Highlights d Macrophages polarized by pancreatic cancer cells release pyrimidine nucleosides d Pyrimidine release is a property of alternatively activated macrophage metabolism d Deoxycytidine from macrophages inhibits gemcitabine treatment of cancer cells d Targeting macrophages enhances gemcitabine treatment of pancreatic cancer

Highlights d We identified ALDH1A family inhibitors (ALDH1Ai) that target CD133 + ovarian CSCs d ALDH1Ai triggers calcium-dependent cell-programmed necrosis d ALDH1Ai induces mitochondrial uncoupling proteins affecting cellular metabolism d ADH1Ai overcomes chemotherapy resistance to increase tumor eradication

Among the tenets of Smart Manufacturing (SM) or Industry 4.0 (I4.0), digital twin (DT), which represents the capabilities of virtual representations of components and systems, has been cited as the biggest technology trend disrupting engineering and design today. DTs have been in use for years in areas such as model-based process control and predictive maintenance, however moving forward a framework is needed that will support the expected pervasiveness of DT technology in the evolution of SM or I4.0. A set of requirements for a DT framework has been derived from analysis of DT definitions, DTs in use today, expected DT applications in the near future, and longer-term DT trends and the DT vision in SM. These requirements include elements of re-usability, interoperability, interchangeability, maintainability, extensibility, and autonomy across the entire DT lifecycle. A baseline framework for DT technology has been developed that addresses many aspects of these requirements and enables the addressing of the requirements more fully through additional specification. The baseline framework includes a definition of a DT and an object-oriented (O-O) architecture for DTs that defines generalization, aggregation and instantiation of DT classes. Case studies using and extending the baseline framework illustrate its advantages in supporting DT solutions and trends in SM.

Pancreatic Ductal Adenocarcinoma (PDA) is characterized by abundant infiltration of tumor associated macrophages (TAMs). TAMs have been reported to drive resistance to gemcitabine, the front-line chemotherapy in PDA, though the mechanism of this resistance remains unclear. Profiling metabolite exchange, we demonstrate macrophages programmed by PDA cells release a spectrum of pyrimidine species. These include deoxycytidine, which inhibits gemcitabine through molecular competition at the level of drug uptake and metabolism.Accordingly, genetic or pharmacological depletion of TAMs in murine models of PDA sensitizes these tumors to gemcitabine. Consistent with this, patients with low macrophage burden demonstrate superior response to gemcitabine treatment. Additionally, we report pyrimidine release is a general function of anti-inflammatory myeloid cells, suggesting an unknown physiological role of pyrimidine exchange by immune cells.

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