Medical Biology - Research Publications

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    Efficient detection and classification of epigenomic changes under multiple conditions
    Baldoni, PL ; Rashid, NU ; Ibrahim, JG (WILEY, 2021-05-03)
    Epigenomics, the study of the human genome and its interactions with proteins and other cellular elements, has become of significant interest in recent years. Such interactions have been shown to regulate essential cellular functions and are associated with multiple complex diseases. Therefore, understanding how these interactions may change across conditions is central in biomedical research. Chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-seq) is one of several techniques to detect local changes in epigenomic activity (peaks). However, existing methods for differential peak calling are not optimized for the diversity in ChIP-seq signal profiles, are limited to the analysis of two conditions, or cannot classify specific patterns of differential change when multiple patterns exist. To address these limitations, we present a flexible and efficient method for the detection of differential epigenomic activity across multiple conditions. We utilize data from the ENCODE Consortium and show that the presented method, epigraHMM, exhibits superior performance to current tools and it is among the fastest algorithms available, while allowing the classification of combinatorial patterns of differential epigenomic activity and the characterization of chromatin regulatory states.
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    Outcomes for Australian children with relapsed/refractory acute lymphoblastic leukaemia treated with blinatumomab.
    Sutton, R ; Pozza, LD ; Khaw, SL ; Fraser, C ; Revesz, T ; Chamberlain, J ; Mitchell, R ; Trahair, TN ; Bateman, CM ; Venn, NC ; Law, T ; Ong, E ; Heatley, SL ; McClure, BJ ; Meyer, C ; Marschalek, R ; Henderson, MJ ; Cross, S ; White, DL ; Kotecha, RS (Wiley, 2021-05)
    We report on the Australian experience of blinatumomab for treatment of 24 children with relapsed/refractory precursor B-cell acute lymphoblastic leukaemia (B-ALL) and high-risk genetics, resulting in a minimal residual disease (MRD) response rate of 58%, 2-year progression-free survival (PFS) of 39% and 2-year overall survival of 63%. In total, 83% (n = 20/24) proceeded to haematopoietic stem cell transplant, directly after blinatumomab (n = 12) or following additional salvage therapy (n = 8). Four patients successfully received CD19-directed chimeric antigen receptor T-cell therapy despite prior blinatumomab exposure. Inferior 2-year PFS was associated with MRD positivity (20%, n = 15) and in KMT2A-rearranged infants (15%, n = 9). Our findings highlight that not all children with relapsed/refractory B-ALL respond to blinatumomab and factors such as blast genotype may affect prognosis.
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    Glutaminase inhibition impairs CD8 T cell activation in STK11-/Lkb1-deficient lung cancer.
    Best, SA ; Gubser, PM ; Sethumadhavan, S ; Kersbergen, A ; Negrón Abril, YL ; Goldford, J ; Sellers, K ; Abeysekera, W ; Garnham, AL ; McDonald, JA ; Weeden, CE ; Anderson, D ; Pirman, D ; Roddy, TP ; Creek, DJ ; Kallies, A ; Kingsbury, G ; Sutherland, KD (Elsevier BV, 2022-06-07)
    The tumor microenvironment (TME) contains a rich source of nutrients that sustains cell growth and facilitate tumor development. Glucose and glutamine in the TME are essential for the development and activation of effector T cells that exert antitumor function. Immunotherapy unleashes T cell antitumor function, and although many solid tumors respond well, a significant proportion of patients do not benefit. In patients with KRAS-mutant lung adenocarcinoma, KEAP1 and STK11/Lkb1 co-mutations are associated with impaired response to immunotherapy. To investigate the metabolic and immune microenvironment of KRAS-mutant lung adenocarcinoma, we generated murine models that reflect the KEAP1 and STK11/Lkb1 mutational landscape in these patients. Here, we show increased glutamate abundance in the Lkb1-deficient TME associated with CD8 T cell activation in response to anti-PD1. Combination treatment with the glutaminase inhibitor CB-839 inhibited clonal expansion and activation of CD8 T cells. Thus, glutaminase inhibition negatively impacts CD8 T cells activated by anti-PD1 immunotherapy.
