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The BCL2 inhibitor venetoclax (VEN) in combination with azacitidine (5-AZA) is currently transforming acute myeloid leukemia (AML) therapy. However, there is a lack of clinically relevant biomarkers that predict response to 5-AZA/VEN. Here, we integrated transcriptomic, proteomic, functional, and clinical data to identify predictors of 5-AZA/VEN response. Although cultured monocytic AML cells displayed upfront resistance, monocytic differentiation was not clinically predictive in our patient cohort. We identified leukemic stem cells (LSC) as primary targets of 5-AZA/VEN whose elimination determined the therapy outcome. LSCs of 5-AZA/VEN-refractory patients displayed perturbed apoptotic dependencies. We developed and validated a flow cytometry-based “Mediators of apoptosis combinatorial score” (MAC-Score) linking the ratio of protein expression of BCL2, BCL-xL, and MCL1 in LSCs. MAC scoring predicts initial response with a positive predictive value of more than 97% associated with increased event-free survival. In summary, combinatorial levels of BCL2 family members in AML-LSCs are a key denominator of response, and MAC scoring reliably predicts patient response to 5-AZA/VEN. Significance: Venetoclax/azacitidine treatment has become an alternative to standard chemotherapy for patients with AML. However, prediction of response to treatment is hampered by the lack of clinically useful biomarkers. Here, we present easy-to-implement MAC scoring in LSCs as a novel strategy to predict treatment response and facilitate clinical decision-making.

This article presents a model-based mutation framework for creating mutant systems implemented in IEC61131-3 languages. The framework is based on a meta-model of the IEC61131-3 standard. It supports 21 mutation operations, such as the addition or removal of POUs or the mutation of Structured Text and Sequential Functional Charts. Moreover, operations can be combined to create higher-order changes, such as Type III code clones. The mutation framework can be used to evaluate and improve development tools for supporting the evolution of manufacturing systems, such as regression test suite generators or clone detectors.

During the development of intralogistics systems (ILS), heterogeneous models are created, which represent discipline-specific views, e.g., control software developed by automation engineers or discrete-event simulation models created by simulation engineers. These models represent discipline-specific views on the system but contain overlapping information. Thereby, keeping the information in different development models consistent is challenging and currently requires high manual effort, which highly depends on the developers’ experience. To overcome this challenge, an approach to link heterogeneous model data and identify potential information inconsistencies within and between models automatically is proposed. The concept is evaluated with a use case containing three typical inconsistencies from five representative engineering models applied in ILS development.

Despite routine use of DNA-hypomethylating agents (HMAs) in AML/MDS therapy, their mechanisms of action are not yet unraveled. Pleiotropic effects of HMAs include global methylome and transcriptome changes. We asked whether in blasts and T-cells from AML patients HMA-induced in vivo demethylation and remethylation occur randomly or non-randomly, and whether gene demethylation is associated with gene induction. Peripheral blood AML blasts from patients receiving decitabine (20 mg/m2 day 1–5) were serially isolated for methylome analyses (days 0, 8 and 15, n = 28) and methylome-plus-transcriptome analyses (days 0 and 8, n = 23), respectively. T-cells were isolated for methylome analyses (days 0 and 8; n = 16). We noted massive, non-random demethylation at day 8, which was variable between patients. In contrast, T-cells disclosed a thousand-fold lesser, random demethylation, indicating selectivity of the demethylation for the malignant blasts. The integrative analysis of DNA demethylation and transcript induction revealed 87 genes displaying a significant inverse correlation, e.g. the tumor suppressor gene IFI27, whose derepression was validated in two AML cell lines. These results support HMA-induced, non-random early in vivo demethylation events in AML blasts associated with gene induction. Larger patient cohorts are needed to determine whether a demethylation signature may be predictive for response to this treatment.

