Biomarkers of response to ibrutinib plus nivolumab in relapsed diffuse large B-cell lymphoma, follicular lymphoma, or Richter's transformation

Biomarcadors; Ibrutinib; Limfoma no hodgkinBiomarkers; Ibrutinib; Non-hodgkin's lymphomaBiomarcadores; Ibrutinib; Linfoma no hodgkinWe analyzed potential biomarkers of response to ibrutinib plus nivolumab in biopsies from patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and Richter's transformation (RT) from the LYM1002 phase I/IIa study, using programmed death ligand 1 (PD-L1) immunohistochemistry, whole exome sequencing (WES), and gene expression profiling (GEP). In DLBCL, PD-L1 elevation was more frequent in responders versus nonresponders (5/8 [62.5%] vs. 3/16 [18.8%]; p = 0.065; complete response 37.5% vs. 0%; p = 0.028). Overall response rates for patients with WES and GEP data, respectively, were: DLBCL (38.5% and 29.6%); FL (46.2% and 43.5%); RT (76.5% and 81.3%). In DLBCL, WES analyses demonstrated that mutations in RNF213 (40.0% vs. 6.2%; p = 0.055), KLHL14 (30.0% vs. 0%; p = 0.046), and LRP1B (30.0% vs. 6.2%; p = 0.264) were more frequent in responders. No responders had mutations in EBF1, ADAMTS20, AKAP9, TP53, MYD88 , or TNFRSF14 , while the frequency of these mutations in nonresponders ranged from 12.5% to 18.8%. In FL and RT, genes with different mutation frequencies in responders versus nonresponders were: BCL2 (75.0% vs. 28.6%; p = 0.047) and ROS1 (0% vs. 50.0%; p = 0.044), respectively. Per GEP, the most upregulated genes in responders were LEF1 and BTLA (overall), and CRTAM (germinal center B-cell–like DLBCL). Enriched pathways were related to immune activation in responders and resistance-associated proliferation/replication in nonresponders. This preliminary work may help to generate hypotheses regarding genetically defined subsets of DLBCL, FL, and RT patients most likely to benefit from ibrutinib plus nivolumab.Sponsored by Janssen Research & Development, LLC

Biomarkers of response to ibrutinib plus nivolumab in relapsed diffuse large B-cell lymphoma, follicular lymphoma, or Richter's transformation

We analyzed potential biomarkers of response to ibrutinib plus nivolumab in biopsies from patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and Richter's transformation (RT) from the LYM1002 phase I/IIa study, using programmed death ligand 1 (PD-L1) immunohistochemistry, whole exome sequencing (WES), and gene expression profiling (GEP). In DLBCL, PD-L1 elevation was more frequent in responders versus nonresponders (5/8 [62.5%] vs. 3/16 [18.8%]; p = 0.065; complete response 37.5% vs. 0%; p = 0.028). Overall response rates for patients with WES and GEP data, respectively, were: DLBCL (38.5% and 29.6%); FL (46.2% and 43.5%); RT (76.5% and 81.3%). In DLBCL, WES analyses demonstrated that mutations in RNF213 (40.0% vs. 6.2%; p = 0.055), KLHL14 (30.0% vs. 0%; p = 0.046), and LRP1B (30.0% vs. 6.2%; p = 0.264) were more frequent in responders. No responders had mutations in EBF1, ADAMTS20, AKAP9, TP53, MYD88, or TNFRSF14, while the frequency of these mutations in nonresponders ranged from 12.5% to 18.8%. In FL and RT, genes with different mutation frequencies in responders versus nonresponders were: BCL2 (75.0% vs. 28.6%; p = 0.047) and ROS1 (0% vs. 50.0%; p = 0.044), respectively. Per GEP, the most upregulated genes in responders were LEF1 and BTLA (overall), and CRTAM (germinal center B-cell-like DLBCL). Enriched pathways were related to immune activation in responders and resistance-associated proliferation/replication in nonresponders. This preliminary work may help to generate hypotheses regarding genetically defined subsets of DLBCL, FL, and RT patients most likely to benefit from ibrutinib plus nivoluma

LIFE in a ZOO: Henri Lefebvre and the (social) production of (abstract) space in Liverpool

