Publications by authors named "Lauren A MacDonald"

5 Publications

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Patients with BRCA mutated ovarian cancer may have fewer circulating MDSC and more peripheral CD8 T cells compared with women with BRCA wild-type disease during the early disease course.

Oncol Lett 2019 Oct 7;18(4):3914-3924. Epub 2019 Aug 7.

Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.

Immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) are associated with immunologic tolerance and poor prognosis in ovarian cancer (OvCa). We hypothesized that women with germline BRCA1 and BRCA2 mutation-associated (gBRCAm) OvCa would have fewer circulating immunosuppressive immune cells compared to those with BRCA wild-type (BRCAwt) disease during their early disease course (<5 years post-diagnosis) where gBRCAm is a favorable prognostic factor. We collected and viably froze peripheral blood mononuclear cells (PBMCs) from patients with recurrent OvCa olaparib clinical trials (NCT01445418/NCT01237067). Immune subset analyses were performed using flow cytometry for Tregs, exhausted CD8 T cells, monocytes and MDSCs. Functional marker expression, including cytotoxic T lymphocyte-associated protein 4 (CTLA-4), T cell immunoglobulin and mucin domain 3 (TIM-3) and programmed cell death protein 1 (PD-1) was evaluated. Data were analyzed using FlowJo. Pretreatment PBMCs were collected from 41 patients (16 gBRCAm/25 BRCAwt). The percentage of MDSCs among viable CD45 PBMC was lower in gBRCAm OvCa compared with BRCAwt OvCa (median 0.565 vs. 0.93%, P=0.0086) but this difference was not seen in those women >5 years post-diagnosis. CD8 T cells among viable CD45 PBMCs and CTLA-4/CD8 T cells were higher in gBRCAm carriers than patients with BRCAwt, in particular for those <5 years post-diagnosis (median 20.4 vs. 9.78%, P=0.031 and median MFI 0.19 vs. 0.22, P=0.0074, respectively). TIM-3 expression on Tregs was associated with poor progression-free survival, independent of gBRCAm status (P<0.001). Our pilot data suggested that patients with gBRCAm OvCa may have fewer circulating MDSCs but higher CD8 T cells in PBMCs during their early disease course. This may contribute to the observed survival benefit for these women in their first post-diagnosis decade.
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http://dx.doi.org/10.3892/ol.2019.10731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732977PMC
October 2019

Epigenetic Reprogramming Strategies to Reverse Global Loss of 5-Hydroxymethylcytosine, a Prognostic Factor for Poor Survival in High-grade Serous Ovarian Cancer.

Clin Cancer Res 2018 03 20;24(6):1389-1401. Epub 2017 Dec 20.

Department of Pathology, Division of Women's and Perinatal Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

A major challenge in platinum-based cancer therapy is the clinical management of chemoresistant tumors, which have a largely unknown pathogenesis at the level of epigenetic regulation. We evaluated the potential of using global loss of 5-hydroxymethylcytosine (5-hmC) levels as a novel diagnostic and prognostic epigenetic marker to better assess platinum-based chemotherapy response and clinical outcome in high-grade serous tumors (HGSOC), the most common and deadliest subtype of ovarian cancer. Furthermore, we identified a targetable pathway to reverse these epigenetic changes, both genetically and pharmacologically. This study shows that decreased 5-hmC levels are an epigenetic hallmark for malignancy and tumor progression in HGSOC. In addition, global 5-hmC loss is associated with a decreased response to platinum-based chemotherapy, shorter time to relapse, and poor overall survival in patients newly diagnosed with HGSOC. Interestingly, the rescue of 5-hmC loss restores sensitivity to platinum chemotherapy and , decreases the percentage of tumor cells with cancer stem cell markers, and increases overall survival in an aggressive animal model of platinum-resistant disease. Consequently, a global analysis of patient 5-hmC levels should be included in future clinical trials, which use pretreatment with epigenetic adjuvants to elevate 5-hmC levels and improve the efficacy of current chemotherapies. Identifying prognostic epigenetic markers and altering chemotherapeutic regimens to incorporate DNMTi pretreatment in tumors with low 5-hmC levels could have important clinical implications for newly diagnosed HGSOC disease. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-1958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951622PMC
March 2018

Distribution and diversity of diatom assemblages in surficial sediments of shallow lakes in Wapusk National Park (Manitoba, Canada) region of the Hudson Bay Lowlands.

Ecol Evol 2016 07 9;6(13):4526-40. Epub 2016 Jun 9.

Département de géographie Université Laval Québec City QC Canada G1V 0A6; Centre d'études nordiques Université Laval Québec City QC Canada G1V 0A6.

