Biology subjects

Patterson, J.

Publications and source records attributed to Patterson, J..

3 recordsLinked to original sources

bioRxiv2018

Clonotypic Heterogeneity In Cutaneous T-Cell Lymphoma Revealed By Comprehensive Whole Exome/Transcriptome Sequencing

Mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma, is believed to represent a clonal expansion of a transformed skin resident memory T-cell. T-cell receptor (TCR) clonality (i.e. identical sequences of rearranged TCR, {beta} and {gamma}), the key premise of this hypothesis, has been difficult to document conclusively because malignant cells are not readily distinguishable from the tumor infiltrating, reactive lymphocytes, which contribute to the TCR clonotypic repertoire of MF. Here we have successfully adopted the technique of targeted whole exome and whole transcriptome sequencing (WES/WTS) to identify the repertoire of rearranged TCR genes in tumor enriched samples from patients with MF. Although most of the investigated biopsies of MF had the expected monoclonal rearrangements of TCR{gamma} of the frequency corresponding to the frequency of tumor cells, in half of the samples we detected multiple (up to seven) TCR and -{beta} clonotypes by WES and WTS. Our findings are compatible with the model in which the initial malignant transformation in MF does not occur in mature, memory T-cells but rather at the level of T-lymphocyte progenitor after TCR{gamma} rearrangement but before TCR{beta} or TCR rearrangements. The WES/WTS method is potentially applicable to other types of T-cell lymphomas and enables comprehensive characterization of the TCR repertoire and mutational landscape in these malignancies.

cancer biology↗

bioRxiv2017

Experimental Zika Virus Infection in a New World Monkey Model Reproduces Key Features of the Human Disease

Human infections by Zika virus (ZIKV), a mosquito-borne flavivirus, are associated with a current widespread outbreak in the Americas, and have been associated with neurological complications and adverse fetal outcomes such as microcephaly in pregnant women. A suitable non-human primate model is urgently needed. To evaluate ZIKV infectivity, pathogenesis, and persistence, we inoculated 4 marmosets with ZIKV and followed them by clinical monitoring and serial sampling of body fluids for up to 11 weeks. We found that marmosets experimentally infected with ZIKV reproduced key features of the human disease, including (1) asymptomatic infection, (2) brief period of detectable virus in serum (<1 week), (3) detection in other body fluids (urine, saliva, semen, and stool) for at least 2 weeks following acute infection, and (4) persistence in lymph nodes, but not other tissues, at 1 month post-infection. ZIKV-positive saliva and serum samples, but not urine, were found to be infectious in cell culture. By day 6 post-inoculation, most marmosets exhibited detectable neutralizing antibody responses concurrent with activation of NK cell and B cell subsets and an increase in circulating cytokines associated with type II interferon signaling, Transcriptome profiling revealed enrichment of immune responses to active viral infection, with up-regulation of both type I and II interferon signaling pathways, anduncovered potential host biomarkers. These results suggest that a New World monkey model of acute ZIKV infection mimics the human disease, and is likely to be useful for testing of drug and vaccine candidates.

microbiology↗

bioRxiv2017

Novel insights into the molecular heterogeneity of hepatocellularcarcinoma

Hepatocellular carcinoma (HCC) is influenced by numerous factors, which results in diverse genetic, epigenetic and transcriptional scenarios, thus posing obvious challenges for disease management. We scrutinized the molecular heterogeneity of HCC with a multi-omics approach in two small cohorts of resected and explanted livers. Whole-genome transcriptomics was conducted, including polyadenylated transcripts and micro (mi)-RNAs. Copy number variants (CNV) were inferred from whole genome low-pass sequencing data. Fifty-six cancer-related genes were screened using an oncology panel assay. HCC was associated with a dramatic transcriptional deregulation of hundreds of protein-coding genes suggesting downregulation of drugs catabolism, induction of inflammatory responses, and increased cell proliferation in resected livers. Moreover, several long non-coding RNAs and miRNAs not reported previously in the context of HCC were found deregulated. In explanted livers, downregulation of genes involved in energy-producing processes and upregulation of genes aiding in glycolysis were detected. Numerous CNV events were observed, with conspicuous hotspots on chromosomes 1 and 17. Amplifications were more common than deletions, and spanned regions containing genes potentially involved in tumorigenesis. CSF1R, FGFR3, FLT3, NPM1, PDGFRA, PTEN, SMO and TP53 were mutated in all tumors, while other 26 cancer-related genes were mutated with variable penetrance. Our results highlight a remarkable molecular heterogeneity between HCC tumors and reinforce the notion that precision medicine approaches are urgently needed for cancer treatment. We expect that our results will serve as a valuable dataset that will generate hypotheses for us or other researchers to evaluate to ultimately improve our understanding of HCC biology.

cancer biology↗