Biology subjects

Li, P.

Publications and source records attributed to Li, P..

At least 199 records · Page 11Linked to original sources

bioRxiv2023

Chromosome-level genome assembly provides insights into adaptive evolution of chromosome and important traits in the gecko Gekko japonicus

Gekko japonicus possess excellent flexible climbing and detoxification ability under insectivorous habits, and its chromosomes and the genetic evolutionary mechanisms behind these traits are still unclarified. Here, we assembled a chromosome-level genome of G. japonicus with a total size of 2.53 Gb contained in 19 pairs of chromosomes. The evolutionary breakpoint regions (EBRs) are significantly enriched for some repetitive elements compared to the rest of genome and the genes located in the EBRs are enriched in defense response pathway. G. japonicus specific gene families, expanded gene families and positively selected genes are mainly enriched in some pathways related to the immune, sensory and nervous systems. These results from comprehensive comparative genomics and evolutionary genomics analyses indicated that bitter taste receptor type 2 (T2Rs) expanded in different lineages by tandem gene duplication. The expansion and independent duplication events of T2Rs and positively selected branches were predominantly present in insectivorous species, suggests that T2Rs are associate with clearance of bitter toxins in gekkotans. Detoxification genes in detox and biosynthetic cytochrome P450 of G. japonicas have frequent duplication and loss events, suggests that they undergo more birth and death processes compared to biosynthesis type genes. Pro, Cys, Gly and Ser are the most abundant amino acids in 66 epidermis formation corneous beta proteins (CBPs) of G. japonicas, the abundance of Gly and Cys in CBPs implying significant effects on the flexibility and setae adhesiveness of gekkotans. Some thermosensitive thermoregulatory transient receptor potential channels under relaxed purifying selection or positive selection in G. japonicus, implying that one of the important factors improve the ability to adapt to climate change.

genomics↗

bioRxiv2023

Ultrafast and long-range coordination of wound responses is essential for whole-body regeneration

Injury induces systemic, global responses whose functions remain elusive. In addition, mechanisms that rapidly synchronize wound responses through long distances across the organismal scale are mostly unknown. Using planarians, which have extreme regenerative ability, we report that injury induces Erk activity to travel in a wave-like manner at an unexpected speed ([~]1 mm/h), 10-100 times faster than those measured in other multicellular tissues. This ultrafast signal propagation requires longitudinal body-wall muscles, elongated cells forming dense parallel tracks running the length of the organism. Combining experiments and computational models, we show that the morphological properties of muscles allow them to minimize the number of slow intercellular signaling steps and act as bidirectional superhighways for propagating wound signals and instructing responses in other cell types. Inhibiting Erk propagation prevents cells distant to the wound from responding and blocks regeneration, which can be rescued by a second injury to distal tissues within a narrow time window after the first injury. These results suggest that rapid responses in uninjured tissues far from wounds are essential for regeneration. Our findings provide a mechanism for long-range signal propagation in large and complex tissues to coordinate cellular responses across diverse cell types, and highlights the function of feedback between spatially separated tissues during whole-body regeneration.

developmental biology↗

bioRxiv2023

Reconstruction of TrkB complex assemblies and localizing an-tidepressant targets using Artificial Intelligence

Since Major Depressive Disorder (MDD) represents a neurological pathology caused by inter-synaptic messaging errors, membrane receptors, the source of signal cascades, constitute appealing drugs targets. G protein-coupled receptors (GPCRs) and ion channel receptors chelated antidepressants (ADs) high-resolution architectures were reported to realize receptors physical mechanism and design prototype compounds with minimal side effects. Tyrosine kinase receptor 2 (TrkB), a receptor that directly modulates synaptic plasticity, has a finite three-dimensional chart due to its high molecular mass and intrinsically disordered regions (IDRs). Leveraging breakthroughs in deep learning, the meticulous architecture of TrkB was projected employing Alphfold 2 (AF2). Furthermore, the Alphafold Multimer algorithm (AF-M) models the coupling of intra- and extra-membrane topologies to chaperones: mBDNF, SHP2, Etc. Conjugating firmly dimeric transmembrane helix with novel compounds like 2R,6R-hydroxynorketamine (2R,6R-HNK) expands scopes of drug screening to encompass all coding sequences throughout genomes. The operational implementation of TrkB kinase-SHP2, PLC{gamma}1, and SHC1 ensembles has paved the path for machine learning in which it can forecast structural transitions in the self-assembly and self-dissociation of molecules during trillions of cellular mechanisms. In silicon, the cornerstone of the alteration will be artificial intelligence (AI), empowering signal networks to operate at the atomic level and picosecond timescales.

bioinformatics↗

bioRxiv2023

Spike substitution T813S increases Sarbecovirus fusogenicity by enhancing the usage of TMPRSS2.

