Polymorphisms in the multiple drug resistance protein 1 and in P-glycoprotein 1 are associated with time to event outcomes in patients with advanced multiple myeloma treated with bortezomib and pegylated liposomal doxorubicin

Single nucleotide polymorphisms (SNPs) in the multiple drug resistance protein 1 (MRP1) and P-glycoprotein 1 (MDR1) genes modulate their ability to mediate drug resistance. We therefore sought to retrospectively evaluate their influence on outcomes in relapsed and/or refractory myeloma patients treated with bortezomib or bortezomib with pegylated liposomal doxorubicin (PLD). The MRP1/R723Q polymorphism was found in five subjects among the 279 patient study population, all of whom received PLD + bortezomib. Its presence was associated with a longer time to progression (TTP; median 330 vs. 129 days; p = 0.0008), progression-free survival (PFS; median 338 vs. 129 days; p = 0.0006), and overall survival (p = 0.0045). MDR1/3435(C > T), which was in Hardy–Weinberg equilibrium, showed a trend of association with PFS (p = 0.0578), response rate (p = 0.0782) and TTP (p = 0.0923) in PLD + bortezomib patients, though no correlation was found in the bortezomib arm. In a recessive genetic model, MDR1/3435 T was significantly associated with a better TTP (p = 0.0405) and PFS (p = 0.0186) in PLD + bortezomib patients. These findings suggest a potential role for MRP1 and MDR1 SNPs in modulating the long-term outcome of relapsed and/or refractory myeloma patients treated with PLD + bortezomib. Moreover, they support prospective studies to determine if such data could be used to tailor therapy to the genetic makeup of individual patients

Robust physical methods that enrich genomic regions identical by descent for linkage studies: confirmation of a locus for osteogenesis imperfecta

<p>Abstract</p> <p>Background</p> <p>The monogenic disease osteogenesis imperfecta (OI) is due to single mutations in either of the collagen genes ColA1 or ColA2, but within the same family a given mutation is accompanied by a wide range of disease severity. Although this phenotypic variability implies the existence of modifier gene variants, genome wide scanning of DNA from OI patients has not been reported. Promising genome wide marker-independent physical methods for identifying disease-related loci have lacked robustness for widespread applicability. Therefore we sought to improve these methods and demonstrate their performance to identify known and novel loci relevant to OI.</p> <p>Results</p> <p>We have improved methods for enriching regions of identity-by-descent (IBD) shared between related, afflicted individuals. The extent of enrichment exceeds 10- to 50-fold for some loci. The efficiency of the new process is shown by confirmation of the identification of the Col1A2 locus in osteogenesis imperfecta patients from Amish families. Moreover the analysis revealed additional candidate linkage loci that may harbour modifier genes for OI; a locus on chromosome 1q includes COX-2, a gene implicated in osteogenesis.</p> <p>Conclusion</p> <p>Technology for physical enrichment of IBD loci is now robust and applicable for finding genes for monogenic diseases and genes for complex diseases. The data support the further investigation of genetic loci other than collagen gene loci to identify genes affecting the clinical expression of osteogenesis imperfecta. The discrimination of IBD mapping will be enhanced when the IBD enrichment procedure is coupled with deep resequencing.</p

Assembling Conductive PEBA Copolymer at the Continuous Interface in Ternary Polymer Systems: Morphology and Resistivity

Two ternary blend systems of low-density polyethylene/poly­(ether-<i>block</i>-amide)/polyethylene terephthalate (LDPE/PEBA/PET) and LDPE/PEBA/polyvinylidene fluoride (PVDF) are prepared by melt blending to thermodynamically assemble the ionically conductive PEBA copolymer at the continuous interface. The LDPE/PEBA/PET blend demonstrates weak partial wetting and a novel morphology transition to complete wetting was observed as the PEBA composition increases from 3% to about 10%. The phenomena can be explained by a mechanism based on the competition between dewetting and coalescence of the PEBA phase at the interface. In the completely wet LDPE/PEBA/PVDF system, a minimum concentration is required to form intact PEBA layers with a thickness of ∼100 nm. Assembling PEBA at the interface of the ternary systems results in the formation of conductive pathways of very low percolation thresholds and thus leads to a significant reduction in the resistivity for both ternary systems as compared to binary blends with PEBA. A particularly sharp drop in resistivity is observed for the complete wetting morphology of LDPE/PEBA/PVDF

SURVEY AND SUMMARY: Single nucleotide polymorphism seeking long term association with complex disease

Successful investigation of common diseases requires advances in our understanding of the organization of the genome. Linkage disequilibrium provides a theoretical basis for performing candidate gene or whole-genome association studies to analyze complex disease. However, to constructively interrogate SNPs for these studies, technologies with sufficient throughput and sensitivity are required. A plethora of suitable and reliable methods have been developed, each of which has its own unique advantage. The characteristics of the most promising genotyping and polymorphism scanning technologies are presented. These technologies are examined both in the context of complex disease investigation and in their capacity to face the unique physical and molecular challenges (allele amplification, loss of heterozygosity and stromal contamination) of solid tumor research

Controlling the Hierarchical Structuring of Conductive PEBA in Ternary and Quaternary Blends

When a conductive polymer is blended with commodity polymers such as polyolefins and/or polystyrene (PS) as a ternary blend, it has a tendency to form the core phase due to its high interfacial tension with the other components. This can limit its capacity to reduce resistivity compared to situating it at the interface. In this work, starting with a ternary low-density polyethylene/polystyrene/poly­(ether-<i>block</i>-amide) (LDPE/PS/PEBA) blend, we examine the influence of the conductive PEBA concentration on morphology and resistivity when it exists as a core phase. Then, the hierarchical structuring of the PEBA phase will be modified through two strategies: by the addition of a fourth phase (polyethylene terephthalate (PET) or polyvinylidene fluoride (PVDF)) and by the addition of a copolymer interfacial modifier to the LDPE/PS/PEBA blend. Each of these approaches is shown to be capable of allowing the conductive PEBA to form a percolated structure assembled at the interface of two other continuous phases. The completely wet layered structuring of PEBA between PS and PVDF in the quaternary LDPE/PS/PEBA/PVDF blend leads to an exceptionally low percolation threshold of 0.37% compared to 9.7% in the initial LDPE/PS/PEBA blend where PEBA is the inside or core phase. To the best of our knowledge, this is the lowest value ever reported in the literature for a conductive polymer in melt blended systems

The presence of p53 mutations in human osteosarcomas correlates with high levels of genomic instability

The p53 gene is a critical tumor suppressor that is inactivated in a majority of cancers. The central role of p53 in response to stresses such as DNA damage, hypoxia, and oncogene activation underlies this high frequency of negative selection during tumorigenic transformation. Mutations in p53 disrupt checkpoint responses to DNA damage and result in the potential for destabilization of the genome. Consistent with this, p53 mutant cells have been shown to accumulate genomic alterations in cell culture, mouse models, and some human tumors. The relationship between p53 mutation and genomic instability in human osteosarcoma is addressed in this report. Similar to some other primary human tumors, the mutation of p53 correlates significantly with the presence of high levels of genomic instability in osteosarcomas. Surprisingly, osteosarcomas harboring an amplification of the HDM2 oncogene, which inhibits the tumor-suppressive properties of p53, do not display high levels of genomic instability. These results demonstrate that the inactivation of p53 in osteosarcomas directly by mutation versus indirectly by HDM2 amplification may have different cellular consequences with respect to the stability of the genome