Biology subjects

Chen, J. T.

Publications and source records attributed to Chen, J. T..

5 recordsLinked to original sources

bioRxiv2024

Neuronal toxicity and recovery from early bortezomib-induced neuropathy: targeting the blood nerve barrier but not the dorsal root ganglion

The use of the first in class proteasome inhibitor Bortezomib (BTZ) is highly effective in the treatment of multiple myeloma. However, its long-term use is limited by the fact, that most treated patients develop dose limiting painful polyneuropathy. In some of the treated patients, pain resolves after variable timeframes, in others it persists, despite the discontinuation of treatment, with the underlying mechanisms poorly understood. One condition of neural toxicity is the ability to penetrate the blood nerve barrier. Here we present pathways involved in early bortezomib-induced polyneuropathy (BIPN) development and its resolution, in rats and in myeloma patients. One cycle of BTZ elicited transient mechanical hyperalgesia and cold allodynia in rats. Transcriptomic signature and network analysis revealed regulation of circadian, extracellular matrix, and immune genes within the nerve and modest changes in the dorsal root ganglia. Recovery processes resealed the small molecule leakiness of the perineurial barrier, reversed axonal swelling, and normalized small fiber density in the skin. Expression of the microtubule-associated cytoskeletal protein cortactin matched this process in the perineurium. Netrin-1 (Ntn1) as a known barrier sealer was also upregulated in pain resolution in nerve and skin. In patients with painful BIPN skin NTN1 was independent of axonal damage. In summary, our data demonstrate that early BTZ toxicity targets mainly the nerve and indicates that pain resolution could be supported by protective growth factors like Ntn1 for remodeling of the extracellular matrix and neuronal barriers. SummaryBortezomib leads to dose-limiting painful polyneuropathy. Already in the first cycle, BTZ toxicity weakens the blood nerve barrier which reseals upon upregulation of netrin-1.

neuroscience↗

bioRxiv2023

An epigenome-wide analysis of DNA methylation, racialized and economic inequities, and air pollution

ImportanceDNA methylation (DNAm) provides a plausible mechanism by which adverse exposures become embodied and contribute to health inequities, due to its role in genome regulation and responsiveness to social and biophysical exposures tied to societal context. However, scant epigenome-wide association studies (EWAS) have included structural and lifecourse measures of exposure, especially in relation to structural discrimination. ObjectiveOur study tests the hypothesis that DNAm is a mechanism by which racial discrimination, economic adversity, and air pollution become biologically embodied. DesignA series of cross-sectional EWAS, conducted in My Body My Story (MBMS, biological specimens collected 2008-2010, DNAm assayed in 2021); and the Multi Ethnic Study of Atherosclerosis (MESA; biological specimens collected 2010-2012, DNAm assayed in 2012-2013); using new georeferenced social exposure data for both studies (generated in 2022). SettingMBMS was recruited from four community health centers in Boston; MESA was recruited from four field sites in: Baltimore, MD; Forsyth County, NC; New York City, NY; and St. Paul, MN. ParticipantsTwo population-based samples of US-born Black non-Hispanic (Black NH), white non-Hispanic (white NH), and Hispanic individuals (MBMS; n=224 Black NH and 69 white NH) and (MESA; n=229 Black NH, n=555 white NH and n=191 Hispanic). ExposuresEight social exposures encompassing racial discrimination, economic adversity, and air pollution. Main outcomeGenome-wide changes in DNAm, as measured using the Illumina EPIC BeadChip (MBMS; using frozen blood spots) and Illumina 450k BeadChip (MESA; using purified monocytes). Our hypothesis was formulated after data collection. ResultsWe observed the strongest associations with traffic-related air pollution (measured via black carbon and nitrogen oxides exposure), with evidence from both studies suggesting that air pollution exposure may induce epigenetic changes related to inflammatory processes. We also found suggestive associations of DNAm variation with measures of structural racial discrimination (e.g., for Black NH participants, born in a Jim Crow state; adult exposure to racialized economic residential segregation) situated in genes with plausible links to effects on health. Conclusions and RelevanceOverall, this work suggests that DNAm is a biological mechanism through which structural racism and air pollution become embodied and may lead to health inequities. Key pointsO_ST_ABSQuestionC_ST_ABSCould DNAm be a mechanism by which adversity becomes embodied? FindingsTraffic-related air pollution exposure may induce epigenetic changes related to inflammatory processes and there are suggestive associations with measures of structural racism MeaningDNAm may be a biological mechanism through which structural racism and air pollution become biologically embodied

bioinformatics↗

bioRxiv2021

The impact of low input DNA on the reliability of DNA methylation as measured by the Illumina Infinium MethylationEPIC BeadChip

