Paul G. Richardson

Bio: Paul G. Richardson is an academic researcher from Harvard University. The author has contributed to research in topics: Multiple myeloma & Bortezomib. The author has an hindex of 183, co-authored 1533 publications receiving 155912 citations. Previous affiliations of Paul G. Richardson include Broomfield Hospital & Dartmouth College.

Novel Biologically Based Therapies for Multiple Myeloma

Abstract: Despite improvements in complete responses and prolongation of overall and event-free survival with highdose therapy, multiple myeloma (MM) remains an incurable disease in the majority of patients [I]. Thus, in order to overcome resistance to standard dose and highdose therapies and to improve patient outcome, approaches specifically targeting the mechanisms whereby MM cells grow and survive in the bone marrow (BM) are needed. We are attempting to derive novel biologically based therapies focused upon targeting the MM cell as well as its BM microenvironment [2]. Improved understanding of myeloma cell survival in its microenvironment has provided such new targets. Myeloma cells adhere to the extracellular matrix and to bone marrow stromal cells (BMSC), allowing myeloma cells to proliferate, survive and have anti apoptotic effects against conventional chemotherapies. These effects are partially mediated through various cytokine release, including IL-6, VEGF, TNF-a, and IGF-1. The molecular signals mediating these effects include the Ras/Raf MAPK cascade for proliferation and the PI3-K1Akt pathway which provides drug resistance signals. This understanding has now allowed us to evaluate novel therapies that not only directly target myeloma cells but also act on the bone marrow microenvironment, specifically, the molecular and cytokine targets, to overcome drug resistance. In the past three years, we have used the in vitro and in vivo animal model systems to define novel therapeutic agents directed at targets specific to both the MM cell and its microenvironment, and have then translated these studies from bench to bedside in the related clinical trials. Thalidomide and its analogous immunomodulatory agents (lMiDs), proteasome inhibitor PS341,

Imaging Features of Extramedullary, Relapsed, and Refractory Multiple Myeloma involving the Liver Across Treatment With Cyclophosphamide, Lenalidomide, Bortezomib, and Dexamethasone

Abstract: A 55-year-old white woman presented in June 2003 with stage IIIA Durie-Salmon immunoglobulin (Ig) G κ multiple myeloma (MM) and was initially treated with thalidomide and dexamethasone followed by cyclophosphamide, with concurrent bisphosphonate (zoledronic acid), and intensified by autologous stem-cell transplant (ASCT) after high-dose melphalan conditioning. She remained in complete remission until December 2008, when she experienced relapse with occipital plasmacytoma and symptomatic extramedullary disease (EMD) arising from her skeleton. She was treated with an experimental second-generation proteasome inhibitor (NPI-0052, 0.7 mg/m2 administered intravenously [IV]), combined with low-dose weekly oral dexamethasone. She had evidence of clinical response (disease stabilization and symptomatic improvement). Treatment was completed after 6 months, and she declined maintenance options other than bisphosphonate.

Ixazomib-induced cutaneous necrotizing vasculitis.

Abstract: Ixazomib is a second-generation proteasome inhibitor that has been approved in the combination treatment of multiple myeloma and is currently under clinical investigation for the management of Waldenstrom's macroglobulinemia. While cutaneous adverse events secondary to proteasome inhibitors have been reported, the side effect profile of ixazomib remains to be documented. We report two patients, one with multiple myeloma and one with Waldenstrom's macroglobulinemia, who developed cutaneous necrotizing vasculitis after the initiation of ixazomib. Both patients exhibited no signs of systemic vasculitis and completed their anti-cancer regimens with resolution of their respective eruptions following dose reductions in ixazomib and initiation of low-dose prednisone. A collaborative effort towards the characterization of such cutaneous toxicities facilitates early intervention, maintenance of life-preserving anti-cancer therapy, and allows clinicians opportunity to better understand the pathophysiology of vasculitis. Moreover, appropriate identification and characterization of cutaneous toxicities from novel therapies allows providers to accurately identify safety concerns, treat toxicity, and improve patient quality of life.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

