Biology subjects

Miller, J. L.

Publications and source records attributed to Miller, J. L..

7 recordsLinked to original sources

bioRxiv2026

Exposure to p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) Perturbs Cell State and Stem Cell Markers and Induces an Epidermal Phenotype in Human Breast Cells

Breast cancer is the second leading cause of cancer deaths in U.S. women. Endocrine disruptors, such as the DDT metabolite DDE, are environmental factors linked to breast cancer risk. Emerging evidence shows that during carcinogenesis, cells reacquire stem cell traits and exhibit phenotypic plasticity. In these phenotypically plastic states, breast cells transition between phenotypes, for example, from epithelial to mesenchymal (EMT) phenotypes, or from luminal to basal. Discovering how environmental factors alter cell phenotype may be a critical step in preventing and treating breast cancer. We applied a novel high-content imaging method for the evaluation of expression of stemness and cell state markers (ALDH1A3, CD44, CD24, KRT8, and KRT14) and evaluated these markers after introducing environmentally relevant concentrations of DDE (25 nM to 25 M) to non-tumorigenic MCF10A breast epithelial cells grown in 3D anchorage independent conditions. After identifying surprisingly profound cell state alterations, including a loss of KRT8 and KRT14 expression, by 25 M DDE exposure, we used transcriptomic profiling along with pharmaceutical and genetic knockdown approaches to characterize the molecular mechanisms by which DDE exposure modulates breast epithelial cell state. Keratinization and formation of the cornified envelope were biological pathways upregulated with a maximum fold change of 360.47. We identify DLX3 as a transcription factor which is inducible by DDE exposure and is also highly upregulated in human breast cancers, reflecting a novel mechanism by which environmental exposures may promote cellular plasticity and breast carcinogenesis.

pharmacology and toxicology↗

bioRxiv2026

Pan-neutralization of parainfluenza viruses by a hemagglutinin-neuraminidase antibody

Human parainfluenza viruses (HPIVs) can cause severe respiratory illnesses, such as croup, bronchiolitis, and pneumonia, particularly in children, the elderly and immunocompromised individuals. No vaccines or specific therapeutics are available for use in humans. Here, we report the discovery of a human monoclonal antibody designated PVA269 that broadly and potently neutralizes all four HPIV subtypes, PIV5, and Sendai virus by targeting the hemagglutinin-neuraminidase (HN) glycoprotein. We show that PVA269 inhibits neuraminidase activity and hemagglutination of erythrocytes through insertion of a long heavy chain complementary-determining region 3 in the enzyme active site. We reveal that the antibody markedly remodels its interactions to accommodate distinct viral features across HPIV subtypes, such as HPIV2 N-linked glycans. These results define the molecular basis for the unique PVA269 pan-neutralizing activity of human and animal viruses spanning two genera. PVA269 provides potent prophylactic activity against HPIV3 replication in the upper and lower airways of the clinically predictive cotton rat model, thus supporting translation of its protective efficacy to humans. These data establish PVA269 as a best-in-class monoclonal antibody and a promising clinical candidate to prevent HPIV infection, transmission, and disease in vulnerable populations.

immunology↗

bioRxiv2024

PTEN and ARID1A haploinsufficiency equip colonic epithelium for oncogenic transformation

Normal aged tissues are thought to exist as a patchwork of mutant clones. However, the relevance of driver mutations in normal tissue in terms of cancer initiation has not been well described. Here, we sought a quantitative understanding of how different cancer drivers achieve an age-related mutational footprint in the human colonic epithelium and to relate the clonal behaviours they generate to cancer risk. Metanalysis of contemporary multiregional sampling studies of colorectal tumours revealed many of the weak or moderate cancer drivers are trunk mutations present in the last common ancestor from which cancers arise. To study the processes by which such driver mutations could contribute to cancer predisposition, immunohistochemistry was used to detect PTEN, SMAD4 and ARID1A deficient clones in normal colon FFPE surgical resection samples (N=182 patients). Age-related changes in clone size and frequency identified positive biases in clone dynamics that acted to increase the mutational footprint for ARID1A and PTEN but not SMAD4. In vitro engineered monoallelic loss of PTEN and ARID1A implicated specific altered downstream pathways and acquired pro-oncogenic cellular fates corresponding to haploinsufficiency for these genes. In situ analysis confirmed enhanced proliferation in both PTEN and ARID1A deficient clones and creation of an immune exclusive microenvironment associated with ARID1A deficiency. The behaviours resulting from haploinsufficiency of PTEN and ARID1A exemplify how priming of the tissue through somatic mosaicism could contribute alternative combinations of genetic events leading to transformation.

cancer biology↗

bioRxiv2024

Optimized CART Cell Therapy for Metastatic Aggressive Thyroid Cancer

Most thyroid cancer deaths are attributed to a subset of poorly differentiated, metastatic tumors. To improve treatment options for aggressive thyroid cancers, we developed a novel thyroid-stimulating hormone receptor (TSHR)-targeted chimeric antigen receptor T (CART) cell therapy, which demonstrated antigen-specific activation and antitumor efficacy against TSHR+ cell lines in vitro and in vivo. However, de-differentiated thyroid cancers downregulate TSHR. We therefore developed a potent treatment strategy by combining our novel TSHR-CART cells with mitogen-activated protein kinase (MAPK) inhibitors, which redifferentiate thyroid tumors and upregulate TSHR expression. In patient-derived anaplastic thyroid cancer xenografts, combination therapy of TSHR-CART cells and MAPK inhibitors led to increased TSHR expression on the tumor tissue and significantly enhanced antitumor efficacy and prolonged survival compared to TSHR-CART monotherapy. Based on our data, we are launching a phase I clinical trial for TSHR-CART cell therapy alone or in combination with MAPK inhibitors in patients with metastatic thyroid cancers. STATEMENT OF SIGNIFICANCEPoor target selection and antigen escape limit CART cell efficacy in solid tumors. We developed TSHR-CART cells to treat differentiated thyroid cancers but observed TSHR downregulation in dedifferentiated thyroid cancers. We found that MAPK inhibitors restored TSHR expression and sensitized these cancers to TSHR-CART cell therapy.