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    Blood and immune development in human fetal bone marrow and Down syndrome
    Jardine, L ; Webb, S ; Goh, I ; Londono, MQ ; Reynolds, G ; Mather, M ; Olabi, B ; Stephenson, E ; Botting, RA ; Horsfall, D ; Engelbert, J ; Maunder, D ; Mende, N ; Murnane, C ; Dann, E ; McGrath, J ; King, H ; Kucinski, I ; Queen, R ; Carey, CD ; Shrubsole, C ; Poyner, E ; Acres, M ; Jones, C ; Ness, T ; Coulthard, R ; Elliott, N ; O'Byrne, S ; Haltalli, MLR ; Lawrence, JE ; Lisgo, S ; Balogh, P ; Meyer, KB ; Prigmore, E ; Ambridge, K ; Jain, MS ; Efremova, M ; Pickard, K ; Creasey, T ; Bacardit, J ; Henderson, D ; Coxhead, J ; Filby, A ; Hussain, R ; Dixon, D ; McDonald, D ; Popescu, D-M ; Kowalczyk, MS ; Li, B ; Ashenberg, O ; Tabaka, M ; Dionne, D ; Tickle, TL ; Slyper, M ; Rozenblatt-Rosen, O ; Regev, A ; Behjati, S ; Laurenti, E ; Wilson, NK ; Roy, A ; Goettgens, B ; Roberts, I ; Teichmann, SA ; Haniffa, M (NATURE PORTFOLIO, 2021-09-29)
    Haematopoiesis in the bone marrow (BM) maintains blood and immune cell production throughout postnatal life. Haematopoiesis first emerges in human BM at 11-12 weeks after conception1,2, yet almost nothing is known about how fetal BM (FBM) evolves to meet the highly specialized needs of the fetus and newborn. Here we detail the development of FBM, including stroma, using multi-omic assessment of mRNA and multiplexed protein epitope expression. We find that the full blood and immune cell repertoire is established in FBM in a short time window of 6-7 weeks early in the second trimester. FBM promotes rapid and extensive diversification of myeloid cells, with granulocytes, eosinophils and dendritic cell subsets emerging for the first time. The substantial expansion of B lymphocytes in FBM contrasts with fetal liver at the same gestational age. Haematopoietic progenitors from fetal liver, FBM and cord blood exhibit transcriptional and functional differences that contribute to tissue-specific identity and cellular diversification. Endothelial cell types form distinct vascular structures that we show are regionally compartmentalized within FBM. Finally, we reveal selective disruption of B lymphocyte, erythroid and myeloid development owing to a cell-intrinsic differentiation bias as well as extrinsic regulation through an altered microenvironment in Down syndrome (trisomy 21).
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    Cross-tissue immune cell analysis reveals tissue-specific features in humans
    Conde, CD ; Xu, C ; Jarvis, LB ; Rainbow, DB ; Wells, SB ; Gomes, T ; Howlett, SK ; Suchanek, O ; Polanski, K ; King, HW ; Mamanova, L ; Huang, N ; Szabo, PA ; Richardson, L ; Bolt, L ; Fasouli, ES ; Mahbubani, KT ; Prete, M ; Tuck, L ; Richoz, N ; Tuong, ZK ; Campos, L ; Mousa, HS ; Needham, EJ ; Pritchard, S ; Li, T ; Elmentaite, R ; Park, J ; Rahmani, E ; Chen, D ; Menon, DK ; Bayraktar, OA ; James, LK ; Meyer, KB ; Yosef, N ; Clatworthy, MR ; Sims, PA ; Farber, DL ; Saeb-Parsy, K ; Jones, JL ; Teichmann, SA (AMER ASSOC ADVANCEMENT SCIENCE, 2022-05-13)
    Despite their crucial role in health and disease, our knowledge of immune cells within human tissues remains limited. We surveyed the immune compartment of 16 tissues from 12 adult donors by single-cell RNA sequencing and VDJ sequencing generating a dataset of ~360,000 cells. To systematically resolve immune cell heterogeneity across tissues, we developed CellTypist, a machine learning tool for rapid and precise cell type annotation. Using this approach, combined with detailed curation, we determined the tissue distribution of finely phenotyped immune cell types, revealing hitherto unappreciated tissue-specific features and clonal architecture of T and B cells. Our multitissue approach lays the foundation for identifying highly resolved immune cell types by leveraging a common reference dataset, tissue-integrated expression analysis, and antigen receptor sequencing.