It has been proposed that primary care diagnose and treat hepatitis C virus (HCV) infection. However, a care circuit between primary and specialized care based on electronic consultation (EC) can be just as efficient in the micro-elimination of HCV. It is proposed to study characteristics and predictive factors of continuity of care in a circuit between primary and specialized care.From February/2018 to December/2019, all EC between primary and specialized care were evaluated and those due to HCV were identified. Variables for regression analysis and to identify predictors of completing the care cascade were recorded.From 8098 EC, 138 were performed by 89 (29%) general practitioners over 118 patients (median 50.8 years; 74.6% men) and were related to HCV (1.9%). Ninety-two patients (78%) were diagnosed6 months ago, and 26.3% met criteria for late presentation. Overall, 105 patients required assessment by the hepatologist, 82% (n=86) presented for the appointment, of which 67.6% (n=71) were viraemic, 98.6% of known. Finally, 61.9% (n=65) started treatment. Late-presenting status was identified as an independent predictor to complete the care cascade (OR 1.93, CI 1.71-1.99, p0.001).Communication pathway between Primary and Specialized Care based on EC is effective in avoiding significant losses of viraemic patients. However, the referral rate is very low, high in late-stage diagnoses, heterogeneous, and low in new diagnoses. Therefore, early detection strategies for HCV infection in primary care are urgently needed.

Kurzfassung Vor allem in der deutschen Diskussion über Russlands Angriffskrieg gegen die Ukraine werden immer wieder Forderungen nach diplomatisch verhandelten Kompromissen zur Kriegsbeendigung laut. Verschiedene Möglichkeiten sind vorstellbar, doch hat keine das Potenzial, die Basis für einen halbwegs dauerhaften Friedensschluss zu bilden. Schaut man sich die Geschichte der Beendigung europäischer Kriege an, so zeigt sich, dass in der Konfrontation mit einem derart nationalistisch und kompromisslos auftretenden Akteur wie Russland der einzige Weg zu einem beständigen Frieden ein Regimewechsel ist. Dieser kann und darf nicht von außen bewirkt werden. Daher ist in diesem Fall eine Politik der Gegenmachtbildung des Westens vorerst die einzig verbleibende Strategie.

Eine der größten Herausforderungen der elektrochemischen Umwandlung von CO2 zu CO in Zero-Gap-Elektrolyseuren ist die Skalierung dieser Systeme in den industriellen Maßstab. Trotz der bemerkenswerten Ergebnisse der letzten Jahre, sind bisher nur wenige Fortschritte bei der Skalierung dieser Technologie erzielt worden. In diesem Beitrag wird gezeigt, wie die Steuerung des Wassergehalts an der Kathode es ermöglicht Flutungsprozesse zu minimieren und aussichtsreiche experimentelle Ergebnisse auf größere CO2 Elektrolysesysteme zu übertragen.

The coxsackievirus and adenovirus receptor (CAR) mediates homo- and heterotopic interactions between neighboring cardiomyocytes at the intercalated disc. CAR is upregulated in the hypoxic areas surrounding myocardial infarction (MI). To elucidate whether CAR contributes to hypoxia signaling and MI pathology, we used a gain- and loss-of-function approach in transfected HEK293 cells, H9c2 cardiomyocytes and CAR knockout mice. CAR overexpression increased RhoA activity, HIF-1α expression and cell death in response to chemical and physical hypoxia. In vivo, we subjected cardiomyocyte-specific CAR knockout (KO) and wild-type mice (WT) to coronary artery ligation. Survival was drastically improved in KO mice with largely preserved cardiac function as determined by echocardiography. Histological analysis revealed a less fibrotic, more compact lesion. Thirty days after MI, there was no compensatory hypertrophy or reduced cardiac output in hearts from CAR KO mice, in contrast to control mice with increased heart weight and reduced ejection fraction as signs of the underlying pathology. Based on these findings, we suggest CAR as a therapeutic target for the improved future treatment or prevention of myocardial infarction.