immunology↗

bioRxiv2022

The Queensland Twin Adolescent Brain Project, a longitudinal study of adolescent brain development

We describe the Queensland Twin Adolescent Brain (QTAB) dataset and provide a detailed methodology and technical validation to facilitate data usage. The QTAB dataset comprises multimodal neuroimaging, as well as cognitive and mental health data collected in adolescent twins over two sessions (session 1: N = 422, age 9-14 years; session 2: N = 304, 10-16 years). The MRI protocol consisted of T1-weighted (MP2RAGE), T2-weighted, FLAIR, high-resolution TSE, SWI, resting-state fMRI, DWI, and ASL scans. Two fMRI tasks were added in session 2: an emotional conflict task and a passive movie-watching task. Outside of the scanner, we assessed cognitive function using standardised tests. We also obtained self-reports of symptoms for anxiety and depression, perceived stress, sleepiness, pubertal development measures, and risk and protective factors. We additionally collected several biological samples for genomic and metagenomic analysis. The QTAB project was established to promote health-related research in adolescence.

neuroscience↗

bioRxiv2021

Evaluating Sleep Disturbances in Children with Rare Genetic Neurodevelopmental Syndromes

BackgroundAdequate sleep is important for proper neurodevelopment and positive health outcomes. Sleep disturbances are more prevalent in children with genetically determined neurodevelopmental syndromes compared to typically developing counterparts. We characterize sleep behavior in Rett (RTT), Angelman (AS) and Prader-Willi (PWS) syndromes in order to identify effective approaches for treating sleep problems in these populations. We compared sleep-related symptoms across individuals with these different syndromes to each other, and to typically developing controls. MethodsChildren were recruited from the Rare Diseases Clinical Research Network (RDCRN) consortium registries; unaffected siblings were enrolled as related controls. For each participant, a parent completed multiple sleep questionnaires including: Pediatric Sleep Questionnaire (Sleep-Disordered Breathing [SDB]); Childrens Sleep Habits Questionnaire; Pediatric Daytime Sleepiness Scale. ResultsSleep data were analyzed from 714 participants, ages 2-18 years. Young children with AS had more reported sleep problems than children with RTT or PWS. Older children with RTT had more reported daytime sleepiness than those with AS or PWS. Finally, all individuals with RTT had more evidence of sleep-disordered breathing when compared to individuals with PWS. Notably, typically developing siblings were also reported to have sleep problems, except for sleep-related breathing disturbances which were associated with each of the genetic syndromes. ConclusionsIndividuals with RTT, AS and PWS frequently experience sleep problems, including sleep-disordered breathing. Screening for sleep problems in individuals with these and other neurogenetic disorders should be included in clinical assessment and managements. These data may also be useful in developing treatment strategies and in clinical trials.

genetics↗

bioRxiv2018

Assessment of the petroleum hydrocarbon biodegradation potential of the sediment microbial community from an urban fringing tidal marsh of Northern New England.

We assessed the impact of dodecane, n- hexane and gasoline on the microbial diversity of chronically polluted fringing tidal marsh sediment from the Great Bay Estuary of New Hampshire. Dilution cultures containing saturated alkane concentrations were sampled at zero, one and 10 days, and alkB and cyp153A1 alkane hydroxylase gene libraries and 16S rRNA sequences were analyzed. The initial sediment had the most diverse alkane hydroxylase sequences and phylogenetic composition whereas treated sediments became less functionally and phylogenetically diverse with alkane substrates apparently enriching a few dominant taxa. All 1-and 10-day samples were dominated by Pseudomonas- type alkane hydroxylase sequences except in dodecane treatments where primarily Rhodococcus--type alkane hydroxylases were detected. 16S rRNA profiling revealed that the Gammaproteobacteria, particularly Pseudomonas, dominated all one day samples, especially the n- hexane and gasoline treatments (63.2 and 47.2% respectively) and the 10-day n- hexane treatment (which contained 60.8% Pseudomonas and 18.6%Marinobacter). In contrast, the 10 days of dodecane treatment enriched for Actinobacteria (26.2% Rhodococcus and 32.4%Mycobacterium) and gasoline treatment enriched for Firmicutes (29.7%; mainly Bacillus, Lysinibacillus and Rumelibacillus). Our data indicate that fringing tidal marshes contain microbial communities with alkane-degrading abilities similar to larger meadow marshes, and support the hypothesis that alkane exposure reduces the functional and phylogenetic diversity of microbial communities in an alkane-specific manner. Further research to evaluate the ability of such fringing marsh communities to rebound to pre-pollutant diversity levels should be conducted to better assess the threat of petroleum to these habitats.

microbiology↗