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.

Multiple Myeloma and Amyloidosis: An Evolving Treatment Paradigm Toward the Goal of Tailored Therapy

Abstract: Significant advances over the last 15 years in our understanding of the biology of multiple myeloma (MM) have led to exciting new opportunities for treatment, which have in turn transformed the therapeutic paradigm in the last decade. The successful translation of these derived novel therapies from laboratory bench to bedside with less toxicity and more specific anti-MM activity has dramatically improved patient outcome. The next generation of new molecules has followed, demonstrating exciting responses and improved tolerability, promising further improvements in survival. Combination approaches in particular have generated deep and durable responses that are unprecedented in this disease. In this review, first the molecular heterogeneity of MM and its pathogenesis, prognosis, and therapeutic implications are succinctly reviewed by Avet-Loiseau et al. As Avet-Loiseau et al note, data support that this heterogeneity is primarily related to molecular characteristics of the tumor clone(s), although the contribution of the tumor microenvironment is likely also key. Although genetic changes are the hallmark of the cancer cell, these changes are typically limited in many hematologic neoplasms (such as chronic myeloid leukemia and most acute leukemias). In contrast, solid tumors usually present a wide variety of chromosomal and genomic rearrangements. Myeloma as a genetic entity is probably somewhere in between these two extremes, and a continued improvement in our understanding of this heterogeneity is vital to treatment choices. In this context, current trends in transplant for myeloma in the era of novel therapies are addressed by Moreau et al, who ask a fundamental question: should autologous stem-cell transplantation be used upfront or as salvage treatment as the time of progression in all eligible patients initially treated with novel agents or in specific subgroups? The recent introduction of first-generation novel agents in MM—specifically thalidomide, bortezomib, and lenalidomide—is changing the transplantation scenario in many different ways, and this is broadly discussed by Moreau et al, who also outline future directions. A critical aspect of myeloma management, specifically advances in its imaging and the management of myeloma-related bone disease, is examined by Terpos et al. The combination of novel antimyeloma agents (such as bortezomib, which has potent anabolic effects on bone) with bisphosphonates or with other drugs that enhance osteoblast function (such as anti-Dickkopf-1 agents) may alter our way of managing myeloma-related bone disease in the near future. Novel antiresorptive agents such as denosumab have also demonstrated encouraging results, but additional studies are needed before these agents can be recommended for managing MM-related bone disease. Next, future directions and second-generation novel therapies, together with innovative combinations, are thoughtfully reviewed by Mitsiades et al, who present a clear vision of the future in antimyeloma therapy. They provide a comprehensive review of novel agents for the treatment of myeloma, which is then followed by a critical analysis of clinical research to date and the current translation of these advances into clinical practice. The role of combination regimens in the future of myeloma treatment is addressed as it pertains to individual clinical settings, and then personalized treatment is considered philosophically with a balance between the current state of the art and prospect for the future. Finally, Merlini et al review the increasingly important entity of amyloidosis and provide a state-of-the-art review of its pathogenesis and the impact of new therapeutic options. Given that amyloid, as an entity and as a consequence of MM, is an increasingly important area to better understand in the management of plasma cell dyscrasias overall, this prescient article is especially useful because treatment options are improving for such patients, but major challenges remain. Early and accurate diagnosis is the key to effective therapy, and unequivocal identification of the amyloidogenic protein may require advanced technologies and expertise. Prognosis is dictated by the extent of cardiac involvement, and cardiac staging directs the choice of treatment. The authors emphasize that treatment for light chain amyloidosis is highly individualized on the basis of age, organ dysfunction, and regimen toxicities and should be guided by biomarkers of hematologic and cardiac response. Alkylator-based chemotherapy remains effective in almost two thirds of patients. Novel agents now also prove highly effective, and trials are ongoing to establish their optimal use; the results to date of such studies are then thoughtfully addressed. In summary, this review seeks to provide an overview across both MM and amyloidosis of an evolving treatment paradigm toward the goal of tailored theapy, which will hopefully be useful to clinicians and scientists alike. JOURNAL OF CLINICAL ONCOLOGY O V E R V I E W VOLUME 29 NUMBER 14 MAY 1

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.