Objective: To evaluate the diagnostic accuracy of MRI-hysterosalpingogram (HSG) with semiquantitative dynamic contrast‐enhanced perfusion, against the virtual multislice CT hysterosalpingogram (VHSG) as a reference standard. Methods and Materials: In this prospective study, 26 women (age >18 years) searching for infertility causes and with VHSG physician request. Thereafter, the assessment performance of both techniques was determined by two reader analyses. k statistics were used for the assessment of tubal patency. Receiver operating characteristic (ROC) analysis was used to compare the capability for tubal patency assessment between both exams on a per-patient and per-tube basis. The McNemar test was used to compare the diagnostic accuracy measures. Results: Tubal patency, uterine morphological, ovarian, and extrauterine abnormalities were evaluated through both exams in all 26 women. There was no significant difference between diagnostic performance measurements between the methods. The ROC curve of VHSG was 0.852 for both per-patient and per-tube analyses, and one and 0.938 for MRI-HSG. Sensitivity and specificity for per-patient and per-tube for VHSG were 95.2 and 97.7, 80 and 87.5%, and for MRI-HSG 100% for both analyses and 100 and 87.5%, respectively. Conclusion: This study demonstrates the feasibility of diagnosing tubal patency through MRI, using a semi-quantitative dynamic contrast‐enhanced perfusion sequence, and the satisfactory diagnosing of the uterine morphology, ovarian abnormalities, and ovarian and deep endometriosis. Advances in knowledge: Multiparametric MRI with a perfusion real-time sequence as a HSG method can be used in the evaluation not only for uterine and ovarian abnormilities but also tubal patency.

This article serves as an overview on Gottfried Achenwall’s principles of moral imputation specifically in their early development. In contrast to Joachim Georg Darjes, he claims that moral imputation consists in an application of the law. That is both the reason why Achenwall initially introduced the distinction of imputatio facti et legis to his doctrine on natural law in year 1750, and at the same time why Achenwall had to give up this classification a few years later in year 1754.

Immune checkpoint inhibitors and adoptive T cell therapies have been valuable additions to the toolbox in the fight against cancer. These treatments have profoundly increased the number of patients with a realistic perspective toward a return to a cancer-free life. Yet, in a number of patients and tumor entities, cancer immunotherapies have been ineffective so far. In solid tumors, immune exclusion and the immunosuppressive tumor microenvironment represent substantial roadblocks to successful therapeutic outcomes. A major contributing factor to the depressed anti-tumor activity of immune cells in tumors is the harsh metabolic environment. Hypoxia, nutrient competition with tumor and stromal cells, and accumulating noxious waste products, including lactic acid, pose massive constraints to anti-tumor immune cells. Numerous strategies are being developed to exploit the metabolic vulnerabilities of tumor cells in the hope that these would also alleviate metabolism-inflicted immune suppression. While promising in principle, especially in combination with immunotherapies, these strategies need to be scrutinized for their effect on tumor-fighting immune cells, which share some of their key metabolic properties with tumor cells. Here, we provide an overview of strategies that seek to tackle lactate metabolism in tumor or immune cells to unleash anti-tumor immune responses, thereby opening therapeutic options for patients whose tumors are currently not treatable.

The insulator–metal transition in liquid hydrogen is an important phenomenon to understand the interiors of gas giants, such as Jupiter and Saturn, as well as the physical and chemical behavior of materials at high pressures and temperatures. Here, the path toward an experimental approach is detailed based on spectrally resolved x-ray scattering, tailored to observe and characterize hydrogen metallization in dynamically compressed hydrocarbons in the regime of carbon–hydrogen phase separation. With the help of time-dependent density functional theory calculations and scattering spectra from undriven carbon samples collected at the European x-ray Free-Electron Laser Facility (EuXFEL), we demonstrate sufficient data quality for observing C–H demixing and investigating the presence of liquid metallic hydrogen in future experiments using the reprated drive laser systems at EuXFEL.

Admission to an emergency department (ED) is challenging for older patients with cognitive dysfunction (PWCD). Targeted patient-oriented approaches to improve the care for PWCD are needed. The aim of this pilot study was to design and evaluate a program for volunteers to support PWCD in the ED. Volunteers (N = 9) first received a training and during the following six months (N = 90 shifts), they accompanied PWCD (N = 112) during their stay. Results showed that the training increased volunteers' knowledge and expertise, but not shift-related self-efficacy. The most frequent strategies applied were conversations, holding hands and touching, and providing food and drinks. After six months, volunteers reported a great sense of meaningfulness and felt that they were highly appreciated by the patients. ED nurses' sceptical attitudes towards the program decreased. The program is beneficial for PWCD, appears to be meaningful for volunteers and is appreciated by ED nurses.

