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.

Safety and efficacy of lenalidomide (Len), bortezomib (Bz), and dexamethasone (Dex) in patients (pts) with newly diagnosed multiple myeloma (MM): A phase I/II study

Abstract: 8520 Background: Single-agent Bz and Len/Dex are approved for pts with relapsed MM following ≥1 prior therapy. Len/Bz±Dex is active in relapsed/refractory MM, and Len/Dex and Bz/Dex are active in frontline MM. Primary objectives of this phase I/II study were to define the MTD and assess response rate to Len/Bz/Dex in previously untreated MM pts. Methods: Pts received Len 15–25mg on d 1–14, Bz 1.0–1.3mg/m2 on d 1, 4, 8, 11, and Dex 40/20mg (cycles 1–4/5–8) on day of and after Bz for up to eight 21-d cycles, initially at 4 planned dose levels (table). Dose escalation proceeded depending on dose-limiting toxicities (DLTs). Based on safety data, dose level 4M was added with a reduced Dex starting dose (20/10mg). Toxicities were graded by NCI CTCAE v3.0. Pts with G>2 peripheral neuropathy (PN) were excluded. Responses were assessed by modified EBMT and Uniform Criteria. Pts with ≥PR could proceed to ASCT after ≥4 cycles. Results: 66 pts have been enrolled to date. Data are available on 53 pts (median age 58 yr...

Influence of Disease and Patient Characteristics on Daratumumab Exposure and Clinical Outcomes in Relapsed or Refractory Multiple Myeloma.

Abstract: Objective The aim of this study was to understand the influence of disease and patient characteristics on exposure to daratumumab, an immunoglobulin Gκ (IgGκ) monoclonal antibody, and clinical outcomes in relapsed or refractory multiple myeloma (MM).

Management of Relapsed and Relapsed/Refractory Multiple Myeloma

Abstract: INTRODUCTION Despite recent advances in therapy, relapsed and refractory multiple myeloma (MM) remains a significant challenge and an area of unmet medical need. Median survival and responses to treatment are characteristically short. Relapsed and refractory MM is defined as patients who achieve at least a minor response (MR) or better followed by relapse and then progress on salvage therapy, or experience progression within 60 days of their last therapy. Successive treatment regimens typically result in progressively shorter response durations, which reflects emerging drug resistance. The observed decrease in response duration may also reflect changes in disease biology within each patient, with tumor cells expressing a more aggressive phenotype, higher proliferative thrust, and lower apoptotic rates. Although several prognostic factors have been identified for newly diagnosed myeloma, factors that retain prognostic value in the context of relapsed/refractory disease remain to be comprehensively defined. Nonetheless, patients with poor risk include those with t(4;14) or t(14;16), deletion 17 or deletion 13, hypodiploidy, high- β 2 -microglobulin, light-chain disease, immunoglobulin A (IgA) isotype, and low serum albumin; clinical challenges in the relapsed/refractory population include renal failure, extramedullary disease, hyposecretory myeloma, and advanced bone disease. The advent of novel therapies targeting disease biology and tumor microenvironment has significantly improved the prognosis for patients with relapsed and refractory disease. Bortezomib, a first-in-class proteasome inhibitor, and the immunomodulatory agents thalidomide (Thal) and lenalidomide now constitute “backbone” agents in this setting.

Recent advances in the treatment of Multiple Myeloma.

Abstract: Multiple Myeloma (MM) remains an incurable plasma cell malignancy in the bone marrow (BM) despite conventional therapies as well as high-dose therapies with stem cell support. Therefore novel biologically-based therapeutic approaches are required. Recently, intensive laboratory and preclinical studies have identified and validated therapeutic molecular targets in MM. In particular, recognition of the biologic significance of the BM microenvironment in MM pathogenesis and as a potential target for novel therapeutics has derived several promising approaches. Novel FDA approved agents including thalidomide/thalomid®, its immunomodulatory derivatives lenalidomide/Revlimid®, and proteasome inhibitor bortezomib/Velcade® are directed at molecular targets not only in MM cells but also in its BM milieu, and have already achieved promising results in clinical studies. Here we discuss the mechanisms of action of these novel drugs and their clinical application, alone or combined with conventional or novel drugs.

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.