SARS-CoV Spike (S) protein shares considerable homology with SARS-CoV-2 S, especially in the conserved S2 subunit (S2). S protein mediates coronavirus receptor binding and membrane fusion, and the latter activity can greatly influence coronavirus infection. We observed that SARS-CoV S is less effective in inducing membrane fusion compared with SARS-CoV-2 S. We identify that S813T mutation is sufficient in S2 interfering with the cleavage of SARS-CoV-2 S by TMPRSS2, reducing spike fusogenicity and pseudoparticle entry. Conversely, the mutation of T813S in SARS-CoV S increased fusion ability and viral replication. Our data suggested that residue 813 in the S was critical for the proteolytic activation, and the change from threonine to Serine at 813 position might be an evolutionary feature adopted by SARS-2-related viruses. This finding deepened the understanding of Spike fusogenicity and could provide a new perspective for exploring Sarbecovirus evolution. Author SummaryThe Spike strain of SARS-CoV-2 has accumulated many mutations during its time in circulation, most of which have occurred in the S1 region, and more specifically in the RBD, in an effort to either improve the viruss affinity for the receptor ACE2 or to enhance its ability to evade the immune system. Mutations in the Spike S2 region have more far-reaching effects than those in the S1 region because it is more conserved across sarbecoviruses. By comparing SARS and SARS2, we found that an important substitution at amino acid position 813 in the S2 region (T813S) disrupts the utilization of TMPRSS2 and can significantly influence viral entry into cells. This discovery deepens our knowledge of S proteins and provides new prospects for tracing the evolution of Sarbecoviruses.

microbiology↗

bioRxiv2022

FOXC2 marks and maintains the primitive spermatogonial stem cells subpopulation in the adult testis

In adult mammals, spermatogenesis embodies the complex developmental process from spermatogonial stem cells (SSCs) to spermatozoa. At the top of this developmental hierarchy lie a series of SSC subpopulations. Their individual identities as well as the relationships with each other, however, remain largely elusive. Using single-cell analysis and lineage tracing, we discovered both in mice and humans the quiescent adult SSC subpopulation marked specifically by forkhead box protein C2 (FOXC2). All spermatogenic progenies can be derived from FOXC2+ SSCs and the ablation of FOXC2+ SSCs led to the depletion of the undifferentiated spermatogonia pool. During germline regeneration, FOXC2+ SSCs were activated and able to completely restore the process. Germ cell specific Foxc2 knockout resulted in an accelerated exhaustion of SSCs and eventually led to male infertility. Furthermore, FOXC2 prompts the expressions of negative regulators of cell cycle thereby ensures the SSCs reside in quiescence. Thus, this work proposes that the quiescent FOXC2+ SSCs are essential for maintaining the homeostasis and regeneration of spermatogenesis in adult mammals.

developmental biology↗

bioRxiv2022

A Host-Harbored Metabolic Susceptibility of Coronavirus Enables Broad-Spectrum Targeting

Host-based antivirals could offer broad-spectrum therapeutics and prophylactics against the constantly-mutating viruses including the currently-ravaging coronavirus, yet must target cellular vulnerabilities of viruses without grossly endangering the host. Here we show that the master lipid regulator SREBP1 couples the phospholipid scramblase TMEM41B to constitute a host "metabolism-to-manufacture" cascade that maximizes membrane supplies to support coronaviral genome replication, harboring biosynthetic enzymes including Lipin1 as druggable viral-specific-essential (VSE) host genes. Moreover, pharmacological inhibition of Lipin1, by a moonlight function of the widely-prescribed beta-blocker Propranolol, metabolically uncouples the SREBP1-TMEM41B cascade and consequently exhibits broad-spectrum antiviral effects against coronaviruses, Zika virus, and Dengue virus. The data implicate a metabolism-based antiviral strategy that is well tolerated by the host, and a potential broad-spectrum medication against current and future coronavirus diseases.