The introduction of new targeted therapies to the treatment algorithm of acute myeloid leukemia (AML) offers new opportunities, but also presents new challenges. Patients diagnosed with AML receiving targeted therapies as part of lower intensity regimens will relapse inevitably due to primary or secondary resistance mechanisms. In this review, we summarize the current knowledge on the main mechanisms of resistance to targeted therapies in AML. Resistance to FLT3 inhibitors is mainly mediated by on target mutations and dysregulation of downstream pathways. Switching the FLT3 inhibitor has a potential therapeutic benefit. During treatment with IDH inhibitors resistance can develop due to aberrant cell metabolism or secondary site IDH mutations. As a unique resistance mechanism the mutated IDH isotype may switch from IDH1 to IDH2 or vice versa. Resistance to gemtuzumab-ozogamicin is determined by the CD33 isotype and the degradation of the cytotoxin. The main mechanisms of resistance to venetoclax are the dysregulation of alternative pathways especially the upregulation of the BCL-2-analogues MCL-1 and BCL-XL or the induction of an aberrant cell metabolism. The introduction of therapies targeting immune processes will lead to new forms of therapy resistance. Knowing those mechanisms will help to develop strategies that can overcome resistance to treatment.

The rapid technological leaps of Industry 4.0 increase the pressure and demands on humans working in automation, which is one of the main motivators of Industry 5.0. In particular, automation software development for mechatronic systems becomes increasingly challenging, as both domain knowledge and programming skills are required for high-quality, maintainable software. Especially for small companies from automation and robotics without dedicated software engineering departments, domain-specific low-code platforms become indispensable that enable domain experts to develop code intuitively using visual programming languages, e.g., for tasks such as retrofitting mobile machines. However, for extensive functionalities, visual programs may become overwhelming due to the scaling-up problem. In addition, the ever-shortening time-to-market increases the time pressure on programmers. Thus, an assistance system concept is introduced that can be implemented by low-code platform suppliers based on combining data mining and static code analysis. Domain experts are supported in developing low-code by targeted recommendations, metric-based complexity measurement, and reducing complexity by encapsulating functionalities. The concept is implemented for the industrial low-code platform HAWE eDesign to program hydraulic components in mobile machines, and its benefits are confirmed in a user study and an industrial expert workshop., 8 pages, https://ieeexplore.ieee.org/abstract/document/9839457

We conducted a single-arm, phase 2 trial (German-Austrian Acute Myeloid Leukemia Study Group [AMLSG] 16-10) to evaluate midostaurin with intensive chemotherapy followed by allogeneic hematopoietic-cell transplantation (HCT) and a 1-year midosta urin maintenance therapy in adult patients with acute myeloid leukemia (AML) and fms-related tyrosine kinase 3 (FLT3) internal tandem duplication (ITD). Patients 18 to 70 years of age with newly diagnosed FLT3-ITD-positive AML were eligible. Primary and key secondary endpoints were event-free survival (EFS) and overall survival (OS). Results were compared with a historical cohort of 415 patients treated on 5 prior AMLSG trials; statistical analysis was performed using a double-robust adjustment with propensity score weighting and covariate adjustment. Results were also compared with patients (18-59 years) treated on the placebo arm of the Cancer and Leukemia Group B (CALGB) 10603/RATIFY trial. The trial accrued 440 patients (18-60 years, n = 312; 61-70 years, n = 128). In multivariate analysis, EFS was significantly in favor of patients treated within the AMLSG 16-10 trial compared with the AMLSG control (hazard ratio [HR], 0.55; P < .001); both in younger (HR, 0.59; P < .001) and older patients (HR, 0.42; P < .001). Multivariate analysis also showed a significant beneficial effect on OS compared with the AMLSG control (HR, 0.57; P < .001) as well as to the CALGB 10603/RATIFY trial (HR, 0.71; P = .005). The treatment effect of midostaurin remained significant in sensitivity analysis including allogeneic HCT as a time-dependent covariate. Addition of midostaurin to chemotherapy was safe in younger and older patients. In comparison with historical controls, the addition of midostaurin to intensive therapy led to a significant improvement in outcome in younger and older patients with AML and FLT3-ITD. This trial is registered at clinicaltrialsregistry.eu as Eudra-CT number 2011-003168-63 and at clinicaltrials.gov as NCT01477606.

