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Evolutionary design is a widely accepted practice for defining microservice boundaries. It is performed through a sequence of incremental refactoring tasks (we call it “microservice refactoring”), each restructuring only part of a microservice system (a.k.a., refactoring part) into well-defined services for improving the architecture in a controlled manner. Despite its popularity in practice, microservice refactoring suffers from insufficient methodological support. While there are numerous studies addressing similar software design tasks, i.e., software remodularization and microservitization, their approaches prove inadequate when applied to microservice refactoring. Our analysis reveals that their approaches may even degrade the entire architecture in microservice refactoring, as they only optimize the refactoring part in such applications, but neglect the relationships between the refactoring part and the remaining system. As the first response to the need, Micro2Micro is proposed to re-partition the refactoring part while optimizing three quality objectives including the interdependence between the refactoring and non-refactoring parts. In addition, it allows architects to intervene in the decision-making process by interactively incorporating their knowledge into the iterative search for optimal refactoring solutions. An empirical study on 13 open-source projects of different sizes shows that the solutions from Micro2Micro perform well and exhibit quality improvement with an average up to 45% to the original architecture. Users of Micro2Micro found the suggested solutions highly satisfactory. They acknowledge the advantages in terms of infusing human intelligence into decisions, providing immediate quality feedback, and quick exploration capability. 

Abstract P‐glycoprotein (P‐gp, ABCB1) is a well‐researched ATP‐binding cassette (ABC) drug efflux transporter linked to the development of cancer multidrug resistance (MDR). Despite extensive studies, approved therapies to safely inhibit P‐gp in clinical settings are lacking, necessitating innovative strategies beyond conventional inhibitors or antibodies to reverse MDR. Photodynamic therapy is a globally approved cancer treatment that uses targeted, harmless red light to activate non‐toxic photosensitizers, confining its cytotoxic photochemical effects to disease sites while sparing healthy tissues. This study demonstrates that photodynamic priming (PDP), a sub‐cytotoxic photodynamic therapy process, can inhibit P‐gp function by modulating cellular respiration and ATP levels in light accessible regions. Using chemoresistant (VBL‐MDA‐MB‐231) and chemosensitive (MDA‐MB‐231) triple‐negative breast cancer cell lines, we showed that PDP decreases mitochondrial membrane potential by 54.4% ± 30.4 and reduces mitochondrial ATP production rates by 94.9% ± 3.46. Flow cytometry studies showed PDP can effectively improve the retention of P‐gp substrates (calcein) by up to 228.4% ± 156.3 in chemoresistant VBL‐MDA‐MB‐231 cells, but not in chemosensitive MDA‐MB‐231 cells. Further analysis revealed that PDP did not alter the cell surface expression level of P‐gp in VBL‐MDA‐MB‐231 cells. These findings indicate that PDP can reduce cellular ATP below the levels that is required for the function of P‐gp and improve intracellular substrate retention. We propose that PDP in combination with chemotherapy drugs, might improve the efficacy of chemotherapy and overcome cancer MDR. 

Abstract Accurate detection of ATP-binding cassette drug transporter ABCB1 expression is imperative for precise identification of drug-resistant tumors. Existing detection methods fail to provide the necessary molecular details regarding the functional state of the transporter. Photoimmunoconjugates are a unique class of antibody–dye conjugates for molecular diagnosis and therapeutic treatment. However, conjugating hydrophobic photosensitizers to hydrophilic antibodies is quite challenging. Here, we devise a photoimmunoconjugate that combines a clinically approved benzoporphyrin derivative (BPD) photosensitizer and the conformational-sensitive UIC2 monoclonal antibody to target functionally active human ABCB1 (i.e., ABCB1 in the inward-open conformation). We show that PEGylation of UIC2 enhances the BPD conjugation efficiency and reduces the amount of non-covalently conjugated BPD molecules by 17%. Size exclusion chromatography effectively separates the different molecular weight species found in the UIC2–BPD sample. The binding of UIC2–BPD to ABCB1 was demonstrated in lipidic nanodiscs and ABCB1-overexpressing triple negative breast cancer (TNBC) cells. UIC2–BPD was found to retain the conformation sensitivity of UIC2, as the addition of ABCB1 modulators increases the antibody reactivity in vitro . Thus, the inherent fluorescence capability of BPD can be used to label ABCB1-overexpressing TNBC cells using UIC2–BPD. Our findings provide insight into conjugation of hydrophobic photosensitizers to conformation-sensitive antibodies to target proteins expressed on the surface of cancer cells. 

Mechanical search, the finding and extracting of a known target object from a cluttered environment, is a key challenge in automating warehouse, home, retail, and industrial tasks. In this paper, we consider contexts in which occluding objects are to remain untouched, thus minimizing disruptions and avoiding toppling. We assume a 6-DOF robot with an RGBD camera and unicontact suction gripper mounted on its wrist. With this setup, the robot can move both camera and gripper in order to identify a suitable approach vector, reach in to achieve a suction grasp of the target object, and extract it. We present AVPLUG: Approach Vector PLanning for Unicontact Grasping, an algorithm that uses an octree occupancy model and Minkowski sum computation to find a collision-free grasp approach vector. Experiments in simulation and with a physical Fetch robot suggest that AVPLUG finds an approach vector up to 20× faster than a baseline search policy. 

Abstract Glioblastoma (GBM) is hard to treat due to cellular invasion into functioning brain tissues, limited drug delivery, and evolved treatment resistance. Recurrence is nearly universal even after surgery, chemotherapy, and radiation. Photodynamic therapy (PDT) involves photosensitizer administration followed by light activation to generate reactive oxygen species at tumor sites, thereby killing cells or inducing biological changes. PDT can ablate unresectable GBM and sensitize tumors to chemotherapy. Verteporfin (VP) is a promising photosensitizer that relies on liposomal carriers for clinical use. While lipids increase VP's solubility, they also reduce intracellular photosensitizer accumulation. Here, a pure‐drug nanoformulation of VP, termed “NanoVP”, eliminating the need for lipids, excipients, or stabilizers is reported. NanoVP has a tunable size (65–150 nm) and 1500‐fold higher photosensitizer loading capacity than liposomal VP. NanoVP shows a 2‐fold increase in photosensitizer uptake and superior PDT efficacy in GBM cells compared to liposomal VP. In mouse models, NanoVP‐PDT improved tumor control and extended animal survival, outperforming liposomal VP and 5‐aminolevulinic acid (5‐ALA). Moreover, low‐dose NanoVP‐PDT can safely open the blood‐brain barrier, increasing drug accumulation in rat brains by 5.5‐fold compared to 5‐ALA. NanoVP is a new photosensitizer formulation that has the potential to facilitate PDT for the treatment of GBM.