Building on recent critical contributions towards conceptualising neighbourhood change as socially produced and politically ‘performed’, this paper takes a closer look at the work of Henri Lefebvre to understand the production of urban space as a deeply political process. A common critical characterisation of neighbourhood change—occurring through a grand Lefebvrean struggle between ‘abstract space-makers’ and ‘social space-makers’—is critically examined through an in-depth historical case study of the Granby neighbourhood in Liverpool. Here, these forces are embodied respectively in technocratic state-led comprehensive redevelopment, notably Housing Market Renewal and its LIFE and ZOO zoning models; and in alternative community-led rehabilitation projects such as the Turner Prize-winning Granby Four Streets Community Land Trust. By tracing the surprisingly intimate interactions and multiple contradictions between these apparently opposing spatial projects, the production of neighbourhood is shown to be a complex, often violent political process, whose historical trajectories require disentangling in order to understand how we might construct better urban futures

PICS-Ord: unlimited coding of ambiguous regions by pairwise identity and cost scores ordination

<p>Abstract</p> <p>Background</p> <p>We present a novel method to encode ambiguously aligned regions in fixed multiple sequence alignments by 'Pairwise Identity and Cost Scores Ordination' (PICS-Ord). The method works via ordination of sequence identity or cost scores matrices by means of Principal Coordinates Analysis (PCoA). After identification of ambiguous regions, the method computes pairwise distances as sequence identities or cost scores, ordinates the resulting distance matrix by means of PCoA, and encodes the principal coordinates as ordered integers. Three biological and 100 simulated datasets were used to assess the performance of the new method.</p> <p>Results</p> <p>Including ambiguous regions coded by means of PICS-Ord increased topological accuracy, resolution, and bootstrap support in real biological and simulated datasets compared to the alternative of excluding such regions from the analysis a priori. In terms of accuracy, PICS-Ord performs equal to or better than previously available methods of ambiguous region coding (e.g., INAASE), with the advantage of a practically unlimited alignment size and increased analytical speed and the possibility of PICS-Ord scores to be analyzed together with DNA data in a partitioned maximum likelihood model.</p> <p>Conclusions</p> <p>Advantages of PICS-Ord over step matrix-based ambiguous region coding with INAASE include a practically unlimited number of OTUs and seamless integration of PICS-Ord codes into phylogenetic datasets, as well as the increased speed of phylogenetic analysis. Contrary to word- and frequency-based methods, PICS-Ord maintains the advantage of pairwise sequence alignment to derive distances, and the method is flexible with respect to the calculation of distance scores. In addition to distance and maximum parsimony, PICS-Ord codes can be analyzed in a Bayesian or maximum likelihood framework. RAxML (version 7.2.6 or higher that was developed for this study) allows up to 32-state ordered or unordered characters. A GTR, MK, or ORDERED model can be applied to analyse the PICS-Ord codes partition, with GTR performing slightly better than MK and ORDERED.</p> <p>Availability</p> <p>An implementation of the PICS-Ord algorithm is available from <url>http://scit.us/projects/ngila/wiki/PICS-Ord</url>. It requires both the statistical software, R <url>http://www.r-project.org</url> and the alignment software Ngila <url>http://scit.us/projects/ngila</url>.</p

Longitudinal expression profiling identifies a poor risk subset of patients with ABC-type Diffuse Large B Cell Lymphoma

Despite the effectiveness of immuno-chemotherapy, 40\cell lymphoma (DLBCL) experience relapse or refractory disease. Longitudinal studies have previously focused on the mutational landscape of relapse but fell short of providing a consistent relapse-specific genetic signature. In our study, we have focussed attention on the changes in gene expression profile accompanying DLBCL relapse using archival paired diagnostic/relapse specimens from 38 de novo DLBCL patients. Cell of origin remained stable from diagnosis to relapse in 80\ with only a single patient showing COO switching from ABC to GCB. Analysis of the transcriptomic changes that occur following relapse suggest ABC and GCB relapses are mediated via different mechanisms. We developed a 30-gene discriminator for ABC-DLBCLs derived from relapse-associated genes, that defined clinically distinct high and low risk subgroups in ABC-DLBCLs at diagnosis in datasets comprising both population-based and clinical trial cohorts. This signature also identified a population of \lt;60-year-old patients with superior PFS and OS treated with Ibrutinib-R-CHOP as part of the PHOENIX trial. Altogether this new signature adds to the existing toolkit of putative genetic predictors now available in DLBCL that can be readily assessed as part of prospective clinical trials

A Phylogenetic, Ecological, and Functional Characterization of Non-Photoautotrophic Bacteria in the Lichen Microbiome

