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.

Phase II trial of combination of bortezomib and rituximab in relapsed and/or refractory Waldenstrom macroglobulinemia

Abstract: 8535 Background: This phase II study aimed to determine safety and activity of weekly bortezomib in combination with rituximab in patients with relapsed/refractory Waldenstrom macroglobulinemia (WM). Methods: Patients who had at least one previous therapy for WM and who had relapsed or refractory disease were eligible. NCI CTCAE v3.0 was used for toxicity assessment. All patients received bortezomib IV weekly at 1.6mg/m2 on days 1, 8, 15, q 28 days × 6 cycles, and rituximab 375 mg/m2 at days 1, 8, 15, 22, on cycles 1 and 4. Results: 37 pts (26 men and 11 women, median age 62 years, range 42 - 73) have been treated to date. The median number of lines of prior treatment was 3 (range 1 - 5). All patients had received prior rituximab and 5 pts received prior bortezomib. The median IgM at baseline was 3540 mg/dL (range 700-10,800). The median follow up is 12 months (range 5 - 26 months). Thirty-five pts are evaluable for response. Complete remission and near complete remission occurred in 2 (6%), partial remis...

IgD and IgE variants of myeloma: valuable insights and therapeutic opportunities

Abstract: The real promise of improving patient outcomes in IgD and IgE multiple myeloma lies in multi-drug combinations, next-generation agents, and immunotherapy.

Pomalidomide in lenalidomide-refractory multiple myeloma: Far from futile.

Abstract: In this edition of BJH, Siegel et al (2019) report their findings from Cohort A of MM-014, a phase 2, non-randomized, dual-arm, open-label study conducted at 39 centres throughout the United States and Canada, which was designed to determine the activity of pomalidomide-based regimens in patients with relapsed and refractory multiple myeloma (RRMM) who are relatively early in their treatment course (two prior lines of therapy), with a focus on those whose disease has become refractory to lenalidomide immediately prior to enrolment. Whereas Cohort B (ongoing) examines the addition of daratumumab to the pomalidomide-dexamethasone “backbone” for these patients, Cohort A examines the backbone itself. As the authors highlight, treatment with pomalidomide-dexamethasone alone produced an overall response rate (ORR) of 32%, with a median progression-free survival (PFS) of 12 2 months and a median duration of response (DOR) of 16 6 months, in the setting of a predictably favourable toxicity profile. The fact that these outcomes were achieved in a patient population that had largely (87 5%) just become refractory to lenalidomide is noteworthy, as it confirms that pomalidomide-dexamethasone is capable of not only achieving response in the immediate aftermath of lenalidomide failure, but of maintaining response to a clinically meaningful extent and in a highly tolerable manner. Granted, the ORR and depth of response achieved in this cohort are somewhat less in comparison to those of various triplet regimens which have been recently studied and approved for use in the relapsed/refractory space (Shah et al, 2015; Chari et al, 2017; Dimopolous et al, 2018; Richardson et al, 2019); however, the study retains importance for two main reasons. First, it will help to put to rest the notion that lenalidomide-refractory patients require a “class-switch” away from immunomodulatory drug (IMiD)containing therapy at the time of progression due to IMiD resistance. Second, and just as clinically relevant, it will provide an evidence-based treatment option for lenalidomide-refractory patients for whom, due to a variety of potential factors, a less intensive and more tolerable approach may be important. There are some limitations to this trial and the results thereof; for example, we note that this study, while well-designed and expertly reported, lacks two key subgroup analyses. First, we do not know the ORR or PFS in lenalidomideexposed versus lenalidomide-refractory patients. Although the latter did account for most of the cohort, it remains at least plausible that the former could have accounted for a significant percentage of the responses, to include potentially the most durable ones. Granted, this is most likely not the case, as the MM-002 study of pomalidomide with or without dexamethasone in RRMM found both the ORR and DOR of pomalidomide-dexamethasone in lenalidomide-refractory patients to be comparable to that of the intention to treat (ITT) population (Richardson et al, 2014). It should be noted, however, that in this study, lenalidomide-refractory patients had received a greater number of lines of therapy and did not have to demonstrate refractoriness to lenalidomide immediately prior to enrolment for eligibility. Regardless, it is fair to say that the distinction between “lenalidomide-exposed” and “lenalidomide-refractory” is becoming increasingly and more immediately important in the context of our modern-day approach to treating myeloma (specifically, the use of first-line induction with lenalidomide-proteasome inhibitor-dexamethasone-based therapy followed by lenalidomide-based maintenance until progression either after or in lieu of high-dose melphalan). Owing to this approach, many patients are now lenalidomide-refractory at their first progression, and a majority are likely to be so at their second (Richardson et al, 2019). Although many of these patients will be candidates for potent triplet regimens in the second or third line, others may have significant residual neuropathy, risk of cardiovascular disease, high frailty indices, or lack of access to newer agents that will limit their options, while still others may wish to avoid the inconvenience, cost, and/or potential Correspondence: Clifton C. Mo, Department of Medical Oncology, Dana Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215, USA. E-mail: Clifton_Mo@DFCI.HARVARD.EDU editorial comment

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.