The dynamic scheduling problem of semiconductor manufacturing systems (SMSs) is becoming more complicated and challenging due to internal uncertainties and external demand changes. To this end, this paper addresses integrated release control and production scheduling problems with uncertain processing times and urgent orders and proposes a convolutional neural network and asynchronous advanced actor critic-based method (CNN-A3C) that involves a training phase and a deployment phase. In the training phase, actor–critic networks are trained to predict the evaluation of scheduling decisions and to output the optimal scheduling decision. In the deployment phase, the most appropriate release control and scheduling decisions are periodically generated according to the current production status based on the networks. Furthermore, we improve the four key points in the deep reinforcement learning (DRL) algorithm, state space, action space, reward function, and network structure and design four mechanisms: a slide-window-based two-dimensional state perception mechanism, an adaptive reward function that considers multiple objectives and automatically adjusts to dynamic events, a continuous action space based on composite dispatching rules (CDR) and release strategies, and actor–critic networks based on convolutional neural networks (CNNs). To verify the feasibility and effectiveness of the proposed dynamic scheduling method, it is implemented on a simplified SMS. The simulation experimental results show that the proposed method outperforms the unimproved A3C-based method and the common dispatching rules under the new uncertain scenarios.

Dysregulated calcium homeostasis is common in chronic kidney disease and causally associated with disorders of bone mineralization. However, radiological measures and biomarkers do not allow accurate evaluation of bone calcium balance. Non-radioactive calcium isotopes, 42Ca and 44Ca, are present in our diet and sequestered into body compartments following principles of kinetic isotope fractionation. Isotopically light 42Ca is preferentially incorporated into bone, while heavier 44Ca is excreted. The ratio (44/42Caserum) increases when bone formation exceeds resorption and vice versa, reflecting bone calcium balance. We measured these calcium isotopes by inductively coupled plasma mass-spectrometry in blood, urine and feces of 42 children with chronic kidney disease and 92 receiving dialysis therapy. We compared the isotope ratios with bone biomarkers and determined total bone mineral content by dual-energy x-ray absorptiometry and peripheral quantitative CT expressed as age-adjusted z-scores. The 44/42Caserum ratio positively correlated with serum calcium, 25-hydroxyvitamin D and alkaline phosphatases and inversely with serum parathyroid hormone and other bone resorption markers. The 44/42Caserum ratio positively correlated with age-adjusted z-scores of tibial trabecular bone mineral density and total bone mineral content measured by peripheral quantitative CT, and hip bone mineral density measured by dual-energy X-ray absorptiometry. Significant and independent predictors of total bone mineral content, measured by, were the 44/42Caserum ratio and parathyroid hormone. The 44/42Caserum ratio, repeated after four weeks, highly correlated with baseline values. When adjusted for calcium-containing medications and kidney impairment, the 44/42Caserum ratio in patients receiving dialysis was 157% lower than that of age-matched children and 29% lower than levels in elderly women with osteoporosis, implying significantly lower bone mineral content. Thus, calcium isotope ratios may provide a novel, sensitive and non-invasive method of assessing bone calcium balance in chronic kidney disease.

The prospective multicentre Phase II PTLD-2 trial (NCT02042391) tested modified risk-stratification in adult SOT recipients with CD20-positive PTLD based on principles established in the PTLD-1 trials: sequential treatment and risk-stratification. After rituximab monotherapy induction, patients in complete remission as well as those in partial remission with IPI p = 0.432). 2-year OS in the low-risk group was 100%. Results with R-CHOP-21 in high-risk patients confirmed previous results. Immunochemotherapy intensification in very-high-risk patients was disappointing.

The aim of this study was to characterize the mutational landscape of patients with FLT3-mutated acute myeloid leukemia (AML) treated within the randomized CALGB 10603/RATIFY trial evaluating intensive chemotherapy plus the multi-kinase inhibitor midostaurin versus placebo. We performed sequencing of 262 genes in 475 patients: mutations occurring concurrently with the FLT3-mutation were most frequent in NPM1 (61%), DNMT3A (39%), WT1 (21%), TET2 (12%), NRAS (11%), RUNX1 (11%), PTPN11 (10%), and ASXL1 (8%) genes. To assess effects of clinical and genetic features and their possible interactions, we fitted random survival forests and interpreted the resulting variable importance. Highest prognostic impact was found for WT1 and NPM1 mutations, followed by white blood cell count, FLT3 mutation type (internal tandem duplications vs. tyrosine kinase domain mutations), treatment (midostaurin vs. placebo), ASXL1 mutation, and ECOG performance status. When evaluating two-fold variable combinations the most striking effects were found for WT1:NPM1 (with NPM1 mutation abrogating the negative effect of WT1 mutation), and for WT1:treatment (with midostaurin exerting a beneficial effect in WT1-mutated AML). This targeted gene sequencing study provides important, novel insights into the genomic background of FLT3-mutated AML including the prognostic impact of co-mutations, specific gene–gene interactions, and possible treatment effects of midostaurin.

