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.

Selinexor: Targeting a novel pathway in multiple myeloma

Abstract: Selinexor is an orally bioavailable selective inhibitor of nuclear export compound that inhibits exportin-1 (XPO1), a novel therapeutic target that is overexpressed in multiple myeloma (MM) and is responsible for the transport of ∼220 nuclear proteins to the cytoplasm, including tumour suppressor proteins. Inhibition of this process has demonstrated substantial antimyeloma activity in preclinical studies, both alone and in combination with established MM therapeutics. Based on a clinical trial programme encompassing multiple combination regimens, selinexor-based therapy has been approved for the treatment of relapsed/refractory MM (RRMM), with selinexor-dexamethasone approved in the later-relapse setting for penta-refractory patients and selinexor-bortezomib-dexamethasone approved for patients who have received ≥1 prior therapy. Here, we provide a comprehensive review of the clinical data on selinexor-based regimens, including recent updates from the 2022 American Society of Hematology annual meeting, and summarise ongoing studies of this novel targeted agent in newly diagnosed MM and RRMM.

Modulation of Signaling Cascades by Inhibitors of Histone Deacetylase and Akt

Abstract: In multiple myeloma (MM), the bone marrow (BM) microenvironment plays a crucial role in promoting tumor cell proliferation, survival, migration, and drug resistance It is composed of different types of cellular components, including hematopoietic stem cells, progenitor and precursor cells, immune cells, erythrocytes, BM stromal cells (BMSCs), BM endothelial cells, as well as osteoclasts and osteoblasts These cells not only physically interact with MM cells, but also secrete growth and/or antiapoptotic factors, including interleukin (IL)-6, insulin-like growth factor (IGF)-1, vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF), stromal cell–derived factor (SDF) 1 , and B-cell activating factor (BAFF) These factors trigger several proliferative/antiapoptotic signaling cascades in MM cells: phosphatidylinositide-3 kinase (PI3K)/Akt; Ras/Raf/mitogen-activated protein kinase (MAPK) kinase (MEK)/extracellular signal-related kinase (ERK); Janus kinase (JAK) 2/signal transducers and activators of transcription (STAT)-3; and nuclear factor (NF)– B1 Therefore, cytokines, their receptors, and their downstream protein kinases and transcription factors represent potential therapeutic targets in MM Histone deacetylases (HDACs) are divided into 4 classes: class I, HDAC 1, 2, 3, and 8; class II, HDAC 4, 5, 6, 7, 9, and 10; class III, silent information regulator genes (SIR)1, 2, 3, 4, 5, 6, and 7; and in class IV, HDAC 11 Importantly, class I and IV HDACs are constitutively localized in the nucleus, whereas class II HDACs can shuttle between the nucleus and the cytoplasm interacting with 14-3-3 protein HDAC inhibitors have shown promise as novel antitumor agents for many malignancies, including structurally diverse HDAC inhibitors purified from natural sources or synthetically developed Hypoacetylation of histones is associated with condensed chromatin, resulting in repression of gene transcription, whereas acetylated histones are associated with open chromatin structure and activation of transcription; therefore, HDAC inhibitors trigger transcription However, inhibition of HDAC activity ultimately triggers growth arrest and/or apoptosis of tumor cells Although possible mechanisms of HDAC inhibitor antitumor activities have been extensively studied, their growth inhibitory effects in MM cells have not yet been fully characterized Importantly, recent studies have shown that acetylation of proteins other than histones may be altered by HDACs and their inhibitors HDAC6 has an essential role in recruitment of ubiquitinated proteins for transport to aggresomes, ultimately leading to lysosomal protein degradation2 We have shown that combined inhibition of proteasomes with bortezomib and of aggresomes with HDAC6-specific inhibitor tubacin3 triggers synergistic cytotoxicity in MM cell lines and MM patient tumor cells in vitro4 We further examined whether inhibition of HDAC6 modulates acetylation of proteins Interestingly, HDAC6 was constitutively associated with heat-shock protein (Hsp) 90, which was enhanced by tubacin treatment Consistent with previous studies showing that HDAC6 modulates Hsp90 acetylation,5 tubacin enhanced acetylation of Hsp90 in MM cells Since Akt is a client protein of Hsp90, we next examined whether acetylation of Hsp90 via inhibition of HDAC6 could modulate the activity of Akt Tubacin enhanced phosphorylation of Akt; conversely, Hsp90 inhibitor 17-AAG inhibited its effect Interestingly, enhanced interaction of Hsp90 with Akt was blocked by tubacin Our results therefore suggest that HDAC6 negatively regulates phosphorylation of Akt LBH589 (Novartis Pharmaceuticals) is a hydroxamic acid analog that blocks classes I and II HDAC and has significant antiMM activities6 Importantly, LBH589 synergistically augments MM cell cytotoxicity induced by bortezomib; an international multicenter clinical trial evaluating LBH589 with bortezomib in MM is ongoing We found that LBH589 significantly inhibited phosphorylation of JAK2 and its downstream molecule STAT3, without inhibiting Akt or ERK phosphorylation IL-6 and BMSC coculture markedly augmented JAK2/STAT3 phosphorylation; however, LBH589 completely abrogated this effect It has also been shown that acetylation of p65 (RelA) is crucial for its transcriptional Signaling Pathways in Myeloma

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.