The hydrology of shallow lakes (and ponds) located in the western Hudson Bay Lowlands (HBL) is sensitive to climate warming and associated permafrost thaw. However, their biological characteristics are poorly known, which hampers effective aquatic ecosystem monitoring. Located in northern Manitoba along the southwestern coast of Hudson Bay, Wapusk National Park (WNP) encompasses numerous shallow lakes representative of the subarctic zone. We analyzed the distribution and diversity of diatom (microscopic algae; class Bacillariophyceae) assemblages in surficial sediments of 33 lakes located in three different ecozones spanning a vegetation gradient, from NE to SW: the Coastal Fen (CF), the Interior Peat Plateau (IPP), and the Boreal Spruce Forest (BSF). We found significant differences (P < 0.05) in diatom community composition between CF and IPP lakes, and CF and BSF lakes, but not between IPP and BSF lakes. These results are consistent with water chemistry measurements, which indicated distinct limnological conditions for CF lakes. Diatom communities in CF lakes were generally dominated by alkaliphilous taxa typical of waters with medium to high conductivity, such as Nitzschia denticula. In contrast, several IPP and BSF lakes were dominated by acidophilous and circumneutral diatom taxa with preference for low conductivity (e.g., Tabellaria flocculosa, Eunotia mucophila, E. necompacta var. vixcompacta). This exploratory survey provides a first detailed inventory of the diatom assemblages in the WNP region needed for monitoring programs to detect changes in shallow lake ecosystems and ecozonal shifts in response to climate variations.
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http://dx.doi.org/10.1002/ece3.2179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4930999PMC
July 2016

Paleolimnological assessment of riverine and atmospheric pathways and sources of metal deposition at a floodplain lake (Slave River Delta, Northwest Territories, Canada).

Sci Total Environ 2016 Feb 11;544:811-23. Epub 2015 Dec 11.

Department of Biology, University of Waterloo, Waterloo, ON N2L 3G1, Canada. Electronic address:

Growth of natural resource development in northern Canada has raised concerns about the effects on downstream aquatic ecosystems, but insufficient knowledge of pre-industrial baseline conditions continues to undermine ability of monitoring programs to distinguish industrial-derived contaminants from those supplied by natural processes. Here, we apply a novel paleolimnological approach to define pre-industrial baseline concentrations of 13 priority pollutant metals and vanadium and assess temporal changes, pathways and sources of these metals at a flood-prone lake (SD2) in the Slave River Delta (NWT, Canada) located ~500 km north of Alberta's oil sands development and ~140 km south of a former gold mine at Yellowknife, NWT. Results identify that metal concentrations, normalized to lithium concentration, are not elevated in sediments deposited during intervals of high flood influence or low flood influence since onset of oil sands development (post-1967) relative to the 1920-1967 baseline established at SD2. When compared to a previously defined baseline for the upstream Athabasca River, several metal-Li relations (Cd, Cr, Ni, Zn, V) in post-1967 sediments delivered by floodwaters appear to plot along a different trajectory, suggesting that the Peace and Slave River watersheds are important natural sources of metal deposition at the Slave River Delta. However, analysis revealed unusually high concentrations of As deposited during the 1950s, an interval of very low flood influence at SD2, which corresponded closely with emission history of the Giant Mine gold smelter indicating a legacy of far-field atmospheric pollution. Our study demonstrates the potential for paleolimnological characterization of baseline conditions and detection of pollution from multiple pathways in floodplain ecosystems, but that knowledge of paleohydrological conditions is essential for interpretation of contaminant profiles.
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http://dx.doi.org/10.1016/j.scitotenv.2015.11.173DOI Listing
February 2016

Limnological regime shifts caused by climate warming and Lesser Snow Goose population expansion in the western Hudson Bay Lowlands (Manitoba, Canada).

Ecol Evol 2015 Feb 30;5(4):921-39. Epub 2015 Jan 30.

Department of Biology, University of Waterloo Waterloo, Ontario, N2L 3G1, Canada ; Parks Canada, Western and Northern Service Centre Winnipeg, Manitoba, R3B 0R9, Canada.

Shallow lakes are dominant features in subarctic and Arctic landscapes and are responsive to multiple stressors, which can lead to rapid changes in limnological regimes with consequences for aquatic resources. We address this theme in the coastal tundra region of Wapusk National Park, western Hudson Bay Lowlands (Canada), where climate has warmed during the past century and the Lesser Snow Goose (LSG; Chen caerulescens caerulescens) population has grown rapidly during the past ∽40 years. Integration of limnological and paleolimnological analyses documents profound responses of productivity, nutrient cycling, and aquatic habitat to warming at three ponds ("WAP 12", "WAP 20", and "WAP 21″), and to LSG disturbance at the two ponds located in an active nesting area (WAP 20, WAP 21). Based on multiparameter analysis of (210)Pb-dated sediment records from all three ponds, a regime shift occurred between 1875 and 1900 CE marked by a transition from low productivity, turbid, and nutrient-poor conditions of the Little Ice Age to conditions of higher productivity, lower nitrogen availability, and the development of benthic biofilm habitat as a result of climate warming. Beginning in the mid-1970s, sediment records from WAP 20 and WAP 21 reveal a second regime shift characterized by accelerated productivity and increased nitrogen availability. Coupled with 3 years of limnological data, results suggest that increased productivity at WAP 20 and WAP 21 led to atmospheric CO2 invasion to meet algal photosynthetic demand. This limnological regime shift is attributed to an increase in the supply of catchment-derived nutrients from the arrival of LSG and their subsequent disturbance to the landscape. Collectively, findings discriminate the consequences of warming and LSG disturbance on tundra ponds from which we identify a suite of sensitive limnological and paleolimnological measures that can be utilized to inform aquatic ecosystem monitoring.
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http://dx.doi.org/10.1002/ece3.1354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338974PMC
February 2015
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