A Extensão Universitária (EU) é, assim como o Ensino e a Pesquisa, um elemento importante na formação acadêmica e profissional dos discentes. A EU ajuda a construir e consolidar o conhecimento, auxilia a adquirir um comportamento social que articula e integra a sociedade e a universidade. O objetivo deste estudo é entender a contribuição da Extensão Universitária na formação acadêmica de egressos dos cursos de Educação Física da Universidade Federal de Ouro Preto (UFOP). Dos 61 alunos egressos que participaram de ações extensionistas, 41 responderam ao questionário estruturado que foi enviado, sendo 30 bacharéis (73,17%) e 11 licenciados (26,83%). Como resultado, 90,2% relataram que a participação na extensão contribuiu com o aprendizado na graduação; 95,1% disseram que utilizam conhecimentos adquiridos na extensão no atual emprego; 97,6% afirmaram que a EU contribuiu para a composição do currículo e contratações, e 83,0% ainda se interessam pela área da Educação Física. Concluiu-se que a extensão contribuiu na graduação, auxiliando no melhor desempenho e compreensão das disciplinas da matriz curricular, e também na atuação direta no mercado de trabalho dos egressos. Foi possível perceber a forte relação entre ensino e extensão, associada à teoria e prática vivenciada pelos alunos. Sendo assim, reforçamos a necessidade do maior investimento das universidades e maior incentivo à participação dos alunos nesses projetos. Palavras-chave: Formação Profissional; Promoção da Saúde; Atuação Profissional Contribution of university extension to physical education formation Abstract: The University Extension (EU), like Teaching and Research, is an important element in the academic and professional training of students. The EU helps to build and consolidate knowledge and help to acquire a social behavior that articulates and integrates society and the university. The objective of this study was to identify the contribution of the EU in training graduates of Physical Education courses at the Federal University of Ouro Preto (UFOP), Minas Gerais state, Brazil. As a result, 90.2% reported that participation in the EU program contributed to their undergraduate learning; 95.1% said that they use the knowledge acquired in extension in their current job; 97.6% stated that the EU contributed to the composition of the curriculum and hiring, and 83.0% are still interested in the area of ​​Physical Education. It was concluded that the extension contributed to graduation, helping in the better performance and understanding of the curricular matrix subjects and the direct action in the job market of the graduates. It was possible to perceive the strong relationship between teaching and extension associated with the theory and practice experienced by the students. Therefore, we reinforce the need for more significant investment by universities and greater incentives for student participation in these projects. Keywords: Professional Qualification; Health Promotion; Professional Performance

Patients' participation is part of patient-centeredness, but it is so far unclear whether providers in multidisciplinary tumor conferences (MTCs) with patient participation communicate in a patient-centered way. Our aim is to explore (a) to what extent providers ask questions to breast and gynecological cancer patients during case discussion in MTCs, (b) how providers respond to patients' expressions of emotions during case discussions, and (c) which patient- and context-related characteristics and responses are associated with patients' trust in the treatment team after the case discussion.This observational study included survey data and audio recordings of MTCs with patient participation at three breast and gynecological cancer centers. Providers' questions to patients and responses to patients' emotional expressions were coded using the Verona Coding Definitions of Emotional Sequences. The response can be explicitly or non-explicitly related to the emotion and space-reducing or space-providing. Multiple linear regression analysis was used to determine associations between providers' responses, patient- and context-related characteristics, and patients' trust in the treatment team after the case discussion.We analyzed 82 case discussions (77 breast, 5 breast and gynecological cancer patients). Providers asked a total of 646 questions, of which 86% were polar (yes/no). Providers gave 303 responses to a total of 230 emotional expressions by patients. Non-explicit responses were associated with more trust when they were space-providing, but with less trust when space-reducing.The frequency of providers' closed questions and space-reducing responses to emotions shows that patient-centered communication rarely takes place in MTCs with patient participation.