<p>Although common knowledge dictates that the lichen thallus is formed solely by a fungus (mycobiont) that develops a symbiotic relationship with an alga and/or cyanobacterium (photobiont), the non-photoautotrophic bacteria found in lichen microbiomes are increasingly regarded as integral components of lichen thalli and significant players in the ecology and physiology of lichens. Despite recent interest in this topic, the phylogeny, ecology, and function of these bacteria remain largely unknown. The experiments presented in this dissertation employ culture-free methods to examine the bacteria housed in these unique environments to ultimately inform an assessment of their status with regard to the lichen symbiosis. Microbiotic surveys of lichen thalli using new oligonucleotide-primers targeting the 16S SSU rRNA gene (developed as part of this study to target Bacteria, but exclude sequences derived from chloroplasts and Cyanobacteria) revealed the identity of diverse bacterial associates, including members of an undescribed lineage in the order Rhizobiales (Lichen-Associated Rhizobiales 1; `LAR1'). It is shown that the LAR1 bacterial lineage, uniquely associated with lichen thalli, is widespread among lichens formed by distantly related lichen-forming fungi and is found in lichens collected from the tropics to the arctic. Through extensive molecular cloning of the 16S rRNA gene and 454 16S amplicon sequencing, ecological trends were inferred based on mycobiont, photobiont, and geography. The implications for using lichens as microcosms to study larger principles of ecology and evolution are discussed. In addition to phylogenetic and ecological studies of lichen-associated bacterial communities, this dissertation provides a first assessment of the functions performed by these bacteria within the lichen microbiome in nature through 454 sequencing of two different lichen metatranscriptomes (one from a chlorolichen, <italic>Cladonia grayi</italic>, and one from a cyanolichen, <italic>Peltigera praetextata</italic>). Non-photobiont bacterial genes for nitrogen fixation were not detected in the <italic>Cladonia</italic> thallus (even though transcripts of cyanobacterial nitrogen fixation genes from two different pathways were detected in the cyanolichen thallus), implying that the role of nitrogen fixation in the maintenance of chlorolichens might have previously been overstated. Additionally, bacterial polyol dehydrogenases were found to be expressed in chlorolichen thalli (along with fungal polyol dehydrogenases and kinases from the mycobiont), suggesting the potential for bacteria to begin the process of breaking down the fixed carbon compounds secreted by the photobiont for easier metabolism by the mycobiont. This first look at the group of functional genes expressed at the level of transcription provides initial insights into the symbiotic network of interacting genes within the lichen microbiome.</p>Dissertatio

Recognition of the Parmelia crozalsiana group as the genus Crespoa

Recent molecular phylogenetic analyses of the lichen family Parmeliaceae have revealed that the members of the Parmelia crozalsiana group form a sister clade to one containing members of the genus Parmotrema. The four species in this group were classified first in Parmelia, then Pseudoparmelia, and later Canoparmelia. Recently, the classification of this group was resolved by placing the species in the newly-described Parmotrema subg. Crespoa. This placement was justified by an absence of characters from the fungal reproductive structures distinguishing members of the group from those classified in Parmotrema subg. Parmotrema. As this classification obfuscates a morphologically and phylogenetically discrete group of foliose macrolichens that has always been recognized as distinct from Parmotrema s. str., we here recognize the group as the genus Crespoa. A discussion of taxonomic rank assignment based on character-types that are preconceived as diagnostic is also provided

Hodkinson_and_Lendemer_reptans_Perl_scripts

This zip archive contains two Perl scripts for processing FASTA files exported from GenBank. The Perl script 'fasta_from_NCBI_editor.pl' creates a fasta file with names that can be easily used for downstream applications (e.g., 'Genus_species_GBAcc_GI'). The 'create_data_table_from_NCBI_fasta.pl' script automatically creates a data table with all species identifications, GenBank Accession numbers and GenInfo Identifiers for the exported sequences

Data from: A microbiotic survey of lichen-associated bacteria reveals a new lineage from the Rhizobiales

This study uses a set of PCR-based methods to examine the putative microbiota associated with lichen thalli. In initial experiments, generalized oligonucleotide-primers for the 16S rRNA gene resulted in amplicon pools populated almost exclusively with fragments derived from lichen photobionts (i.e., Cyanobacteria or chloroplasts of algae). This effectively masked the presence of other lichen-associated prokaryotes. In order to facilitate the study of the lichen microbiota, 16S ribosomal oligonucleotide-primers were developed to target Bacteria, but exclude sequences derived from chloroplasts and Cyanobacteria. A preliminary microbiotic survey of lichen thalli using these new primers has revealed the identity of several bacterial associates, including representatives of the extremophilic Acidobacteria, bacteria in the families Acetobacteraceae and Brucellaceae, strains belonging to the genus Methylobacterium, and members of an undescribed lineage in the Rhizobiales. This new lineage was investigated and characterized through molecular cloning, and was found to be present in all examined lichens that are associated with green algae. There is evidence to suggest that members of this lineage may both account for a large proportion of the lichen-associated bacterial community and assist in providing the lichen thallus with crucial nutrients such as fixed nitrogen