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    3, 2, 1, go! Cryptosporidium counts down to sex
    Jex, AR ; Tonkin, CJ ; Ralph, SA (PUBLIC LIBRARY SCIENCE, 2022-05-01)
    Cryptosporidium is a leading cause of death from childhood diarrhea, but its biology is poorly understood. A recent study in PLOS Biology reveals hitherto unknown aspects of the parasite's life cycle that may lead to improvements in ex vivo culture.
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    Malaria transmission structure in the Peruvian Amazon through antibody signatures to Plasmodium vivax.
    Rosado, J ; Carrasco-Escobar, G ; Nolasco, O ; Garro, K ; Rodriguez-Ferruci, H ; Guzman-Guzman, M ; Llanos-Cuentas, A ; Vinetz, JM ; Nekkab, N ; White, MT ; Mueller, I ; Gamboa, D ; Kamel, MG (Public Library of Science (PLoS), 2022-05)
    BACKGROUND: The landscape of malaria transmission in the Peruvian Amazon is temporally and spatially heterogeneous, presenting different micro-geographies with particular epidemiologies. Most cases are asymptomatic and escape routine malaria surveillance based on light microscopy (LM). Following the implementation of control programs in this region, new approaches to stratify transmission and direct efforts at an individual and community level are needed. Antibody responses to serological exposure markers (SEM) to Plasmodium vivax have proven diagnostic performance to identify people exposed in the previous 9 months. METHODOLOGY: We measured antibody responses against 8 SEM to identify recently exposed people and determine the transmission dynamics of P. vivax in peri-urban (Iquitos) and riverine (Mazán) communities of Loreto, communities that have seen significant recent reductions in malaria transmission. Socio-demographic, geo-reference, LM and qPCR diagnosis data were collected from two cross-sectional surveys. Spatial and multilevel analyses were implemented to describe the distribution of seropositive cases and the risk factors associated with exposure to P. vivax. PRINCIPAL FINDINGS: Low local transmission was detected by qPCR in both Iquitos (5.3%) and Mazán (2.7%); however, seroprevalence indicated a higher level of (past) exposure to P. vivax in Mazán (56.5%) than Iquitos (38.2%). Age and being male were factors associated with high odds of being seropositive in both sites. Higher antibody levels were found in individuals >15 years old. The persistence of long-lived antibodies in these individuals could overestimate the detection of recent exposure. Antibody levels in younger populations (<15 years old) could be a better indicator of recent exposure to P. vivax. CONCLUSIONS: The large number of current and past infections detected by SEMs allows for detailed local epidemiological analyses, in contrast to data from qPCR prevalence surveys which did not produce statistically significant associations. Serological surveillance will be increasingly important in the Peruvian Amazon as malaria transmission is reduced by continued control and elimination efforts.