Due to the increase in Artificial Intelligence in the production systems domain, Industry 4.0 (I4.0) experts must collaborate with autonomous systems. Industrial AI raises several concerns about existing standards, which provide guidelines and design patterns. One way to realize I4.0 systems are Industrial Agents (IAs) due to their inherent autonomy and collaboration. Multi-Agent Systems (MASs) are well suited for realizing distributed AI in I4.0 components. Considering the properties of IAs and existing standards, an MAS architecture is presented for flexible and intelligent Cyber-Physical Production Systems. The article compares I4.0 standardization efforts relevant to adapt AI in the form of IAs, illustrates how IA design patterns can be used, and introduces the Multi-Agent aRchitecture for Industrial Automation applying desigN patterNs practicEs “MARIANNE”. An implementation guideline is presented to put this CPPS into practice.

Neuroinflammation plays a pivotal role in the pathogenesis of Alzheimer`s disease (AD). Brain macrophage populations differentially modulate the immune response to AD pathology according to the disease stage. Triggering receptor expressed on myeloid cells 2 (TREM2) is known to play a protective role in AD and has been postulated as a putative therapeutic target. Whether, and to which extent TREM2 expression can be modulated in the aged macrophage population of the brain is unknown, emphasizing the need for a human, patient-specific model. Using cells from AD patients and matched controls (CO) we designed an assay based on monocyte-derived macrophages to mimic brain-infiltrating macrophages and to assess the individualized TREM2 synthesis in vitro. We systematically assessed the effects of short-term (acute—2 days) and long-term (chronic—10 days) M1- (LPS), M2- (IL-10, IL-4, TGF-β), and M0- (vehicle) macrophage differentiation on TREM2 synthesis. Moreover, the effects of retinoic acid (RA), a putative TREM2 modulator, on individualized TREM2 synthesis were assessed. We report increased TREM2 synthesis after acute M2- compared to M1-differentiation in CO- but not AD-derived cells. Chronic M2- and M0-differentiation however resulted in an increase of TREM2 synthesis in both AD- and CO-derived cells while chronic M1-differentiation increased TREM2 in AD-derived cells only. Moreover, chronic M2- and M0-differentiation improved the amyloid-β (Aβ) uptake of the CO-derived whereas M1-differentiation of the AD-derived cells. Interestingly, RA-treatment did not modulate TREM2. In the age of personalized medicine, our individualized model could be used to screen for potential drug-mediated treatment responses in vitro. Graphical Abstract Triggering receptor expressed on myeloid cells 2 (TREM2) has been postulated as a putative therapeutic target in Alzheimer’s disease (AD). Using cells from AD patients and matched controls (CO), we designed a monocyte-derived macrophages (Mo-MФs) assay to assess the individualized TREM2 synthesis in vitro. We report increased TREM2 synthesis after acute M2- compared to M1- macrophage differentiation in CO- but not AD-derived cells. Chronic M2- and M0- differentiation however resulted in an increase of TREM2 synthesis in both AD- and CO-derived cells while chronic M1-differentiation increased TREM2 in AD-cells only

