Prevalence of bortezomib-resistant constitutive NF-kappaB activity in mantle cell lymphoma

<p>Abstract</p> <p>Background</p> <p>The proteasome inhibitor bortezomib can inhibit activation of the transcription factor NF-κB, a mechanism implicated in its anti-neoplastic effects observed in mantle cell lymphoma (MCL). However, NF-κB can be activated through many distinct mechanisms, including proteasome independent pathways. While MCL cells have been shown to harbor constitutive NF-κB activity, what fraction of this activity in primary MCL samples is sensitive or resistant to inhibition by bortezomib remains unclear.</p> <p>Results</p> <p>Proteasome activity in the EBV-negative MCL cell lines Jeko-1 and Rec-1 is inhibited by greater than 80% after exposure to 20 nM bortezomib for 4 hours. This treatment decreased NF-κB activity in Jeko-1 cells, but failed to do so in Rec-1 cells when assessed by electrophoretic mobility shift assay (EMSA). Concurrently, Rec-1 cells were more resistant to the cytotoxic effects of bortezomib than Jeko-1 cells. Consistent with a proteasome inhibitor resistant pathway of activation described in mouse B-lymphoma cells (WEHI231) and a breast carcinoma cell line (MDA-MB-468), the bortezomib-resistant NF-κB activity in Rec-1 cells is inhibited by calcium chelators, calmodulin inhibitors, and perillyl alcohol, a monoterpene capable of blocking L-type calcium channels. Importantly, the combination of perillyl alcohol and bortezomib is synergistic in eliciting Rec-1 cell cytotoxicity. The relevance of these results is illuminated by the additional finding that a considerable fraction of primary MCL samples (8 out of 10) displayed bortezomib-resistant constitutive NF-κB activity.</p> <p>Conclusion</p> <p>Our findings show that bortezomib-resistant NF-κB activity is frequently observed in MCL samples and suggest that this activity may be relevant to MCL biology as well as serve as a potential therapeutic target.</p

Optimization of interaction of agrarian entities as an imperative of ensuring food security of the state

The interaction of agricultural entities is based on modern market relations and the state agrarian policy. Managing the subjects of the agricultural sector of the economy is the primary task of the state, since the provision of food security of the state depends on this. The subject of the study is the establishment of relations of the agricultural sector of the country. In the grouping method, a direct relationship was established between the sum of agricultural production in farms of all categories in the constituent entities of the Russian Federation and the number of employees in the regional agro-industrial complex of the agricultural sector, as well as the number of departments in them. The purpose and objective of the study is to highlight the main functions of state administration of the agricultural sector at the regional level, to identify the lack of an effective mechanism for interaction of the subjects of the agricultural market with each other and with the regional authorities of the agricultural sector. The presented model of optimizing the relationships between the agrarian entities of the region will increase the efficiency of the agrarian sector of the region’s economy and ensure its food security. The necessity of planning and forecasting the volumes of production and use of agricultural products and raw materials is substantiated. The system of such forecasting includes such subsystems as agricultural enterprises, processing enterprises, and the population of the region. It is concluded that each subsystem works on a well-formed and well-founded functional model, which includes input and output information, controls that regulate functioning, as well as mechanisms that ensure such functioning. A special role in the forecasting process is assigned to the regional management bodies of the agro-industrial sector represented by the department for optimizing the interaction of agricultural entities in the region. The final forecast result should be a balance model of the degree of food security in the region's population

Relationship between mathematical confidence and academic performance, among undergraduate biology students

