Evaluation of Material Shortage Effect on Assembly Systems Considering Flexibility Levels

The global pandemic caused delays in global supply chains, and numerous manufacturing companies are experiencing a lack of materials and components. This material shortage affects assembly systems at various levels: process level (decreasing of the resource efficiency), system level (blocking or s tarvation of production entities), and company level (breaking the deadlines for the supplying of the products to customers or retailers). Flexible assembly systems allow dynamic reactions in such uncertain environments. However, online scheduling algorithms of current research are not considering reactions to material shortages. In the present research, we aim to evaluate the influence of material shortage on the assembly system performance. The paper presents a discrete event simulation of an assembly system. The system architecture, its behavior, the resources, their capacities, and product specific operations are included. The material shortage effect on the assembly system is compensated utilizing different system flexibility levels, characterized by operational and routing flexibility. An online control algorithm determines optimal production operation under material shortage uncertain conditions. With industrial data, different simulation scenarios evaluate the benefits of assembly systems with varying flexibility levels. Consideration of flexibility levels might facilitate exploration of the optimal flexibility level with the lowest production makespan that influence further supply chain, as makespan minimization cause reducing of delays for following supply chain entities

WNT signalling in prostate cancer

Genome sequencing and gene expression analyses of prostate tumours have highlighted the potential importance of genetic and epigenetic changes observed in WNT signalling pathway components in prostate tumours-particularly in the development of castration-resistant prostate cancer. WNT signalling is also important in the prostate tumour microenvironment, in which WNT proteins secreted by the tumour stroma promote resistance to therapy, and in prostate cancer stem or progenitor cells, in which WNT-β-catenin signals promote self-renewal or expansion. Preclinical studies have demonstrated the potential of inhibitors that target WNT receptor complexes at the cell membrane or that block the interaction of β-catenin with lymphoid enhancer-binding factor 1 and the androgen receptor, in preventing prostate cancer progression. Some WNT signalling inhibitors are in phase I trials, but they have yet to be tested in patients with prostate cancer

Inflammatory Rheumatic Disorders and Bone

Inflammatory joint diseases such as rheumatoid arthritis, as well as other rheumatic conditions, such as systemic lupus erythematosus (SLE) and ankylosing spondylitis, comprise a heterogeneous group of joint disorders that are all associated with extra-articular side effects, including bone loss and fractures. The concept of osteoimmunology is based on growing insights into the links between the immune system and bone. The pathogenesis of osteoporosis in these patients is multifactorial. We have, more or less as an example, described this extensively for patients with SLE. High disease activity (inflammation) and immobility are common factors that substantially increase fracture risk in these patients, on top of the background fracture risk based on, among other factors, age, body mass index, and gender. Although no fracture reduction has been shown in intervention studies in patients with inflammatory rheumatic diseases, we present treatment options that might be useful for clinicians who are treating these patients

Trabecular Reorganization in Consecutive Iliac Crest Biopsies when Switching from Bisphosphonate to Strontium Ranelate Treatment

BACKGROUND: Several agents are available to treat osteoporosis while addressing patient-specific medical needs. Individuals' residual risk to severe fracture may require changes in treatment strategy. Data at osseous cellular and microstructural levels due to a therapy switch between agents with different modes of action are rare. Our study on a series of five consecutively taken bone biopsies from an osteoporotic individual over a six-year period analyzes changes in cellular characteristics, bone microstructure and mineralization caused by a therapy switch from an antiresorptive (bisphosphonate) to a dual action bone agent (strontium ranelate). METHODOLOGY/PRINCIPAL FINDINGS: Biopsies were progressively taken from the iliac crest of a female patient. Four biopsies were taken during bisphosphonate therapy and one biopsy was taken after one year of strontium ranelate (SR) treatment. Furthermore, serum bone markers and dual x-ray absorptiometry measurements were acquired. Undecalcified histology was used to assess osteoid parameters and bone turnover. Structural indices and degree of mineralization were determined using microcomputed tomography, quantitative backscattered electron imaging, and combined energy dispersive x-ray/µ-x-ray-fluorescence microanalysis. CONCLUSIONS/SIGNIFICANCE: Microstructural data revealed a notable increase in bone volume fraction after one year of SR treatment compared to the bisphosphonate treatment period. Indices of connectivity density, structure model index and trabecular bone pattern factor were predominantly enhanced indicating that the architectural transformation from trabecular rods to plates was responsible for the bone volume increase and less due to changes in trabecular thickness and number. Administration of SR following bisphosphonates led to a maintained mineralization profile with an uptake of strontium on the bone surface level. Reactivated osteoclasts designed tunneling, hook-like intratrabecular resorption sites. The appearance of tunneling resorption lacunae and the formation of both mini-modeling units and osteon-like structures within increased plate-like cancellous bone mass provides additional information on the mechanisms of strontium ranelate following bisphosphonate treatment, which may deserve special attention when monitoring a treatment switch

