{2} mixtures, at a temperature of T=30K and in the wave-vector transfer range 4 nm^{-1}

An alternative CYB5A transcript is expressed in aneuploid ALL and enriched in relapse.

BACKGROUND: B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a genetically heterogenous malignancy with poor prognosis in relapsed adult patients. The genetic basis for relapse in aneuploid subtypes such as near haploid (NH) and high hyperdiploid (HeH) BCP-ALL is only poorly understood. Pathogenic genetic alterations remain to be identified. To this end, we investigated the dynamics of genetic alterations in a matched initial diagnosis-relapse (ID-REL) BCP-ALL cohort. Here, we firstly report the identification of the novel genetic alteration CYB5Aalt, an alternative transcript of CYB5A, in two independent cohorts. METHODS: We identified CYB5alt in the RNAseq-analysis of a matched ID-REL BCP-ALL cohort with 50 patients and quantified its expression in various molecular BCP-ALL subtypes. Findings were validated in an independent cohort of 140 first diagnosis samples from adult BCP-ALL patients. Derived from patient material, the alternative open reading frame of CYB5Aalt was cloned (pCYB5Aalt) and pCYB5Aalt or the empty vector were stably overexpressed in NALM-6 cells. RNA sequencing was performed of pCYB5Aalt clones and empty vector controls followed by differential expression analysis, gene set enrichment analysis and complementing cell death and viability assays to determine functional implications of CYB5Aalt. RESULTS: RNAseq data analysis revealed non-canonical exon usage of CYB5Aalt starting from a previously undescribed transcription start site. CYB5Aalt expression was increased in relapsed BCP-ALL and its occurrence was specific towards the shared gene expression cluster of NH and HeH BCP-ALL in independent cohorts. Overexpression of pCYB5Aalt in NALM-6 cells induced a distinct transcriptional program compared to empty vector controls with downregulation of pathways related to reported functions of CYB5A wildtype. Interestingly, CYB5A wildtype expression was decreased in CYB5Aalt samples in silico and in vitro. Additionally, pCYB5Aalt NALM-6 elicited a more resistant drug response. CONCLUSIONS: Across all age groups, CYB5Aalt was the most frequent secondary genetic event in relapsed NH and HeH BCP-ALL. In addition to its high subgroup specificity, CYB5Aalt is a novel candidate to be potentially implicated in therapy resistance in NH and HeH BCP-ALL. This is underlined by overexpressing CYB5Aalt providing first evidence for a functional role in BCL2-mediated apoptosis.

The Selective 5-HT1A Agonist SR57746A Protects Intestinal Epithelial Cells and Enteric Glia Cells and Promotes Mucosal Recovery in Experimental Colitis.

BACKGROUND: Neurotrophic growth factors can stabilize the intestinal barrier by preventing the apoptosis of enteric glial cells (EGCs) and enterocytes. We reasoned that a selective 5-HT1A receptor agonist may have neuroprotective properties in the gut and that topical application of SR57746A might be an effective treatment strategy in inflammatory bowel disease (IBD). METHODS: The therapeutic potential of 5-HT1A receptor agonist SR57746A in IBD was evaluated in vitro (nontransformed NCM460 colonic epithelial cells, SW480 colorectal carcinoma cells) and in vivo (murine dextran sulfate sodium [DSS] colitis and CD4-T-cell transfer colitis). In vitro, we analyzed the effect of SR57746A on apoptosis in intestinal epithelial cells (IECs) and EGCs, and upon proliferation, migration, and intracellular signaling in IECs. In vivo, the effect of topical application of SR57746 on disease activity and on histological and endoscopic findings was compared with intraperitoneal infliximab and placebo, respectively. RESULTS: The SR57746A activates PI3-K/AKT- and ERK-signaling in IECs. Depending on ERK- and AKT activation, SR57746A potently prevents apoptosis of IECs without inducing proliferation or migration in these cells. Moreover, SR57746A prevented apoptosis in EGCs in vitro. Topical SR57746A treatment significantly reduced mucosal injury in 2 experimental murine colitis models and was as effective as intraperitoneal infliximab treatment. CONCLUSIONS: Treatment with SR57746A prevents inflammatory cell damage and apoptosis in IECs and EGCs, similar to the neurotrophic effects of EGCs on IECs. Topical treatment with SR57746A could be a candidate for clinical evaluation in the treatment of IBD.

Making Sense of Sanctions: An Agent-Based Model of Sanction Recognition.

Theories of norm emergence are a central building block for comprehending the emergence of society. The article investigates a central terminus in theories of norms, in particular rational choice theory: The notion of sanctions. Sanctions are an unexplained theoretical term for securing norm conformity. Agent-based models inspired by evolutionary game theory show that the evolution of cooperation can be enforced by sanctions. However, in behavioral terms, sanctions are a form of aggression. An empirical investigation of the violent collapse of a criminal group reveals that interpretation is necessary for recognizing aggression as sanction. Whereas theories of norms attempt to explain the emergence of social structure, successful sanction recognition imposes the existence of social structure in the form of normative authorities. In the absence of social structure for securing social order such as the state monopoly of violence this interpretation remains ambiguous and error prone. Simulation experiments with an agent-based model investigate the conditions for the emergence of a normative authority.

Individual attitude change and societal dynamics: Computational experiments with psychological theories.

We present an agent-based model for studying the societal implications of attitude change theories. Various psychological theories of persuasive communication at the individual level are implemented as simulation experiments. The model allows us to investigate the effects of contagion and assimilation, motivated cognition, polarity, source credibility, and idiosyncratic attitude formation. Simulations show that different theories produce different characteristic macrolevel patterns. Contagion and assimilation are central mechanisms for generating consensus, however, contagion generates a radicalized consensus. Motivated cognition causes societal polarization or the fragmentation of attitudes. Polarity and source credibility have comparatively little effect on the societal distribution of attitudes. We discuss how the simulations provide a bridge between microlevel psychological theories and the aggregated macrolevel studied by sociology. This approach enables new types of evidence for evaluating psychological theory to complement experimental approaches, thus answering calls to enhance the role of coherent and formalized theory in psychological science. (PsycInfo Database Record (c) 2021 APA, all rights reserved).