BackgroundDNA methylation (DNAm) is commonly assayed using the Illumina Infinium MethylationEPIC BeadChip, but there is currently little published evidence to define the lower limits of the amount of DNA that can be used whilst preserving data quality. Such evidence is valuable for analyses utilising precious or limited DNA sources. Materials and methodsWe use a single pooled sample of DNA in quadruplicate at three dilutions to define replicability and noise, and an independent population dataset of 328 individuals (from a community-based study including US-born non-Hispanic Black and white persons) to assess the impact of total DNA input on the quality of data generated using the Illumina Infinium MethylationEPIC BeadChip. ResultsData are less reliable and more noisy as DNA input decreases to 40ng, with clear reductions in data quality; however samples with a total input as low as 40ng pass standard quality control tests, and we observe little evidence that low input DNA obscures the associations between DNAm and two phenotypes, age and smoking status. ConclusionsDNA input as low as 40ng can be used with the Illumina Infinium MethylationEPIC BeadChip, provided quality checks and sensitivity analyses are undertaken.

bioinformatics↗

bioRxiv2021

Exquisite Sensitivity to Dual BRG1/BRM ATPase Inhibitors Reveals Broad SWI/SNF Dependencies in Acute Myeloid Leukemia

Various subunits of mammalian SWI/SNF chromatin remodeling complexes display loss-of-function mutations characteristic of tumor suppressors in different cancers, but an additional role for SWI/SNF supporting cell survival in distinct cancer contexts is emerging. In particular, genetic dependence on the catalytic subunit BRG1/SMARCA4 has been observed in acute myeloid leukemia (AML), yet the feasibility of direct therapeutic targeting of SWI/SNF catalytic activity in leukemia remains unknown. Here, we evaluated the activity of dual BRG1/BRM ATPase inhibitors across a genetically diverse panel of cancer cell lines and observed that hematopoietic cancer cell lines were among the most sensitive compared to other lineages. This result was striking in comparison to data from pooled short hairpin RNA screens, which showed that only a subset of leukemia cell lines display sensitivity to BRG1 knockdown. We demonstrate that combined genetic knockdown of BRG1 and BRM is required to recapitulate the effects of dual inhibitors, suggesting that SWI/SNF dependency in human leukemia extends beyond a predominantly BRG1-driven mechanism. Through gene expression and chromatin accessibility studies, we show that the dual inhibitors act at genomic loci associated with oncogenic transcription factors, and observe a downregulation of leukemic pathway genes including MYC, a well-established target of BRG1 activity in AML. Overall, small molecule inhibition of BRG1/BRM induced common transcriptional responses across leukemia models resulting in a spectrum of cellular phenotypes. Our studies reveal the breadth of SWI/SNF dependency and support targeting SWI/SNF catalytic function as a potential therapeutic strategy in AML.

cancer biology↗

bioRxiv2019

Kelch13 and MDR1 Polymorphisms, and Drug Effectiveness at Day 3 after Dihydroartemisinin-Piperaquine Treatment for Plasmodium falciparum Malaria on Bioko Island, Equatorial Guinea: 2014-2017

Artemisinin (ART) combination therapies were introduced on malaria endemic Bioko Island in 2004 through Bioko Island Malaria Control Project. Recently, ART-resistant Plasmodium falciparum strain with Kelch13 (K13) propeller M579I mutation originating from Equatorial Guinea was observed as an increased parasite clearance time on day 3 after dihydroartemisinin-Piperaquine (DHA-PIP) treatment (D3 positivity). Here, we surveyed DHA-PIP effectiveness and molecular markers of drug resistance at D3 after DHA-PIP treatment on Bioko Island from 2014 to 2017. Among the 371 uncomplicated P. falciparum patients, 86.3% (320/471) were successfully followed up at D3. 5.9% (19/320) of patients showed D3 positivity. K13 and MDR1 gene were successfully sequenced from 46 patients collected at D0 (baseline population) and 19 D3-positivity patients. Five non-synonymous K13 mutations (H136N; K189N; K248N; K326E; K332N) were found. There was no statistical difference in the frequency of these K13 mutations between baseline population and D3-positivity samples (p>0.05). Additionally, none of the K13 propeller polymorphisms known to be involved in ART-resistance in Asia or Africa were detected. For MDR1 gene, 38.5% (25/65) carried N86Y mutation; 73.8% (48/65) the Y184F mutation. Parasites surviving DHA-PIP at D3 post-treatment were significantly more likely than the baseline population to carry the N86Y (p <0.05). These results suggest that K13 is not the best predictive molecular marker for ART resistance in Africa. More isolates from cases with delayed parasite clearance after DHA-PIP treatment indicated that in vitro and in vivo monitoring for ART derivatives and ACT partner drugs should be regularly performed on Bioko Island, Equatorial Guinea.

epidemiology↗