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.

Elotuzumab Plus Pomalidomide and Dexamethasone for Relapsed/Refractory Multiple Myeloma: Final Overall Survival Analysis From the Randomized Phase II ELOQUENT-3 Trial

Abstract: PURPOSE In the phase II ELOQUENT-3 trial (ClinicalTrials.gov identifier: NCT02654132), elotuzumab combined with pomalidomide/dexamethasone (EPd) significantly improved progression-free survival (PFS) versus pomalidomide/dexamethasone (Pd) in patients with relapsed/refractory multiple myeloma (RRMM) previously treated with lenalidomide and a proteasome inhibitor (PI). Here, we present the final overall survival (OS) results. METHODS Patients with RRMM who had received ≥ 2 prior lines of therapy, with disease refractory to last therapy and either refractory or relapsed and refractory to lenalidomide and a PI were randomly assigned (1:1) to receive EPd or Pd. The primary end point was PFS per investigator assessment. ORR and OS were secondary end points planned to be tested hierarchically. RESULTS A total of 117 patients were randomly assigned to EPd (n = 60) and Pd (n = 57). Among treated patients (EPd 60, Pd 55), there were 37 (61.7%) deaths in the EPd group and 41 (74.5%) in the Pd group, most commonly because of disease progression (EPd 41.7%, Pd 49.1%). Median (95% CI) OS was significantly improved with EPd (29.8 [22.9 to 45.7] months) versus Pd (17.4 [13.8 to 27.7] months), with a hazard ratio of 0.59 (95% CI, 0.37 to 0.93; P = .0217). OS benefit with EPd was observed in most patient subgroups. The safety profile of EPd was consistent with prior reports with no new safety signals detected. CONCLUSION EPd demonstrated a statistically significant improvement in OS versus Pd in patients with RRMM previously treated with lenalidomide and a PI who had disease refractory to last therapy. In this setting, ELOQUENT-3 is the first randomized study of a triplet regimen incorporating a monoclonal antibody and Pd to improve both PFS and OS significantly.

The challenge of cross-trial comparisons using limited data.

Abstract: The manuscript by Dr David Siegel and colleagues,[1][1] “Integrated safety profile of single-agent carfilzomib: experience from 526 patients enrolled in 4 phase 2 clinical studies”, provides a comprehensive assessment of the available safety data associated with the new proteasome inhibitor

Hemostatic complications of hematopoietic stem cell transplantation: from hemorrhage to microangiopathies and VOD.

Abstract: Patients who undergo hematopoietic stem cell transplantation (SCT) have unique toxicities and correspondingly specialized requirements in supportive care given the intensity of cytotoxic therapy to which they are exposed, the severe immuno-suppression they undergo, their temporary inability to produce blood cells, and the fact that their blood type may change as they become a temporary or permanent chimera in the allogeneic setting. Hemorrhagic complications in SCT most commonly occur in the context of thrombocytopenia. Platelets are transfused either to prevent bleeding or to treat active bleeding. It has become common practice for physicians to use platelet transfusions to prevent serious bleeding when the platelet count is less than 20,000/ L [1]. However, more recent data has shown that serious bleeding usually occurs only when the platelet count is below 10,000/ L and fatal bleeding is unlikely to occur at platelet counts above 5,000/ L. Various studies have shown that the threshold for prophylactic platelet transfusion should be 10,000/ L or less and thus a National Institute of Health (NIH) consensus conference recommended that the 20,000/ L value threshold traditionally used for prophylactic platelet transfusion could be safely lowered for many patients. Currently, many physicians and hospital guidelines use platelet counts of 10,000 or 5,000/ L as the indication for transfusion for uncomplicated patients. However, many SCT recipients are febrile and often have intercurrent lesions such as mucositis, and thus many of these patients are transfused at platelet counts of 20,000/ L or higher. In actively bleeding patients, platelet transfusions should be considered in those with a platelet count of less than approximately 75,000/ L and an attempt to achieve a level of above 50,000/ L is usually recommended. In special situations where patients’ platelets may be dysfunctional due to drugs (e.g. cyclophosphamide) or uremia, the bleeding time may be much longer than would be expected based on the degree of thrombocytopenia and in such situations the decision to give a platelet transfusion can be made on clinical grounds alone. There is a dose response effect from platelet transfusion such that within one hour after transfusion the platelet count increases approximately 10,000/ L when 1 1011 platelets are transfused into an average (70 kg) patient. Typically, one platelet concentrate per 10 kg of body weight is administered to increase the platelet count by approximately 40,000/ L and a one-hour post transfusion platelet count is useful as an excellent predictor of an effective platelet transfusion, with the corrected count increment as a common calculation used to determine refractoriness. It now seems clear that ABO incompatible platelet transfusions are associated with reduced post transfusional platelet recovery [2, 3]. Thus the use of ABO matched platelets that are approximately 24 h in storage can be tried to produce a satisfactory increment, and if these are unsuccessful, efforts should then be made to use platelets that are an HLA-match Hemostatic Complications of Hematopoietic Stem Cell Transplantation: From Hemorrhage to Microangiopathies and VOD

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.