Background The interconnectivity between the nature and origins of mathematics and science cannot be overstated. However, studies over the past decade have shown that approx. 50% of life science students lack confidence in their mathematical abilities, and as a result, often adopt a rigid attitude to learning mathematics. This is particularly problematic in undergraduate life sciences, when the focus shifts to data handling and calculations. It was hypothesised that this ‘rigidity’ would relate to lower academic performance in biology and mathematics. Aims This study was framed using Bandura (1977) self-efficacy theory and aimed to determine whether low mathematical confidence amongst undergraduate biology students would relate to low academic performance in biology mathematics. Design and methods Students enrolled in an introductory biology course (n=254) at a major research focused university were surveyed as to their attitudes to mathematics, using a modified version of the Fennema-Sherman Attitude Scale (5-point Likert items). Based on their responses to the confidence sub-scale, students were categorised as either possessing ‘low’ (mean Likert score 3.5) confidence, they were then matched to their mean final grades in mathematics and biology, and compared using a student’s independent samples t-test. Results No differences were found between students who possessed ‘low’ or ‘high’ mathematical confidence, in terms of mean final grades in biology. Interestingly, for mathematics, students who were categorised a possessing ‘high’ mathematical confidence, achieved significantly lower grades compared to those students who possessed ‘low’ mathematical confidence. In other words students who were less mathematically confident, achieved significantly higher grades relative to their more mathematically confident peers. Conclusions The recognition that students possess a high degree of additional complexity, with regards to the learning of mathematics and biology, is beneficial to educators. Such that more effective learning and teaching interventions may be developed, to encourage students to develop attitudes to learning that relate to improved educational outcomes

Bone marrow stromal cells from multiple myeloma patients uniquely induce bortezomib resistant NF-κB activity in myeloma cells

<p>Abstract</p> <p>Background</p> <p>Components of the microenvironment such as bone marrow stromal cells (BMSCs) are well known to support multiple myeloma (MM) disease progression and resistance to chemotherapy including the proteasome inhibitor bortezomib. However, functional distinctions between BMSCs in MM patients and those in disease-free marrow are not completely understood. We and other investigators have recently reported that NF-κB activity in primary MM cells is largely resistant to the proteasome inhibitor bortezomib, and that further enhancement of NF-κB by BMSCs is similarly resistant to bortezomib and may mediate resistance to this therapy. The mediating factor(s) of this bortezomib-resistant NF-κB activity is induced by BMSCs is not currently understood.</p> <p>Results</p> <p>Here we report that BMSCs specifically derived from MM patients are capable of further activating bortezomib-resistant NF-κB activity in MM cells. This induced activity is mediated by soluble proteinaceous factors secreted by MM BMSCs. Among the multiple factors evaluated, interleukin-8 was secreted by BMSCs from MM patients at significantly higher levels compared to those from non-MM sources, and we found that IL-8 contributes to BMSC-induced NF-κB activity.</p> <p>Conclusions</p> <p>BMSCs from MM patients uniquely enhance constitutive NF-κB activity in MM cells via a proteinaceous secreted factor in part in conjunction with IL-8. Since NF-κB is known to potentiate MM cell survival and confer resistance to drugs including bortezomib, further identification of the NF-κB activating factors produced specifically by MM-derived BMSCs may provide a novel biomarker and/or drug target for the treatment of this commonly fatal disease.</p

Making personalised nutrition the easy choice: creating policies to break down the barriers and reap the benefits

Personalised diets based on people\u27s existing food choices,and/or phenotypic, and/or genetic information hold potential to improve public dietary-related health. The aim of this analysis, therefore, has been to examine the degree to which factors which determine uptake of personalised nutrition vary between EU countries to better target of policies to encourage uptake, and optimise the health benefits of personalised nutrition technology. A questionnaire developed from previous qualitative research was used to survey nationally representative samples from 9 EU countries (N=9381). Perceived barriersto the uptake of personalised nutrition comprised three factors (data protection; the eating context; and societal acceptance). Trust insources of information comprised 4 factors (commerce and media;practitioners; government; family and friends). Benefits comprised single factor. Analysis of Variance (ANOVA) was employed to comparedifferences in responses between the United Kingdom; Ireland; Portugal;Poland; Norway; the Netherlands; Germany; and Spain. The resultsindicated that those in Greece, Poland, Ireland, Portugal and Spain,rated the benefits of personalised nutrition highest, suggesting aparticular readiness in these countries to adopt personalised nutritioninterventions. Greek participants were more likely to perceive the socialcontext of eating as a barrier to adoption of personalised nutrition,implying a need for support in negotiating social situations whilst on aprescribed diet. Those in Spain, Germany, Portugal and Poland scoredhighest on perceived barriers related to data protection. Government wasmore trusted than commerce to deliver and provide information onpersonalised nutrition overall. This was particularly the case inIreland, Portugal and Greece, indicating an imperative to build trust,particularly in the ability of commercial service providers to deliverpersonalised dietary regimes effectively in these countries. These findings, obtained from a nationally representative sample of EU citizensimply that a parallel, integrated, public-private delivery system would capture the needs of most potential consumer

