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.

From the bench to the bedside : emerging new treatments in multiple myeloma

Abstract: Several novel drug classes have been developed for multiple myeloma treatment within the last decade. The immunomodulatory drugs, thalidomide and lenalidomide, and the first-in-class proteasome inhibitor, bortezomib, target not only the malignant plasma cells but also key stromal cell support for the neoplastic clone. All three compounds have proven efficacy in advanced disease and increasing evidence for excellent response rates and clinical benefit in newly diagnosed patients. Attention is now focused on producing rational molecularly based drug combinations, incorporating both novel agents and conventional drugs, to further improve outcome. In the setting of autologous stem cell transplantation, the incorporation of these therapies into transplant-based treatment has recently been shown to result in superior overall survival, as have other combinations in relapsed disease, such as bortezomib with liposomally encapsulated doxorubicin. Several new agents are now in clinical trials or are at advanced stages of pre-clinical studies. These include second generation proteasome inhibitors, as well as inhibitors of heat shock proteins, histone deacetylases, receptor tyrosine kinases, and agents targeting the microenvironment of tumors, including defibrotide.

Phase 2 Study of the Safety and Tolerability of Maraviroc-Containing Regimens to Prevent HIV Infection in Men Who Have Sex With Men (HPTN 069/ACTG A5305).

Abstract: Author(s): Gulick, Roy M; Wilkin, Timothy J; Chen, Ying Q; Landovitz, Raphael J; Amico, K Rivet; Young, Alicia M; Richardson, Paul; Marzinke, Mark A; Hendrix, Craig W; Eshleman, Susan H; McGowan, Ian; Cottle, Leslie M; Andrade, Adriana; Marcus, Cheryl; Klingman, Karin L; Chege, Wairimu; Rinehart, Alex R; Rooney, James F; Andrew, Philip; Salata, Robert A; Magnus, Manya; Farley, Jason E; Liu, Albert; Frank, Ian; Ho, Ken; Santana, Jorge; Stekler, Joanne D; McCauley, Marybeth; Mayer, Kenneth H | Abstract: BackgroundMaraviroc (MVC) is a candidate for human immunodeficiency virus (HIV) pre-exposure prophylaxis.MethodsPhase 2 48-week safety/tolerability study was conducted, comparing 4 regimens: MVC alone, MVC plus emtricitabine (FTC), MVC plus tenofovir disoproxil fumarate (TDF), and TDF plus FTC. Eligible participants were HIV-uninfected men and transgender women reporting condomless anal intercourse with ≥1 HIV-infected or unknown-serostatus man within 90 days. At each visit, assessments, laboratory testing, and counseling were done. Analyses were intention to treat.ResultsAmong 406 participants, 84% completed follow-up, 7% stopped early, and 9% were lost to follow-up; 9% discontinued their regimen early. The number discontinuing and the time to discontinuation did not differ among study regimens (P = .60). Rates of grade 3-4 adverse events did not differ among regimens (P = .37). In a randomly selected subset, 77% demonstrated detectable drug concentrations at week 48. Five participants acquired HIV infection (4 MVC alone, 1 MVC + TDF; overall annualized incidence, 1.4% [95% confidence interval, .5%-3.3%], without differences by regimen; P = .32); 2 had undetectable drug concentrations at every visit, 2 had low concentrations at the seroconversion visit, and 1 had variable concentrations.ConclusionsMVC-containing regimens were safe and well tolerated compared with TDF + FTC; this study was not powered for efficacy. Among those acquiring HIV infection, drug concentrations were absent, low, or variable. MVC-containing regimens may warrant further study for pre-exposure prophylaxis.Clinical trials registrationNCT01505114.

Closing the Gaps on Human Chromosome 19 Revealed Genes With a High Density of Repetitive Tandemly Arrayed Elements

Abstract: The reported human genome sequence includes about 400 gaps of unknown sequence that were not found in the bacterial artificial chromosome (BAC) and cosmid libraries used for sequencing of the genome. These missing sequences correspond to approximately 1% of euchromatic regions of the human genome. Gap filling is a laborious process because it relies on analysis of random clones of numerous genomic BAC or cosmid libraries. In this work we demonstrate that closing the gaps can be accelerated by a selective recombinational capture of missing chromosomal segments in yeast. The use of both methodologies allowed us to close the four remaining gaps on the human chromosome 19. Analysis of the gap sequences revealed that they contain several abnormalities that could result in instability of the sequences in microbe hosts, including large blocks of micro- and minisatellites and a high density of Alu repeats. Sequencing of the gap regions, in both BAC and YAC forms, allowed us to generate a complete sequence of four genes, including the neuronal cell signaling gene SCK1/SLI. The SCK1/SLI gene contains a record number of minisatellites, most of which are polymorphic and transmitted through meiosis following a Mendelian inheritance. In conclusion, the use of the alternative recombinational cloning system in yeast may greatly accelerate work on closing the remaining gaps in the human genome (as well as in other complex genomes) to achieve the goal of annotation of all human genes.

Histone Deacetylase Inhibitors in Multiple Myeloma: Rationale and Evidence for Their Use in Combination Therapy

Abstract: Multiple myeloma (MM) arises from abnormal proliferation and survival (ie, a high proliferative index and a low apoptotic index) of mature immunoglobulin-producing plasma cells in the bone marrow. Development of novel therapeutic options, such as proteasome inhibitors and immunomodulatory agents (IMiDs), has improved treatment outcomes. However, patients often develop relapsed and refractory MM, thus requiring alternative treatment approaches. Histone acetyltransferases and histone deacetylases (HDACs) control the acetylation status of proteins and affect a broad array of physiologic processes (eg, cell cycle, apoptosis, and protein folding) involved in cell growth and survival. The discovery that HDACs might have a role in various hematologic malignancies, including MM, has led to the development of HDAC inhibitors as potential antitumor agents. Preclinical evidence from studies of HDAC inhibitors in combination with proteasome inhibitors (eg, bortezomib and carfilzomib), other antimyeloma agents, including IMiDs (eg, lenalidomide), and cytotoxic agents (eg, melphalan, pegylated liposomal doxorubicin), provides a strong scientific rationale for the evaluation of these regimens. Results from early stage clinical trials further support the use of HDAC inhibitors as a therapeutic option for MM, in combination with current and emerging antimyeloma agents. In this review, we examine the role of protein acetylation that underlies the antimyeloma effects of HDAC inhibitors, discuss the preclinical rationale for the use of HDAC inhibitors in combination with other antimyeloma agents, and provide an overview of the current clinical evidence supporting the use of HDAC inhibitors as a therapeutic option in MM.

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.