Carbonaceous soot particles are formed during incomplete combustion of fossil fuels, biofuels or biomass and are considered to be a significant proportion of aerosol emission, especially in polluted areas, and to contain light-absorbing carbon fractions. The light-absorbing carbon components make these particles exhibit positive radiative forcing and thus they contribute to atmospheric warming processes. The exact contribution to this process however still has significant uncertainties. One of the sources of uncertainty is related to the capacity to accurately describe soot spectral optical properties (MAC/MSC/MEC - mass absorption/scattering/extinction cross-sections in m2g-1; CRI - complex refractive index), due to significant uncertainties for key measurements like the absorption coefficient or absorbing mass fraction. A second source is considered to be the change of the optical properties with the variable physico-chemical state of soot (e.g. chemical composition, morphology, primary particle size, aggregate size distribution, coating and mixing state) which depends on (i) the combustion conditions/sources and is (ii) known to change during atmospheric lifetime due to ageing and mixing processes.The present work aims at providing new measurements of soot spectral optical properties and investigating their dependence on particles’ physico-chemical state and the role of measurement uncertainties. For this, a set of original experiments was performed in the 4.3m3 CESAM atmospheric simulation chamber (https://cesam.cnrs.fr/) on soot aerosols generated by a commercial propane diffusion flame soot generator (miniCAST model 6204 TYPE C, JING). In these experiments, the variability of soot properties due to (i) generation and (ii) atmospheric ageing was explored. Different combustion conditions going from fuel–leaner to fuel-richer were set to produce soot aerosol with different effective densities, EC/TC-ratios ranging from 0.8 ± 0.1 to 0.0 ± 0.1 and size distributions with median diameters between 30 and 120 nm. Selected aerosols were subjected to ageing in a N2/O2 atmosphere under simulated atmospheric conditions (humid, with/without illumination, up to 26 hours lifetime). In these conditions, physical and chemical ageing, under the presence of different gaseous phases (O3, SO2) and addition of a second aerosol phase produced by photo-oxidation of SO2 or the ozonolysis of α-pinene, led to changes in the physico-chemical properties of the soot.State-of-the-art techniques were used to generate an extensive dataset of physico-chemical parameters (mass concentration, morphology, effective density, composition, size distribution) and spectral optical properties (absorption, scattering, extinction coefficients) for different soot aerosols and different ageing states of these. The absorption coefficient in particular was measured by both filter-based (AE - Aethalometer, MAAP - Multi-Angle Absorption Photometer, MWAA – Multi-Wavelength Absorbance Analyzer, PP_UniMI - Polar Photometer by University of Milano) and extinction minus scattering techniques. The MAC, MSC and MEC datasets, retrieved by combining these measurements, will be presented for the ensemble of chamber experiments and the variability of these parameters in link with variations in the particles’ physico-chemical properties will be discussed together with key relevant uncertainties.

Aim: To review clinical evidence for current and emerging treatments for patients with acute myeloid leukemia (AML) who are ineligible for first-line induction chemotherapy. Methods: A systematic literature review was performed (28 October 2021) to identify clinical outcomes including overall survival (OS), event-free survival (EFS), relapse-free survival (RFS) and adverse events (AEs). Results: Of 233 references that met prespecified criteria, 26 studies were included. Adding targeted therapies (venetoclax/ivosidenib) to hypomethylating agents (HMAs) yielded better OS hazard ratios (HRs) (0.44–0.66) and EFS HRs (0.33–0.63) compared with other agents. AEs were more frequent with combination therapies than control arms, except with ivosidenib plus azacitidine. Conclusion: Targeted therapy combined with a HMA shows the most promising results in this difficult-to-treat population.

Transcriptomic and functional characterization of LSC-like cells

Cell line sensitivity and additional patient data

Comparison of MAC-Score and BH-3 profiling based response prediction

MAC-Score predict response within mutational subgroups

The BCL2 inhibitor venetoclax (VEN) in combination with azacitidine (5-AZA) is currently transforming acute myeloid leukemia (AML) therapy. However, there is a lack of clinically relevant biomarkers that predict response to 5-AZA/VEN. Here, we integrated transcriptomic, proteomic, functional, and clinical data to identify predictors of 5-AZA/VEN response. Although cultured monocytic AML cells displayed upfront resistance, monocytic differentiation was not clinically predictive in our patient cohort. We identified leukemic stem cells (LSC) as primary targets of 5-AZA/VEN whose elimination determined the therapy outcome. LSCs of 5-AZA/VEN-refractory patients displayed perturbed apoptotic dependencies. We developed and validated a flow cytometry-based “Mediators of apoptosis combinatorial score” (MAC-Score) linking the ratio of protein expression of BCL2, BCL-xL, and MCL1 in LSCs. MAC scoring predicts initial response with a positive predictive value of more than 97% associated with increased event-free survival. In summary, combinatorial levels of BCL2 family members in AML-LSCs are a key denominator of response, and MAC scoring reliably predicts patient response to 5-AZA/VEN.Significance:Venetoclax/azacitidine treatment has become an alternative to standard chemotherapy for patients with AML. However, prediction of response to treatment is hampered by the lack of clinically useful biomarkers. Here, we present easy-to-implement MAC scoring in LSCs as a novel strategy to predict treatment response and facilitate clinical decision-making.