Integrated Multimodal Genomic Analyses Reveal Novel Mechanisms of Glucocorticoid Resistance in Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Much has been discovered in recent decades regarding ALL biology, and the outcome of patients with ALL has vastly improved, especially in pediatric ALL patients. Despite very promising overall cure rates, patients who relapse have a greatly decreased prognosis with survival rates ranging from 30-60%. These numbers stand to improve even further with new targeted therapies that seek to improve or maintain cure rates while reducing treatment related toxicities which affect patients both acutely and chronically. Glucocorticoids (GCs) are essential components of modern chemotherapeutic intervention for ALL. Resistance to glucocorticoids is an important factor in determining early treatment response and overall patient survival. Reduction of glucocorticoid induced toxicities, such as osteonecrosis, can significantly affect patient quality of life and are associated with high dose glucocorticoid treatment in pediatric patients. Both endogenous and exogenous glucocorticoids exert their mechanism of action through various pleiotropic effects that regulate numerous cellular functions and can cause selective cytotoxicity in lymphoid malignancies. The complex mechanism of action of glucocorticoids is evident in the number of diverse clinically relevant molecular pathways that have been previously associated with resistance to glucocorticoids in ALL.The identification of genomic and epigenomic mechanisms of glucocorticoid resistance are important for improving ALL treatment outcomes. We used an agnostic genome-wide method to interrogate multiple types of genomic information (mRNA and miRNA expression, DNA methylation, SNPs, CNAs and SNVs/Indels) in primary human acute lymphoblastic leuk

Automatic replenishment: the relationship between resource commitment and program performance

Some firms have adopted a new approach to order fulfillment, i.e., automatic inventory replenishment. With automatic replenishment programs (ARPs), sellers replenish or restock inventory based upon actual product usage and stock level information provided by buyers. This paper reports on a recent survey of logistics professionals regarding .ARP involvement. In addition to providing a profile of current usage, the research also examines the relationship between investment in automatic replenishment related resources and .ARP performance. Firms making a greater commitment to ARP (in terms of resource allocation) reported enhanced day-to-day operational performance and greater success in the overall performance of the trading relationship

Characterization of Metabolic, Diffusion, and Perfusion Properties in GBM: Contrast-Enhancing versus Non-Enhancing Tumor.

BackgroundAlthough the contrast-enhancing (CE) lesion on T1-weighted MR images is widely used as a surrogate for glioblastoma (GBM), there are also non-enhancing regions of infiltrative tumor within the T2-weighted lesion, which elude radiologic detection. Because non-enhancing GBM (Enh-) challenges clinical patient management as latent disease, this study sought to characterize ex vivo metabolic profiles from Enh- and CE GBM (Enh+) samples, alongside histological and in vivo MR parameters, to assist in defining criteria for estimating total tumor burden.MethodsFifty-six patients with newly diagnosed GBM received a multi-parametric pre-surgical MR examination. Targets for obtaining image-guided tissue samples were defined based on in vivo parameters that were suspicious for tumor. The actual location from where tissue samples were obtained was recorded, and half of each sample was analyzed for histopathology while the other half was scanned using HR-MAS spectroscopy.ResultsThe Enh+ and Enh- tumor samples demonstrated comparable mitotic activity, but also significant heterogeneity in microvascular morphology. Ex vivo spectroscopic parameters indicated similar levels of total choline and N-acetylaspartate between these contrast-based radiographic subtypes of GBM, and characteristic differences in the levels of myo-inositol, creatine/phosphocreatine, and phosphoethanolamine. Analysis of in vivo parameters at the sample locations were consistent with histological and ex vivo metabolic data.ConclusionsThe similarity between ex vivo levels of choline and NAA, and between in vivo levels of choline, NAA and nADC in Enh+ and Enh- tumor, indicate that these parameters can be used in defining non-invasive metrics of total tumor burden for patients with GBM

Urbanness and Its Implications for Logistics Strategy: A Revised Perspective

Due to rapid urbanization, logistics providers are dealing with the conundrum of misaligned strategies for urban environments. Logistics providers often see the urbanness of an activity region as a constraint, while at the same time urban actors view logistics activities within their immediate environment as disruption. These attitudes obscure the value that logistics can provide for urban areas. The current research synchronizes the notions of urban and logistics by reconceptualizing urbanness (i.e., an area’s state of being urban) from the logistics service provider’s perspective. Utilizing a conceptual abstraction technique, the concept of urbanness is revised and differentiated to redefine urban areas as value clusters looking to balance supply and demand globally while also providing access to service at the local urban level. Further, logistics service providers are seen as offering value to urban areas through network logistics and localized logistics. Identifying these differentiated value propositions suggests that transportation providers should respond to urbanness not as a constraint, but as a context where ambidextrous strategies provide the greatest return. Our conceptual revision of urbanness offers promising future avenues of research dealing with urban complexity and logistics providers value appropriation

Bending the Chain: The Surprising Challenge of Integrating Purchasing and Logistics

Over the last several decades, supply chain (SC) professionals have focused on performance issues that have emerged from a lack of commercial/business alignment with supply chain operations. Significant improvements have been made, and systemic processes (IBP—integrated business planning—and S&OP—sales and operations planning) have been developed to drive a fully integrated business. As business integration has continued to improve, the biggest SC opportunities have shifted. Every year, the University of Tennessee’s Global Supply Chain Institute networks with hundreds of companies, requesting information on emerging supply chain issues. Our recent research shows that one of the greatest business integration opportunities is found within the traditional supply chain functions themselves. (“We have met the enemy and he is us!”). Specifically, we believe a major strategic integration opportunity exists between purchasing and logistics, and failing to capitalize on this opportunity is very clearly causing many firms to miss important opportunities to create value

Coding sequences of sarcoplasmic reticulum calcium ATPase regulatory peptides and expression of calcium regulatory genes in recurrent exertional rhabdomyolysis

Background: Sarcolipin (SLN), myoregulin (MRLN), and dwarf open reading frame (DWORF) are transmembrane regulators of the sarcoplasmic reticulum calcium transporting ATPase (SERCA) that we hypothesized played a role in recurrent exertional rhabdomyolysis (RER). Objectives: Compare coding sequences of SLN, MRLN, DWORF across species and between RER and control horses. Compare expression of muscle Ca2+ regulatory genes between RER and control horses. Animals: Twenty Thoroughbreds (TB), 5 Standardbreds (STD), 6 Quarter Horses (QH) with RER and 39 breed-matched controls. Methods: Sanger sequencing of SERCA regulatory genes with comparison of amino acid (AA) sequences among control, RER horses, human, mouse, and rabbit reference genomes. In RER and control gluteal muscle, quantitative real-time polymerase chain reaction of SERCA regulatory peptides, the calcium release channel (RYR1), and its accessory proteins calsequestrin (CASQ1), and calstabin (FKBP1A). Results: The SLN gene was the highest expressed horse SERCA regulatory gene with a uniquely truncated AA sequence (29 versus 31) versus other species. Coding sequences of SLN, MRLN, and DWORF were identical in RER and control horses. A sex-by-phenotype effect occurred with lower CASQ1 expression in RER males versus control males (P \u3c .001) and RER females (P = .05) and higher FKBP1A (P = .01) expression in RER males versus control males. Conclusions and Clinical Importance: The SLN gene encodes a uniquely truncated peptide in the horse versus other species. Variants in the coding sequence of SLN, MLRN, or DWORF were not associated with RER. Males with RER have differential gene expression that could reflect adaptations to stabilize RYR1