cell biology↗

bioRxiv2022

13C ENDOR Spectroscopy-Guided MD Computations Reveals the Structure of the Enzyme-Substrate Complex of an Active, N-linked Glycosylated Lipoxygenase

Lipoxygenases (LOXs) are enzymes responsible for producing important cell signaling mediators and have been extensively studied for their potential clinical relevance as well as to advance our understanding of enzyme catalysis. The common inability to capture and characterize LOX-substrate complexes by Xray co-crystallography requires the development of alternative structural methods. We previously reported the integration of 13C/1H electron nuclear double resonance (ENDOR) spectroscopy and molecular dynamics (MD) to visualize the complex structure of the paradigmatic LOX from soybean, SLO, with substrate linoleic acid (LA). However, this required substitution of the catalytic mononuclear, nonheme iron by the structurally faithful, yet inactive Mn2+ ion as a spin-probe. Unlike canonical Fe-LOXs from plants and animals, LOXs from pathogenic fungi contain active mononuclear manganese metallocentres. Here, we report the ground-state active-site structure of the native, fully glycosylated fungal LOX from M. oryzae, MoLOX complexed with LA obtained through the 13C/1H ENDOR-guided MD approach. The Mn-oxygen-to-LA donor carbon distance (DAD) for MoLOX-LA, 3.4 {+/-} 0.3 [A], matches the distance in the single representative X-ray co-structure of an animal 8R-LOX with its natural fatty acid substrate, and slightly elongated from that of the SLO-LA complex, 3.1 {+/-} 0.2 [A], despite its carboxylate-out substrate binding orientation versus carboxylate-in for SLO. The results provide unique insight into the evolutionary divergence of the ground-state DAD in the LOX family, which influences the activation barrier for hydrogen tunneling, and give a structural basis for guiding development of MoLOX inhibitors. The work highlights the robustness of ENDOR-guided MD approach to describe LOX-substrate structures that elude conventional X-ray techniques.

biochemistry↗

bioRxiv2022

Comparative genomic analysis between Leonurus japonicus and Leonurus sibiricus

Leonurus japonicus Houtt. is an important medicinal plant in East Asia and is now widely recognized for its role in treating cerebral apoplexy and lowering blood lipids. Here, we report two sets of chromosome-level genome sequences for leonurine-producing Leonurus japonicus and for its closely related species leonurine-free Leonurus sibiricus, where 99.78% of 518.19 Mb of L. japonicus was assembled into ten pseudochromosomes with a contig N50 of 17.62 Mb and 99.33% of 472.29 Mb of L. sibiricus was assembled into nine pseudochromosomes with a contig N50 of 13.29 MB. The reference genomes of Leonurus will accelerate the decoding of novel bioactive molecules in medicinal plants, especially in the Lamiaceae family.

plant biology↗

bioRxiv2022

Distinct super-enhancer elements differentially control Il2ra gene expression in a cell-type specific fashion

The IL-2 receptor -chain (IL-2R/CD25) is constitutively expressed on DN2/DN3 thymocytes and Treg cells but induced by IL-2 on mature T and NK cells. Il2ra expression is regulated by a super-enhancer extensively bound by STAT5 in mature T cells. Here, we demonstrate that STAT5 cooperates with Notch to induce/maintain Il2ra/CD25 expression in DN2/DN3 cells. Moreover, we systematically investigated CD25 regulation using a series of mice with deletions spanning STAT5 binding elements. Deleting the upstream super-enhancer region mainly affected constitutive CD25 expression on DN2/DN3 thymocytes and Tregs, whereas deleting an intronic region primarily decreased IL-2-induced CD25 on peripheral T and NK cells. Thus, distinct elements preferentially control constitutive versus inducible expression in a cell-type-specific manner, with the MED1 coactivator co-localizing with specific STAT5 binding sites. Moreover, the intronic region was a dominant element whose deletion altered the structure throughout the super-enhancer in mature T cells. These results demonstrate differential functions for distinct super-enhancer elements, thereby indicating ways to manipulate CD25 expression in a cell-type specific fashion.

