Nature Methods, 2020
Authors
Ottar N Bjørnstad, Katriona Shea, Martin Krzywinski, Naomi Altman.
Publication Abstract

In the next few articles, we will discuss mathematical and statistical models that are commonly used to study the spread of infectious diseases. Such models are used to inform decisions on disease prevention, surveillance, control and treatment and can be applied to new epidemics, such as the ongoing COVID-19 outbreak.

The journals of gerontology. Series A, Biological sciences and medical sciences, 2020
Authors
Tindale, Lauren C, Thiessen, Nina, Leach, Stephen, Brooks-Wilson, Angela R
Publication Abstract
The genetic basis of healthy aging and longevity remains largely unexplained. One hypothesis as to why long-lived individuals do not appear to have a lower number of common-complex disease variants, is that despite carrying risk variants, they express disease-linked alleles at a lower level than the wild-type alleles. Allele-specific abundance (ASA) is the different transcript abundance of the two haplotypes of a diploid individual. We sequenced the transcriptomes of four healthy centenarians and four mid-life controls. CIBERSORT was used to estimate blood cell fractions: neutrophils were the most abundant source of RNA, followed by CD8+ T cells, resting NK cells, and monocytes. ASA variants were more common in noncoding than coding regions. Centenarians and controls had a comparable distribution of ASA variants by predicted effect, and we did not observe an overall bias in expression toward major or minor alleles. Immune pathways were most highly represented among the gene set that showed ASA. Although we found evidence of ASA in disease-associated genes and transcription factors, we did not observe any differences in the pattern of expression between centenarians and controls in this small pilot study.

Nature cell biology, 2020
Authors
Martinez-Høyer, Sergio, Deng, Yu, Parker, Jeremy, Jiang, Jihong, Mo, Angela, Docking, T Roderick, Gharaee, Nadia, Li, Jenny, Umlandt, Patricia, Fuller, Megan, Jädersten, Martin, Kulasekararaj, Austin, Malcovati, Luca, List, Alan F, Hellström-Lindberg, Eva, Platzbecker, Uwe, Karsan, Aly
Publication Abstract
Interstitial deletion of the long arm of chromosome 5 (del(5q)) is the most common structural genomic variant in myelodysplastic syndromes (MDS){{sup}}1{{/sup}}. Lenalidomide (LEN) is the treatment of choice for patients with del(5q) MDS, but half of the responding patients become resistant{{sup}}2{{/sup}} within 2 years. TP53 mutations are detected in ~20% of LEN-resistant patients{{sup}}3{{/sup}}. Here we show that patients who become resistant to LEN harbour recurrent variants of TP53 or RUNX1. LEN upregulated RUNX1 protein and function in a CRBN- and TP53-dependent manner in del(5q) cells, and mutation or downregulation of RUNX1 rendered cells resistant to LEN. LEN induced megakaryocytic differentiation of del(5q) cells followed by cell death that was dependent on calpain activation and CSNK1A1 degradation{{sup}}4,5{{/sup}}. We also identified GATA2 as a LEN-responsive gene that is required for LEN-induced megakaryocyte differentiation. Megakaryocytic gene-promoter analyses suggested that LEN-induced degradation of IKZF1 enables a RUNX1-GATA2 complex to drive megakaryocytic differentiation. Overexpression of GATA2 restored LEN sensitivity in the context of RUNX1 or TP53 mutations by enhancing LEN-induced megakaryocytic differentiation. Screening for mutations that block LEN-induced megakaryocytic differentiation should identify patients who are resistant to LEN.

Cancer Cell
Authors
George W Wright, Da Wei Huang, James D Phelan, Zana A Coulibaly, Sandrine Roulland, Ryan M Young, James Q Wang, Roland Schmitz, Ryan D Morin, Jeffrey Tang, Aixiang Jiang, Aleksander Bagaev, Olga Plotnikova, Nikita Kotlov, Calvin A Johnson, Wyndham H Wilson, David W Scott, Louis M Staudt
Publication Abstract

The development of precision medicine approaches for diffuse large B cell lymphoma (DLBCL) is confounded by its pronounced genetic, phenotypic, and clinical heterogeneity. Recent multiplatform genomic studies revealed the existence of genetic subtypes of DLBCL using clustering methodologies. Here, we describe an algorithm that determines the probability that a patient's lymphoma belongs to one of seven genetic subtypes based on its genetic features. This classification reveals genetic similarities between these DLBCL subtypes and various indolent and extranodal lymphoma types, suggesting a shared pathogenesis. These genetic subtypes also have distinct gene expression profiles, immune microenvironments, and outcomes following immunochemotherapy. Functional analysis of genetic subtype models highlights distinct vulnerabilities to targeted therapy, supporting the use of this classification in precision medicine trials.

Organic Letters
Authors
Kalindi D Morgan, David E Williams, Brian O Patrick, Marion Remigy, Carmen A Banuelos, Marianne D Sadar, Katherine S Ryan, Raymond J Andersen
Publication Abstract

Methods for the focused isolation of low-abundance natural products with specific chemical substructures could expand known bioactive chemical diversity for drug discovery. Here we report the combined use of genome mining and an 15N NMR-based screening method for the targeted isolation of the low-abundance piperazic-acid-containing peptides incarnatapeptins A (1) and B (3). Incarnatapeptin B (3) shows in vitro cytotoxicity to LNCaP prostate cancer cells.

