Biology subjects

Huang, D.

Publications and source records attributed to Huang, D..

6 recordsLinked to original sources

bioRxiv2018

Whole-Genome Genomics Correlates of Response To Anti-PD1 Therapy in Relapsed/Refractory Natural Killer/T Cell Lymphoma

AbstractThis study aims to identify recurrent genetic alterations in relapsed or refractory (RR) natural-killer/T-cell lymphoma (NKTL) patients who have achieved complete response (CR) with programmed cell death 1 (PD-1) blockade therapy. Seven of the eleven patients treated with pembrolizumab achieved CR while the remaining four had progressive disease (PD). Using whole genome sequencing (WGS), we found recurrent clonal structural rearrangements (SR) of the PD-L1 gene in four of the seven (57%) CR patients pretreated tumors. These PD-L1 SRs consist of inter-chromosomal translocations, tandem duplication and micro-inversion that disrupted the suppressive function of PD-L1 3UTR. Interestingly, recurrent JAK3-activating (p.A573V) mutations were also validated in two CR patients tumors that did not harbor the PD-L1 SR. Importantly, these mutations were absent in the four PD cases. With immunohistochemistry (IHC), PD-L1 positivity could not discriminate patients who archived CR (range: 6%-100%) from patients who had PD (range: 35%-90%). PD-1 blockade with pembrolizumab is a potent strategy for RR NKTL patients and genomic screening could potentially accompany PD-L1 IHC positivity to better select patients for anti-PD-1 therapy.

genomics↗

bioRxiv2018

HIV-1 vaccine design through minimizing envelope metastability

Overcoming envelope metastability is crucial to trimer-based HIV-1 vaccine design. Here, we present a coherent vaccine strategy by minimizing metastability. For ten strains across five clades, we demonstrate that gp41 ectodomain (gp41ECTO) is the main source of envelope metastability by replacing wild-type gp41ECTO with BG505 gp41ECTO of the uncleaved prefusion-optimized (UFO) design. These gp41ECTO-swapped trimers can be produced in CHO cells with high yield and high purity. Crystal structure of a gp41ECTO-swapped trimer elucidates how a neutralization-resistant tier 3 virus evades antibody recognition of the V2 apex. UFO trimers of transmitted/founder (T/F) viruses and UFO trimers containing a consensus-based ancestral gp41ECTO suggest an evolutionary root of the metastability. Gp41ECTO-stabilized trimers can be readily displayed on 24- and 60-meric nanoparticles, with incorporation of additional T cell help illustrated for a hyperstable 60-mer. In mice and rabbits, gp140 nanoparticles induced more effective tier 2 neutralizing antibody response than trimers with statistical significance.\n\nHIGHLIGHTSO_LIgp41 is the main source of HIV-1 envelope metastability\nC_LIO_LIBG505 gp41 of the UFO design stabilizes gp140 trimers of diverse subtypes\nC_LIO_LIgp41 stabilization facilitates gp140 nanoparticle assembly and improves production\nC_LIO_LINanoparticles elicit tier 2 neutralizing antibodies more effectively than trimers\nC_LI

microbiology↗

bioRxiv2018

Identification of genes affecting saturated fat acid content in Elaeis guineensis by genome-wide association analysis

Oil palm is the highest yielding oil crop per unit area worldwide. Unfortunately, palm oil is often considered unhealthy. In particular, palmic acid (C16:0) is a major component of palm oil. In this study a total of 1 261 501 SNP markers were produced in a diversity panel of 200 oil palm individuals. Oil content in this population varied from 29.8% to 70.3%, palmic acid varied from 31.3% to 48.8%, and oleic acid varied from 31.3% to 50.1%. We identified 274 SNP markers significantly associated with fatty acid compositions; 44 candidate genes in the flanking regions of these SNPs were involved in fatty acid biosynthesis and metabolism. Among them, two acyl-ACP thioesterase B genes had differential expression patterns between the mesocarp and kernel, tissues which show different oil profiles in oil palm (high palmic acid and high lauric acid respectively). Overexpression of both genes caused a significant increase in palmic acid content, while overexpression of the EgFatB2 gene also caused an accumulation of lauric acid and myristic acid. Our research provides genome-wide SNPs, a set of markers significantly associated with fatty acid content, and validated candidate genes for future targeted breeding of lower saturated fat content in palm oil.