Perceived barriers to the uptake of personalised nutrition: A comparison between European countries

[resumo][abstract

Making personalised nutrition the easy choice: creating policies to break down the barriers and reap the benefits

YesPersonalised diets based on people’s existing food choices, and/or phenotypic, and/or genetic information hold potential to improve public dietary-related health. The aim of this analysis, therefore, has been to examine the degree to which factors which determine uptake of personalised nutrition vary between EU countries to better target policies to encourage uptake, and optimise the health benefits of personalised nutrition technology. A questionnaire developed from previous qualitative research was used to survey nationally representative samples from 9 EU countries (N = 9381). Perceived barriers to the uptake of personalised nutrition comprised three factors (data protection; the eating context; and, societal acceptance). Trust in sources of information comprised four factors (commerce and media; practitioners; government; family and, friends). Benefits comprised a single factor. Analysis of Variance (ANOVA) was employed to compare differences in responses between the United Kingdom; Ireland; Portugal; Poland; Norway; the Netherlands; Germany; and, Spain. The results indicated that respondents in Greece, Poland, Ireland, Portugal and Spain, rated the benefits of personalised nutrition highest, suggesting a particular readiness in these countries to adopt personalised nutrition interventions. Greek participants were more likely to perceive the social context of eating as a barrier to adoption of personalised nutrition, implying a need for support in negotiating social situations while on a prescribed diet. Those in Spain, Germany, Portugal and Poland scored highest on perceived barriers related to data protection. Government was more trusted than commerce to deliver and provide information on personalised nutrition overall. This was particularly the case in Ireland, Portugal and Greece, indicating an imperative to build trust, particularly in the ability of commercial service providers to deliver personalised dietary regimes effectively in these countries. These findings, obtained from a nationally representative sample of EU citizens, imply that a parallel, integrated, public-private delivery system would capture the needs of most potential consumers.Food4me is the acronym of the EU FP7 Project ‘‘Personalised nutrition: an integrated analysis of opportunities and challenges” (Contract No. KBBE.2010.2.3-02, ProjectNo.265494), http:// www.food4me.org/

Deletion of chromosomal region 8p21 confers resistance to Bortezomib and is associated with upregulated Decoy trail receptor expression in patients with multiple myeloma

Loss of the chromosomal region 8p21 negatively effects survival in patients with multiple myeloma (MM) that undergo autologous stem cell transplantation (ASCT). In this study, we aimed to identify the immunological and molecular consequences of del(8)(p21) with regards to treatment response and bortezomib resistance. In patients receiving bortezomib as a single first line agent without any high-dose therapy, we have observed that patients with del(8)(p21) responded poorly to bortezomib with 50% showing no response while patients without the deletion had a response rate of 90%. In vitro analysis revealed a higher resistance to bortezomib possibly due to an altered gene expression profile caused by del(8)(p21) including genes such as TRAIL-R4, CCDC25, RHOBTB2, PTK2B, SCARA3, MYC, BCL2 and TP53. Furthermore, while bortezomib sensitized MM cells without del(8)(p21) to TRAIL/APO2L mediated apoptosis, in cells with del(8)(p21) bortezomib failed to upregulate the pro-apoptotic death receptors TRAIL-R1 and TRAIL-R2 which are located on the 8p21 region. Also expressing higher levels of the decoy death receptor TRAIL-R4, these cells were largely resistant to TRAIL/APO2L mediated apoptosis. Corroborating the clinical outcome of the patients, our data provides a potential explanation regarding the poor response of MM patients with del(8)(p21) to bortezomib treatment. Furthermore, our clinical analysis suggests that including immunomodulatory agents such as Lenalidomide in the treatment regimen may help to overcome this negative effect, providing an alternative consideration in treatment planning of MM patients with del(8)(p21)

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