Blood, 2020
Authors
Hanyang Lin, Katharina Rothe, Min Chen, Andrew Wu, Artem Babaian, Ryan Yen, Jonathan Zeng, Jens Ruschmann, Oleh I Petriv, Kieran O'Neill, Tobias Maetzig, David J H F Knapp, Naoto Nakamichi, Ryan Brinkman, Inanc Birol, Donna L Forrest, Carl Hansen, Keith Keith Humphries, Connie J Eaves, Xiaoyan Jiang
Publication Abstract

Overcoming drug resistance and targeting cancer stem cells remain challenges for curative cancer treatment. To investigate the role of miRNAs in regulating drug resistance and leukemic stem cell (LSCs) fate, we performed global transcriptome profiling in treatment-naïve chronic myeloid leukemia (CML) stem/progenitor cells and identified that miR-185 levels anticipate their response to ABL tyrosine kinase inhibitors (TKIs). miR-185 functions as a tumor suppressor; its restored expression impaired survival of drug-resistant cells, sensitized them to TKIs in vitro, and markedly eliminated long-term repopulating LSCs and infiltrating blast cells, conferring a survival advantage in pre-clinical xenotransplantation models. Integrative analysis with mRNA profiles uncovered PAK6 as a crucial target of miR-185 and pharmacological inhibition of PAK6 perturbed the RAS/MAPK pathway and mitochondrial activity, sensitizing therapy-resistant cells to TKIs. Thus, miR-185 presents as a potential predictive biomarker, and dual targeting of miR-185-mediated PAK6 activity and BCR-ABL may provide a valuable strategy for overcoming drug resistance in patients.

ACS Pharmacology & Translational Science, 2019
Authors
Jon K Obst, Jun Wang, Kunzhong Jian, David E Williams, Amy H Tien, Nasrin Mawji, Teresa Tam, Yu Chi Yang, Raymond J Andersen, Kim N Chi, Bruce Montgomery, Marianne D Sadar
Publication Abstract

Inhibition of the androgen receptor (AR) is the mainstay treatment for advanced prostate cancer. Ralaniten (formally EPI-002) prevents AR transcriptional activity by binding to its N-terminal domain (NTD) which is essential for transcriptional activity. Ralaniten acetate (EPI-506) the triacetate pro-drug of ralaniten, remains the only AR-NTD inhibitor to have entered clinical trials (NCT02606123). While well tolerated, the trial was ultimately terminated due to poor pharmacokinetic properties and resulting pill burden. Here we discovered that ralaniten was glucuronidated which resulted in decreased potency. Long-term treatment of prostate cancer cells with ralaniten results in upregulation of UGT2B enzymes with concomitant loss of potency. This has proven to be a useful model with which to facilitate the development of more potent second-generation AR-NTD inhibitors. Glucuronidated metabolites of ralaniten were also detected in the serum of patients in Phase 1 clinical trials. Therefore, we tested an analogue of ralaniten (EPI-045) which was resistant to glucuronidation and demonstrated superiority to ralaniten in our resistant model. These data support that analogues of ralaniten designed to mitigate glucuronidation may optimize clinical responses to AR-NTD inhibitors.

Nature Reviews Genetics, 2020
Authors
Maui Hudson, Nanibaa' A Garrison, Rogena Sterling, Nadine R Caron, Keolu Fox, Joseph Yracheta, Jane Anderson, Phil Wilcox, Laura Arbour, Alex Brown, Maile Taualii, Tahu Kukutai, Rodney Haring, Ben Te Aika, Gareth S Baynam, Peter K Dearden, David Chagné, Ripan S Malhi, Ibrahim Garba, Nicki Tiffin, Deborah Bolnick, Matthew Stott, Anna K Rolleston, Leah L Ballantyne, Ray Lovett, Dominique David-Chavez, Andrew Martinez, Andrew Sporle, Maggie Walter, Jeff Reading, Stephanie Russo Carroll
Publication Abstract

Addressing Indigenous rights and interests in genetic resources has become increasingly challenging in an open science environment that promotes unrestricted access to genomic data. Although Indigenous experiences with genetic research have been shaped by a series of negative interactions, there is increasing recognition that equitable benefits can only be realized through greater participation of Indigenous communities. Issues of trust, accountability and equity underpin Indigenous critiques of genetic research and the sharing of genomic data. This Perspectives article highlights identified issues for Indigenous communities around the sharing of genomic data and suggests principles and actions that genomic researchers can adopt to recognize community rights and interests in data.

Bioinformatics (Oxford, England), 2020
Authors
Nieuwoudt, Christina, Brooks-Wilson, Angela, Graham, Jinko
Publication Abstract
We present the R package SimRVSequences to simulate sequence data for pedigrees. SimRVSequences allows for simulations of large numbers of single-nucleotide variants (SNVs) and scales well with increasing numbers of pedigrees. Users provide a sample of pedigrees and SNV data from a sample of unrelated individuals.

Cancer Epidemiology, Biomarkers & Prevention
Authors
Samantha Jean Jones, Sumara Stroshein, Amy M Williams, Dongmeng Liu, John J Spinelli, Joseph M Connors, Angela R Brooks-Wilson
Publication Abstract

Familial aggregation of lymphoid cancers and immune-related disorders suggests a role for genetic susceptibility; however, few studies examine environmental factors. According to the hygiene hypothesis, adult-onset-immune-related diseases may be a consequence of reduced childhood infectious exposures and aberrant immune development. In a cohort of 196 multiple-case lymphoid cancer families, we analyzed environmental factors related to the hygiene hypothesis.

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