A process mining maturity model: Enabling organizations to assess and improve their process mining activities

Organizations employ process mining to discover, check, or enhance process models based on data from information systems to improve business processes. Even though process mining is increasingly relevant in academia and organizations, achieving process mining excellence and generating business value through its application is elusive. Maturity models can help to manage interdisciplinary teams in their efforts to plan, implement, and manage process mining in organizations. However, while numerous maturity models on business process management (BPM) are available, recent calls for process mining maturity models indicate a gap in the current knowledge base. We systematically design and develop a comprehensive process mining maturity model that consists of five factors comprising 23 elements, which organizations need to develop to apply process mining sustainably and successfully. We contribute to the knowledge base by the exaptation of existing BPM maturity models, and validate our model through its application to a real-world scenario

Myeloprotection by Cytidine Deaminase Gene Transfer in Antileukemic Therapy

Gene transfer of drug resistance (CTX-R) genes can be used to protect the hematopoietic system from the toxicity of anticancer chemotherapy and this concept recently has been proven by overexpression of a mutant O6-methylguaninemethyltransferase in the hematopoietic system of glioblastoma patients treated with temozolomide. Given its protection capacity against such relevant drugs as cytosine arabinoside (ara-C), gemcitabine, decitabine, or azacytidine and the highly hematopoiesis-specific toxicity profile of several of these agents, cytidine deaminase (CDD) represents another interesting candidate CTX-R gene and our group recently has established the myeloprotective capacity of CDD gene transfer in a number of murine transplant studies. Clinically, CDD overexpression appears particularly suited to optimize treatment strategies for acute leukemias and myelodysplasias given the efficacy of ara-C (and to a lesser degree decitabine and azacytidine) in these disease entities. This article will review the current state of the art with regard to CDD gene transfer and point out potential scenarios for a clinical application of this strategy. In addition, risks and potential side effects associated with this approach as well as strategies to overcome these problems will be highlighted

Proportional Fair Coding for Wireless Mesh Networks

We consider multi–hop wireless networks carrying unicast flows for multiple users. Each flow has a specified delay deadline, and the lossy wireless links are modelled as binary symmetric channels (BSCs). Since transmission time, also called airtime, on the links is shared amongst flows, increasing the airtime for one flow comes at the cost of reducing the airtime available to other flows sharing the same link. We derive the joint allocation of flow airtimes and coding rates that achieves the proportionally fair throughput allocation. This utility optimisation problem is non–convex, and one of the technical contributions of this paper is to show that the proportional fair utility optimisation can nevertheless be decomposed into a sequence of convex optimisation problems. The solution to this sequence of convex problems is the unique solution to the original non–convex optimisation. Surprisingly, this solution can be written in an explicit form that yields considerable insight into the nature of the proportional fair joint airtime/coding rate allocation. To our knowledge, this is the first time that the utility fair joint allocation of airtime/coding rate has been analysed, and also, one of the first times that utility fairness with delay deadlines has been considered

Additional file 5: Table S1. of Chemoprotection of murine hematopoietic cells by combined gene transfer of cytidine deaminase (CDD) and multidrug resistance 1 gene (MDR1)

In vitro selection of primary hematopoietic gene-modified cells. Data for in vitro selection experiments are given as % GFP+ cells (three days post treatment). (DOC 28 kb

Additional file 4: Figure S4. of Chemoprotection of murine hematopoietic cells by combined gene transfer of cytidine deaminase (CDD) and multidrug resistance 1 gene (MDR1)

Mock-transduced primary murine hematopoietic cells are susceptible to cytotoxic drug treatment. (A-C) Mock-transduced as well as FACS sorted CTX-R gene-modified lin− hematopoietic progenitor cells were seeded in a clonogenic assays in the absence or presence of cytotoxic drugs [n = 1; data are given as mean (technical duplicates)]. (D-F) Mock-transduced and non-sorted genetically modified lin− cells were treated with cytotoxic drugs in mIL-3/h-GCSF supported suspension culture (n = 2–4; data are given as mean ± SD). (PDF 157 kb

Additional file 1: Figure S1. of Chemoprotection of murine hematopoietic cells by combined gene transfer of cytidine deaminase (CDD) and multidrug resistance 1 gene (MDR1)

Transgene expression of hMDR1 and hCDD in gene-modified 32D cells. Transgene expression of gene-modified cells was analyzed either before or after three day exposure to daunorubicin [50nM], Ara-C [1000nM] or both cytotoxic drugs (daunorunicin/Ara-C: [50nM/1000nM] combination). (A) hMDR1 mRNA expression is shown in LV.SFFV.MDR1 and LV.SFFV.CDD.2A.MDR1 transduced 32D cells (n = 1, technical replicates are shown; data are given relative to untransduced (non-treated) control) and (B) expression of hCDD protein is shown for LV.SFFV.CDD and LV.SFFV.CDD.2A.MDR1 gene-modified cells (n = 1; vinculin used as loading control). (PDF 292 kb