Dasatinib as a Bone-Modifying Agent: Anabolic and Anti-Resorptive Effects

This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al.[Background]: Bone loss, in malignant or non-malignant diseases, is caused by increased osteoclast resorption and/or reduced osteoblast bone formation, and is commonly associated with skeletal complications. Thus, there is a need to identify new agents capable of influencing bone remodeling. We aimed to further pre-clinically evaluate the effects of dasatinib (BMS-354825), a multitargeted tyrosine kinase inhibitor, on osteoblast and osteoclast differentiation and function. [Methods]: For studies on osteoblasts, primary human bone marrow mensenchymal stem cells (hMSCs) together with the hMSC-TERT and the MG-63 cell lines were employed. Osteoclasts were generated from peripheral blood mononuclear cells (PBMC) of healthy volunteers. Skeletally-immature CD1 mice were used in the in vivo model. [Results]: Dasatinib inhibited the platelet derived growth factor receptor-β (PDGFR-β), c-Src and c-Kit phosphorylation in hMSC-TERT and MG-63 cell lines, which was associated with decreased cell proliferation and activation of canonical Wnt signaling. Treatment of MSCs from healthy donors, but also from multiple myeloma patients with low doses of dasatinib (2-5 nM), promoted its osteogenic differentiation and matrix mineralization. The bone anabolic effect of dasatinib was also observed in vivo by targeting endogenous osteoprogenitors, as assessed by elevated serum levels of bone formation markers, and increased trabecular microarchitecture and number of osteoblast-like cells. By in vitro exposure of hemopoietic progenitors to a similar range of dasatinib concentrations (1-2 nM), novel biological sequelae relative to inhibition of osteoclast formation and resorptive function were identified, including F-actin ring disruption, reduced levels of c-Fos and of nuclear factor of activated T cells 1 (NFATc1) in the nucleus, together with lowered cathepsin K, αVβ3 integrin and CCR1 expression. [Conclusions]: Low dasatinib concentrations show convergent bone anabolic and reduced bone resorption effects, which suggests its potential use for the treatment of bone diseases such as osteoporosis, osteolytic bone metastasis and myeloma bone disease. © 2012 Garcia-Gomez et al.This work was supported by grants from the Spanish Ministry of Science and Innovation – ISCIII (PI081825); Mutua Madrileña Medical Research Foundation (AP27262008); Centro en Red of Regenerative Medicine and Cellular Therapy from Castilla y León, Consejería de Sanidad JCyL – ISCIII; the Cooperative Research Thematic Network in Cancer (RTICC; RD06/0020/0006 and RD03/0020/0041); and Spanish FIS (PS09/01897). AG-G and CS are supported by the Centro en Red of Regenerative Medicine and Cellular Therapy from Castilla y León Project.Peer Reviewe

Nonlinear viscoelastic characterization of bovine trabecular bone

The time-independent elastic properties of trabecular bone have been extensively investigated, and several stiffness–density relations have been proposed. Although it is recognized that trabecular bone exhibits time-dependent mechanical behaviour, a property of viscoelastic materials, the characterization of this behaviour has received limited attention. The objective of the present study was to investigate the time-dependent behaviour of bovine trabecular bone through a series of compressive creep–recovery experiments and to identify its nonlinear constitutive viscoelastic material parameters. Uniaxial compressive creep and recovery experiments at multiple loads were performed on cylindrical bovine trabecular bone samples ([Formula: see text] ). Creep response was found to be significant and always comprised of recoverable and irrecoverable strains, even at low stress/strain levels. This response was also found to vary nonlinearly with applied stress. A systematic methodology was developed to separate recoverable (nonlinear viscoelastic) and irrecoverable (permanent) strains from the total experimental strain response. We found that Schapery’s nonlinear viscoelastic constitutive model describes the viscoelastic response of the trabecular bone, and parameters associated with this model were estimated from the multiple load creep–recovery (MLCR) experiments. Nonlinear viscoelastic recovery compliance was found to have a decreasing and then increasing trend with increasing stress level, indicating possible stiffening and softening behaviour of trabecular bone due to creep. The obtained parameters from MLCR tests, expressed as second-order polynomial functions of stress, showed a similar trend for all the samples, and also demonstrate stiffening–softening behaviour with increasing stress