While multiple myeloma (MM) treatment with proteasome inhibitors and other agents yields encouraging results, primary and secondary resistance remains an emerging problem. An important factor in such treatment resistance is the overexpression of several proteins. The present study comprehensively evaluates the expression of POMP, PSMB5, NRF2, XBP1, cMAF and MAFb proteins in plasma cells isolated from the bone marrow of 39 MM patients treated with bortezomib-based regimens using enzyme-linked immunosorbent assay (ELISA). The proteins were selected on the basis of previous laboratory and clinical studies in bortezomib treated MM patients. It was found that the expression of the investigated proteins did not significantly differ between bortezomib-sensitive and bortezomib-refractory patients. However, the expression of some proteins correlated with overall survival (OS); this was significantly shorter in patients with higher POMP expression (HR 2.8, 95% CI: 1.1-7.0, p = 0.0277) and longer in those with higher MAFB expression (HR 0.32, 95% CI: 0.13-0.80, p = 0.0147). Our results indicate that high expression of POMP and MAFB in MM plasma cells may serve as predictors of OS in MM patients treated with bortezomib-based regimens. However, further studies are needed to determine the role of these factors in effective strategies for improving anti-myeloma therapy.

Multiple myeloma (MM) is characterized by the malignant proliferation of monoclonal plasma cells in the bone marrow with an elevation in monoclonal paraprotein, renal impairment, hypercalcemia, lytic bony lesions, and anemia. Immune cells and associated cytokines play a significant role in MM growth, progression, and dissemination. While some cytokines and their clinical significance are well described in MM biology, others remain relatively unknown. The aim of the present study was to assess the impact of pretreatment serum levels of 27 selected cytokines on progression-free survival (PFS) and overall survival (OS) in MM patients before first-line therapy with bortezomib-based regimens. Serum cytokine levels were assayed with a Bio-Rad Bio-Plex Pro Human Cytokine 27-Plex Assay on the MAGPIX Multiplex Reader and the Bio-Plex® 200 System (Bio-Rad) including IL-1β, IL-1Ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-17, Eotaxin, FGF, G-CSF, GM-CSF, IFN-γ, IP-10, MCP-1, MIP-1α, MIP-1β, PDGF-BB, RANTES, TNF-α, and VEGF. A total of 61 MM patients were examined. Most patients received a bortezomib, cyclophosphamide and dexamethasone (VCD) chemotherapy regimen. In the final multivariate model, IL-13 cytokine level (HR 0.1411, 95% CI: 0.0240-0.8291, p = 0.0302), and ASCT (HR 0.3722, 95% CI: 0.1826-0.7585, p=0.0065) significantly impacted PFS. Furthermore, ASCT (HR 0.142, 95% CI: 0.046-0.438, p=0.0007), presence of bone disease at diagnosis (HR 3.826, 95% CI: 1.471-9.949, p=0.0059) and two cytokine levels- IL-1Ra (HR 1.017, 95% CI: 1.004-1.030, p= 0.0091) and IL-4 (HR 0.161, 95% CI: 0.037-0.698, p = 0.0147) were independent predictors of OS. Three clusters of MM patients were identified with different cytokine profiles. In conclusion, serum pretreatment levels of IL-13 and IL-4 are predictors of better PFS and OS, respectively, whereas IL-1Ra pretreatment levels negatively impact OS in MM patients treated with bortezomib-based chemotherapy. Cytokine signature profile may have a potential influence on the outcome of patients treated with bortezomib.

The sudden onset of natural hazards such as a flash flood events can be devastating to a country or region, often affecting numerous communities, and humanitarian supply chains play a major role in enabling the timely recovery of economic and social activities. However, the uncertainty and suddenness of natural disasters such as flash floods, as well as the potential for aftershocks, require humanitarian supply chains to be resilient during the relief process. This research first adopts the Delphi and literature review methods to identify the key indicators in the humanitarian supply chain to form an evaluation index system. Then, taking the 2021 mega-flash flood event which affected four cities in the mountainous region under the jurisdiction of the Zhengzhou municipal government, the ANP method is used to calculate the weights of each indicator and combines the weighted results with the Multi-styling and stereotyping method under Pythagorean fuzzy (PFs-VIKOR) to make an evaluation of the resilience of the humanitarian supply chain in the relief process. The findings suggest that policy makers and decision makers should pay close attention to the coordination of the parties involved in the humanitarian supply chain and improve the level of resilience of the entire supply chain by enhancing the resource scheduling capacity and responsiveness. At the same time, the VIKOR evaluation of the 4 cities highlighted the humanitarian supply chain in Dengfeng City to be most effective in this event due to the close cooperation and positive response of all parties involved in the humanitarian supply chain. The findings of this research provide some useful suggestions and guidance to the various practitioners involved in the humanitarian supply chain. Furthermore, the evaluation of the performance of the four cities in this mega-flash flood event provides some helpful indication of the importance of the various emergency measures which can help to inform policy recommendations for the Zhengzhou municipal government.

Product Design is getting nowadays new challenges on developing new products, since the industry is in a rush to introduce products into the marketplace, where customers demand products faster, cheaper, and free of failures. In the meantime, global companies are always trying to improve their Product Design process to get advantages over their competitors using proven tools like FEMA and mixing methodologies like Fuzzy theories with FMEA. Even today using all this tools and combination of methodologies there is a gap to address and it is required a robust risk analysis solving current issues in the electronic industry. This document aims to reveal a novel integrated method, where Failure Mode and Effect Analysis, Pythagorean Fuzzy Sets and Dimensional Analysis are cohesive into a model that minimize the uncertainty of the ranking and prioritization over the Failure Mode and Effect Analysis execution, helping to identify risks within an accurate grade over possible failures in the Product Design process. A real practical example is used to show the proposed method, where it is identified a robust methodology integration and solid and results using a sensitivity analysis.

Manufacturing systems need to meet I4.0 guidelines to deal with uncertainty in scenarios of turbulent demand for products. The engineering concepts to define the service’s resources to manufacture the products will be more flexible, ensuring the possibility of re-planning in operation. These can follow the engineering paradigm based on capabilities. The virtualization of industry components and assets achieves the RAMI 4.0 guidelines and (I4.0C), which describes the Asset Administration Shell (AAS). However, AAS are passive components that provide information about I4.0 assets. The proposal of specific paradigms is exposed for managing these components, as is the case of multi-agent systems (MAS) that attribute intelligence to objects. The implementation of resource coalitions with evolutionary architectures (EAS) applies cooperation and capabilities’ association. Therefore, this work focuses on designing a method for modeling the asset administration shell (AAS) as virtual elements orchestrating intelligent agents (MAS) that attribute cooperation and negotiation through contracts to coalitions based on the engineering capabilities concept. The systematic method suggested in this work is partitioned for the composition of objects, AAS elements, and activities that guarantee the relationship between entities. Finally, Production Flow Schema (PFS) refinements are applied to generate the final Petri net models (PN) and validate them with Snoopy simulations. The results achieved demonstrate the validation of the procedure, eliminating interlocking and enabling liveliness to integrate elements behavior.