Tumor Infiltration with CD20+CD73+ B Cells Correlates with Better Outcome in Colorectal Cancer

Immunotherapy has become increasingly important in the treatment of colorectal cancer (CRC). Currently, CD73, also known as ecto-5′-nucleotidase (NT5E), has gained considerable interest as a potential therapeutic target. CD73 is one of the key enzymes catalyzing the conversion of extracellular ATP into adenosine, which in turn exerts potent immune suppressive effects. However, the role of CD73 expression on various cell types within the CRC tumor microenvironment remains unresolved. The expression of CD73 on various cell types has been described recently, but the role of CD73 on B-cells in CRC remains unclear. Therefore, we analyzed CD73 on B-cells, especially on tumor-infiltrating B-cells, in paired tumor and adjacent normal tissue samples from 62 eligible CRC patients. The highest expression of CD73 on tumor-infiltrating B-cells was identified on class-switched memory B-cells, followed by naive B-cells, whereas no CD73 expression was observed on plasmablasts. Clinicopathological correlation analysis revealed that higher CD73⁺ B-cells infiltration in the CRC tumors was associated with better overall survival. Moreover, metastasized patients showed a significantly decreased number of tumor-infiltrating CD73⁺ B-cells. Finally, neoadjuvant therapy correlated with reduced CD73⁺ B-cell numbers and CD73 expression on B-cells in the CRC tumors. As promising new immune therapies are being developed, the role of CD73⁺ B-cells and their subsets in the development of colorectal cancer should be further explored to find new therapeutic options.     

Cytopathological Outcomes of Knocking down Expression of Mitochondrial Complex II Subunits in Dictyostelium discoideum

Mitochondrial Complex II is composed of four core subunits and mutations to any of the subunits result in lowered Complex II activity. Surprisingly, although mutations in any of the subunits can yield similar clinical outcomes, there are distinct differences in the patterns of clinical disease most commonly associated with mutations in different subunits. Thus, mutations to the SdhA subunit most often result in mitochondrial disease phenotypes, whilst mutations to the other subunits SdhB-D more commonly result in tumour formation. The reason the clinical outcomes are so different is unknown. Here, we individually antisense-inhibited three of the Complex II subunits, SdhA, SdhB or SdhC, in the simple model organism Dictyostelium discoideum. Whilst SdhB and SdhC knockdown resulted in growth defects on bacterial lawns, antisense inhibition of SdhA expression resulted in a different pattern of phenotypic defects, including impairments of growth in liquid medium, enhanced intracellular proliferation of the bacterial pathogen Legionella pneumophila and phagocytosis. Knockdown of the individual subunits also produced different abnormalities in mitochondrial function with only SdhA knockdown resulting in broad mitochondrial dysfunction. Furthermore, these defects were shown to be mediated by the chronic activation of the cellular energy sensor AMP-activated protein kinase. Our results are in agreement with a role for loss of function of SdhA but not the other Complex II subunits in impairing mitochondrial oxidative phosphorylation and they suggest a role for AMP-activated protein kinase in mediating the cytopathological outcomes.     

A simulation based supply partner selection decision support tool for service provision in Dell

Partner selection is an important aspect of all outsourcing processes. Traditional partner selection typically involves steps to determine the criteria for outsourcing, followed by a qualification of potential suppliers and concluding with a final selection of partner(s). Reverse auctions (RAs) have widely been used for partner selection in recent times. However, RAs, although proven successful in initial price reduction strategies for product and service provision, can suffer from reduced effectiveness as the number of executions increases.This paper illustrates Dell’s experience of such diminishing returns for its outsourced after sales product repair service and presents the development of a new partner selection methodology, which incorporates a new process improvement stage to be executed in combination with the final selection phase. This new methodology is underpinned by the development of a computer based simulation supply partner selection decision support tool for service provision. The paper highlights the significant additional cost saving benefits and improvement in service achievable through the use of advanced simulation based decision supports.     

The illusion of requirements in software development

This viewpoint explores the possibility that many software development projects may have no useful requirements. Specifically, for problems (e.g., knowledge worker burnout) with two completely different solutions (e.g., better tool support or hire more employees), an analyst may state a goal (e.g., decrease work hours) but more specific desiderata are contingent on the chosen solution. Furthermore, without fully exploring the design space, the designer cannot be sure whether there exists another approach, which would achieve the goal without any commonality with known approaches. In these situations of sparse requirements, analysts may misrepresent design decisions as requirements, creating an illusion of requirements in software development.     

Aqueous-Develop,Photosensitive Polynorbornene Dielectric: Optimization of Mechanical and Electrical Properties

The impact of thermal cure conditions on the mechanical and electrical properties of an epoxy cross-linked network incorporating a polynorbornene (PNB) dielectric polymer was studied. The cross-linking of the dielectric composition was achieved by an acid-catalyzed cationic cure reaction initiated by either thermal or photolytic activation of a photoacid generator. It is proposed that the observed mechanical and electrical properties of the fully cured polymer composition are the result of the development of a three-dimensional cross-linked network tying together the PNB polymer and multifunctional epoxy additives. The epoxy ring-opening reaction was measured using Fourier-transform infrared spectroscopy. The reduced modulus, internal film stress, dielectric constant, and swelling behavior of cross-linked films were studied as a function of curing temperature. Trends in the observed properties are explained by formation of a three-dimensional cross-linked network and degradation of the cross-links between the multifunctional epoxy additives at high temperature. It was also found that exposure of the film to aqueous base plays a role in the cure process and has a positive effect on the final properties. The optimum values of modulus, dielectric constant, residual stress, and moisture content were found for films cured at 160°C for 1 h. This relatively low cure temperature is potentially advantageous in device assembly and processing.