plant biology↗

bioRxiv2017

TNER: A Novel Bayesian Background Error Suppression Method for Mutation Detection in Circulating Tumor DNA

The use of ultra-deep, next generation sequencing of circulating tumor DNA (ctDNA) holds great promise for early detection of cancer as well as a tool for monitoring disease progression and therapeutic responses. However, the low abundance of ctDNA in the bloodstream coupled with technical errors introduced during library construction and sequencing complicates mutation detection. To achieve high accuracy of variant calling via better distinguishing low frequency ctDNA mutations from background errors, we introduce TNER (Tri-Nucleotide Error Reducer), a novel background error suppression method that provides a robust estimation of background noise to reduce sequencing errors. It significantly enhances the specificity for downstream ctDNA mutation detection without sacrificing sensitivity. Results on both simulated and real healthy subjects data demonstrate that the proposed algorithm consistently outperforms a current, state of the art, position-specific error polishing model, particularly when the sample size of healthy subjects is small. TNER is publicly available at https://github.com/ctDNA/TNER.

bioinformatics↗

bioRxiv2017

Mapping Human Hematopoietic Hierarchy At Single Cell Resolution By Microwell-seq

The classical hematopoietic hierarchy, which is mainly built with fluorescence-activated cell sorting (FACS) technology, proves to be inaccurate in recent studies. Single cell RNA-seq (scRNA-seq) analysis provides a solution to overcome the limit of FACS-based cell type definition system for the dissection of complex cellular hierarchy. However, large-scale scRNA-seq is constrained by the throughput and cost of traditional methods. Here, we developed Microwell-seq, a high-throughput and low-cost scRNA-seq platform using extremely simple devices. Using Microwell-seq, we constructed a single-cell resolution transcriptome atlas of human hematopoietic differentiation hierarchy by profiling more than 50,000 single cells throughout adult human hematopoietic system. We found that adult human hematopoietic stem and progenitor cell (HSPC) compartment is dominated by progenitors primed with lineage specific regulators. Our analysis revealed differentiation pathways for each cell types, through which HSPCs directly progress to lineage biased progenitors before differentiation. We propose a revised adult human hematopoietic hierarchy independent of oligopotent progenitors. Our study also demonstrates the broad applicability of Microwell-seq technology.

cell biology↗

bioRxiv2017

The role of Cdx2 as a lineage specific transcriptional repressor for pluripotent network during trophectoderm and inner cell mass specification

The first cellular differentiation event in mouse development leads to the formation of the blastocyst consisting of the inner cell mass (ICM) and an outer functional epithelium called trophectoderm (TE). The lineage specific transcription factor CDX2 is required for proper TE specification, where it promotes expression of TE genes, and represses expression of Pou5f1 (OCT4) by inhibiting OCT4 from promoting its own expression. However its downstream network in the developing early embryo is not fully characterized. Here, we performed high-throughput single embryo qPCR analysis in Cdx2 null embryos to identify components of the CDX2-regulated network in vivo. To identify genes likely to be regulated by CDX2 directly, we performed CDX2 ChIP-Seq on trophoblast stem (TS) cells, derived from the TE. In addition, we examined the dynamics of gene expression changes using an inducible CDX2 embryonic stem (ES) cell system, so that we could predict which CDX2-bound genes are activated or repressed by CDX2 binding. By integrating these data with observations of chromatin modifications, we were able to identify novel regulatory elements that are likely to repress gene expression in a lineage-specific manner. Interestingly, we found CDX2 binding sites within regulatory elements of key pluripotent genes such as Pou5f1 and Nanog, pointing to the existence of a novel mechanism by which CDX2 maintains repression of OCT4 in trophoblast. Our study proposes a general mechanism in regulating lineage segregation during mammalian development.

cell biology↗