Murine iPSC-Derived Macrophages as a Tool for Disease Modeling of Hereditary Pulmonary Alveolar Proteinosis due to Csf2rb Deficiency

Summary Induced pluripotent stem cells (iPSCs) represent an innovative source for the standardized in vitro generation of macrophages (Mφ). We here describe a robust and efficient protocol to obtain mature and functional Mφ from healthy as well as disease-specific murine iPSCs. With regard to morphology, surface phenotype, and function, our iPSC-derived Mφ (iPSC-Mφ) closely resemble their counterparts generated in vitro from bone marrow cells. Moreover, when we investigated the feasibility of our differentiation system to serve as a model for rare congenital diseases associated with Mφ malfunction, we were able to faithfully recapitulate the pathognomonic defects in GM-CSF signaling and Mφ function present in hereditary pulmonary alveolar proteinosis (herPAP). Thus, our studies may help to overcome the limitations placed on research into certain rare disease entities by the lack of an adequate supply of disease-specific primary cells, and may aid the development of novel therapeutic approaches for herPAP patients

Genetic Correction of IL-10RB Deficiency Reconstitutes Anti-Inflammatory Regulation in iPSC-Derived Macrophages

Patient material from rare diseases such as very early-onset inflammatory bowel disease (VEO-IBD) is often limited. The use of patient-derived induced pluripotent stem cells (iPSCs) for disease modeling is a promising approach to investigate disease pathomechanisms and therapeutic strategies. We successfully developed VEO-IBD patient-derived iPSC lines harboring a mutation in the IL-10 receptor β-chain (IL-10RB) associated with defective IL-10 signaling. To characterize the disease phenotype, healthy control and VEO-IBD iPSCs were differentiated into macrophages. IL-10 stimulation induced characteristic signal transducer and activator of transcription 3 (STAT3) and suppressor of cytokine signaling 3 (SOCS3) downstream signaling and anti-inflammatory regulation of lipopolysaccharide (LPS)-mediated cytokine secretion in healthy control iPSC-derived macrophages. In contrast, IL-10 stimulation of macrophages derived from patient iPSCs did not result in STAT3 phosphorylation and subsequent SOCS3 expression, recapitulating the phenotype of cells from patients with IL-10RB deficiency. In line with this, LPS-induced cytokine secretion (e.g., IL-6 and tumor necrosis factor-α (TNF-α)) could not be downregulated by exogenous IL-10 stimulation in VEO-IBD iPSC-derived macrophages. Correction of the IL-10RB defect via lentiviral gene therapy or genome editing in the adeno-associated virus integration site 1 (AAVS1) safe harbor locus led to reconstitution of the anti-inflammatory response. Corrected cells showed IL-10RB expression, IL-10-inducible phosphorylation of STAT3, and subsequent SOCS3 expression. Furthermore, LPS-mediated TNF-α secretion could be modulated by IL-10 stimulation in gene-edited VEO-IBD iPSC-derived macrophages. Our established disease models provide the opportunity to identify and validate new curative molecular therapies and to investigate phenotypes and consequences of additional individual IL-10 signaling pathway-dependent VEO-IBD mutations

Large-Scale Hematopoietic Differentiation of Human Induced Pluripotent Stem Cells Provides Granulocytes or Macrophages for Cell Replacement Therapies

Summary Interleukin-3 (IL-3) is capable of supporting the proliferation of a broad range of hematopoietic cell types, whereas granulocyte colony-stimulating factor (G-CSF) and macrophage CSF (M-CSF) represent critical cytokines in myeloid differentiation. When this was investigated in a pluripotent-stem-cell-based hematopoietic differentiation model, IL-3/G-CSF or IL-3/M-CSF exposure resulted in the continuous generation of myeloid cells from an intermediate myeloid-cell-forming complex containing CD34+ clonogenic progenitor cells for more than 2 months. Whereas IL-3/G-CSF directed differentiation toward CD45+CD11b+CD15+CD16+CD66b+ granulocytic cells of various differentiation stages up to a segmented morphology displaying the capacity of cytokine-directed migration, respiratory burst response, and neutrophil-extracellular-trap formation, exposure to IL-3/M-CSF resulted in CD45+CD11b+CD14+CD163+CD68+ monocyte/macrophage-type cells capable of phagocytosis and cytokine secretion. Hence, we show here that myeloid specification of human pluripotent stem cells by IL-3/G-CSF or IL-3/M-CSF allows for prolonged and large-scale production of myeloid cells, and thus is suited for cell-fate and disease-modeling studies as well as gene- and cell-therapy applications