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    De novo-designed transmembrane domains tune engineered receptor functions
    Elazar, A ; Chandler, NJ ; Davey, AS ; Weinstein, JY ; Nguyen, J ; Trenker, R ; Cross, RS ; Jenkins, MR ; Call, MJ ; Call, ME ; Fleishman, SJ (eLIFE SCIENCES PUBL LTD, 2022-05-04)
    De novo-designed receptor transmembrane domains (TMDs) present opportunities for precise control of cellular receptor functions. We developed a de novo design strategy for generating programmed membrane proteins (proMPs): single-pass α-helical TMDs that self-assemble through computationally defined and crystallographically validated interfaces. We used these proMPs to program specific oligomeric interactions into a chimeric antigen receptor (CAR) that we expressed in mouse primary T cells and found that both in vitro CAR T cell cytokine release and in vivo antitumor activity scaled linearly with the oligomeric state encoded by the receptor TMD, from monomers up to tetramers. All programmed CARs stimulated substantially lower T cell cytokine release relative to the commonly used CD28 TMD, which we show elevated cytokine release through lateral recruitment of the endogenous T cell costimulatory receptor CD28. Precise design using orthogonal and modular TMDs thus provides a new way to program receptor structure and predictably tune activity for basic or applied synthetic biology.
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    ALLSorts: an RNA-Seq subtype classifier for B-cell acute lymphoblastic leukemia.
    Schmidt, B ; Brown, LM ; Ryland, GL ; Lonsdale, A ; Kosasih, HJ ; Ludlow, LE ; Majewski, IJ ; Blombery, P ; Ekert, PG ; Davidson, NM ; Oshlack, A (American Society of Hematology, 2022-07-26)
    B-cell acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer. Subtypes within B-ALL are distinguished by characteristic structural variants and mutations, which in some instances strongly correlate with responses to treatment. The World Health Organisation (WHO) recognises seven distinct classifications, or subtypes, as of 2016. However, recent studies have demonstrated that B-ALL can be segmented into 23 subtypes based on a combination of genomic features and gene expression profiles. A method to identify a patient's subtype would have clear utility. Despite this, no publically available classification methods using RNA-Seq exist for this purpose. Here we present ALLSorts: a publicly available method that uses RNA-Seq data to classify B-ALL samples to 18 known subtypes and five meta-subtypes. ALLSorts is the result of a hierarchical supervised machine learning algorithm applied to a training set of 1223 B-ALL samples aggregated from multiple cohorts. Validation revealed that ALLSorts can accurately attribute samples to subtypes and can attribute multiple subtypes to a sample. Furthermore, when applied to both paediatric and adult cohorts, ALLSorts was able to classify previously undefined samples into subtypes. ALLSorts is available and documented on GitHub (https://github.com/Oshlack/AllSorts/).
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    Molecular profiling reveals features of clinical immunity and immunosuppression in asymptomatic P. falciparum malaria
    Studniberg, S ; Ioannidis, LJ ; Utami, RAS ; Trianty, L ; Liao, Y ; Abeysekera, W ; Li-Wai-Suen, CSN ; Pietrzak, HM ; Healer, J ; Puspitasari, AM ; Apriyanti, D ; Coutrier, F ; Poespoprodjo, JR ; Kenangalem, E ; Andries, B ; Prayoga, P ; Sariyanti, N ; Smyth, GK ; Cowman, AF ; Price, RN ; Noviyanti, R ; Shi, W ; Garnham, AL ; Hansen, DS (WILEY, 2022-04-01)
    Clinical immunity to P. falciparum malaria is non-sterilizing, with adults often experiencing asymptomatic infection. Historically, asymptomatic malaria has been viewed as beneficial and required to help maintain clinical immunity. Emerging views suggest that these infections are detrimental and constitute a parasite reservoir that perpetuates transmission. To define the impact of asymptomatic malaria, we pursued a systems approach integrating antibody responses, mass cytometry, and transcriptional profiling of individuals experiencing symptomatic and asymptomatic P. falciparum infection. Defined populations of classical and atypical memory B cells and a TH2 cell bias were associated with reduced risk of clinical malaria. Despite these protective responses, asymptomatic malaria featured an immunosuppressive transcriptional signature with upregulation of pathways involved in the inhibition of T-cell function, and CTLA-4 as a predicted regulator in these processes. As proof of concept, we demonstrated a role for CTLA-4 in the development of asymptomatic parasitemia in infection models. The results suggest that asymptomatic malaria is not innocuous and might not support the induction of immune processes to fully control parasitemia or efficiently respond to malaria vaccines.