The Pfam protein families database

Abstract: Pfam is a widely used database of protein families and domains. This article describes a set of major updates that we have implemented in the latest release (version 24.0). The most important change is that we now use HMMER3, the latest version of the popular profile hidden Markov model package. This software is approximately 100 times faster than HMMER2 and is more sensitive due to the routine use of the forward algorithm. The move to HMMER3 has necessitated numerous changes to Pfam that are described in detail. Pfam release 24.0 contains 11,912 families, of which a large number have been significantly updated during the past two years. Pfam is available via servers in the UK (http://pfam.sanger.ac.uk/), the USA (http://pfam.janelia.org/) and Sweden (http://pfam.sbc.su.se/).

The sequence of the human genome.

Abstract: A 2.91-billion base pair (bp) consensus sequence of the euchromatic portion of the human genome was generated by the whole-genome shotgun sequencing method. The 14.8-billion bp DNA sequence was generated over 9 months from 27,271,853 high-quality sequence reads (5.11-fold coverage of the genome) from both ends of plasmid clones made from the DNA of five individuals. Two assembly strategies-a whole-genome assembly and a regional chromosome assembly-were used, each combining sequence data from Celera and the publicly funded genome effort. The public data were shredded into 550-bp segments to create a 2.9-fold coverage of those genome regions that had been sequenced, without including biases inherent in the cloning and assembly procedure used by the publicly funded group. This brought the effective coverage in the assemblies to eightfold, reducing the number and size of gaps in the final assembly over what would be obtained with 5.11-fold coverage. The two assembly strategies yielded very similar results that largely agree with independent mapping data. The assemblies effectively cover the euchromatic regions of the human chromosomes. More than 90% of the genome is in scaffold assemblies of 100,000 bp or more, and 25% of the genome is in scaffolds of 10 million bp or larger. Analysis of the genome sequence revealed 26,588 protein-encoding transcripts for which there was strong corroborating evidence and an additional approximately 12,000 computationally derived genes with mouse matches or other weak supporting evidence. Although gene-dense clusters are obvious, almost half the genes are dispersed in low G+C sequence separated by large tracts of apparently noncoding sequence. Only 1.1% of the genome is spanned by exons, whereas 24% is in introns, with 75% of the genome being intergenic DNA. Duplications of segmental blocks, ranging in size up to chromosomal lengths, are abundant throughout the genome and reveal a complex evolutionary history. Comparative genomic analysis indicates vertebrate expansions of genes associated with neuronal function, with tissue-specific developmental regulation, and with the hemostasis and immune systems. DNA sequence comparisons between the consensus sequence and publicly funded genome data provided locations of 2.1 million single-nucleotide polymorphisms (SNPs). A random pair of human haploid genomes differed at a rate of 1 bp per 1250 on average, but there was marked heterogeneity in the level of polymorphism across the genome. Less than 1% of all SNPs resulted in variation in proteins, but the task of determining which SNPs have functional consequences remains an open challenge.

The Human Genome Browser at UCSC

Abstract: As vertebrate genome sequences near completion and research refocuses to their analysis, the issue of effective genome annotation display becomes critical. A mature web tool for rapid and reliable display of any requested portion of the genome at any scale, together with several dozen aligned annotation tracks, is provided at http://genome.ucsc.edu. This browser displays assembly contigs and gaps, mRNA and expressed sequence tag alignments, multiple gene predictions, cross-species homologies, single nucleotide polymorphisms, sequence-tagged sites, radiation hybrid data, transposon repeats, and more as a stack of coregistered tracks. Text and sequence-based searches provide quick and precise access to any region of specific interest. Secondary links from individual features lead to sequence details and supplementary off-site databases. One-half of the annotation tracks are computed at the University of California, Santa Cruz from publicly available sequence data; collaborators worldwide provide the rest. Users can stably add their own custom tracks to the browser for educational or research purposes. The conceptual and technical framework of the browser, its underlying MYSQL database, and overall use are described. The web site currently serves over 50,000 pages per day to over 3000 different users.