immunology↗

bioRxiv2022

Structural Insights into Branch Site Proofreading by Human Spliceosome

Selection of the pre-mRNA branch site (BS) by U2 snRNP is crucial to prespliceosome (A complex) assembly. The RNA helicase PRP5 proofreads BS selection; but the underlying mechanism remains unclear. Here we report the atomic structures of two sequential complexes leading to prespliceosome assembly: human 17S U2 snRNP and a cross-exon pre-A complex. PRP5 is anchored on 17S U2 snRNP mainly through occupation of the RNA path of SF3B1 by an acidic loop of PRP5; the helicase domain of PRP5 associates with U2 snRNA; the BS-interacting stem loop (BSL) of U2 snRNA is shielded by the splicing factor TAT-SF1, unable to engage the BS. In the pre-A complex, an initial U2/BS duplex is formed; the translocated helicase domain of PRP5 stays with U2 snRNA; the acidic loop still occupies the RNA path. The pre-A conformation is specifically stabilized by the splicing factors SF1, DNAJC8 and SF3A2. Cancer-derived mutations in SF3B1 damage its association with PRP5, compromising BS proofreading. Together, these findings reveal key insights into prespliceosome assembly and BS selection/proofreading by PRP5.

biochemistry↗

bioRxiv2022

CTCF mediates the Activity-by-contact derived cis-regulatory hubs

The 3D chromatin architecture establishes a complex network of genes and regulatory elements necessary for transcriptomic regulation in development and disease. This network can be modelled by cis-regulatory hubs (CRH), which underscore the local functional interactions between enhancers and promoter regions and differ from other higher-order chromatin structures such as topologically associated domains (TAD). The Activity-by-contact (ABC) model of enhancer-promoter regulation has been recently used in the identification of these CRHs, but little is known about the role of CTCF on the ABC scores and the consequent impact on CRHs. Here we show that the loss of CTCF leads to a reorganization of the ABC-derived rankings of the putative enhancers in the mouse heart, a global reduction of the total number of CRHs and an increase in the size of the CRHs. Furthermore, CTCF loss leads to a higher percentage of CRHs that cross TAD boundaries. These results provide another layer of evidence to support the importance of CTCF in the formation of regulatory networks necessary for gene regulation. SummaryDeletion of CTCF in mouse cardiomyocytes led to reorganization of the activity-by-contact scores of the heart enhancers and changes in the cis-regulatory hubs

molecular biology↗

bioRxiv2022

USP10 strikes down Wnt/β-catenin signaling by dual-wielding deubiquitinase activity and phase transition potential

Wnt/{beta}-catenin signaling is a conserved pathway crucially governing development, homeostasis and oncogenesis. Discovery of novel regulators holds great values in both basic and translational research. Through screening, we identified a deubiquitinase (DUB) USP10 as a novel and critical modulator of {beta}-catenin. Mechanistically, USP10 binds to key scaffold Axin1 via conserved motifs and stabilizes Axin1 through K48-linked deubiquitination, and surprisingly, tethers Axin1 and {beta}-catenin physically while promoting phase separation for {beta}-catenin suppression regardless of its enzymatic activity. Functionally, USP10 prominently regulates embryonic development and intestinal homeostasis by antagonizing {beta}-catenin via DUB activity. In colorectal cancer, USP10 substantially represses cancer growth mainly through physical binding compensation and phase separation promotion and correlates with Wnt/{beta}-catenin magnitude clinically. Collectively, we discovered USP10 functioning in multiple biological processes against {beta}-catenin and unearthed a novel enzyme-dependent and -independent "dual-regulating" mechanism by which USP10 utilizes parallelly and context-dependently. USP10 inhibitor was suggested in treating certain Wnt-related diseases.

cell biology↗

bioRxiv2022

Development of Scaffold-free 3D Cholangiocyte Organoids to Study the Progression of Primary Sclerosing Cholangitis

Organoids are novel in vitro models to study intercellular crosstalk between the different types of cells in the pathophysiology of disease. To better understand the underlying mechanisms driving the progression of primary sclerosing cholangitis (PSC), we developed scaffold-free multi-cellular 3D cholangiocyte organoids (3D-CHO) using primary liver cell lines derived from normal and PSC patients. Human liver samples from healthy donors and late-stage PSC patients were used to isolate primary cholangiocytes (EPCAM+/CK-19+), liver endothelial cells (LECs, CD31+), and hepatic stellate cells (HSCs, CD31-/CD68-/Desmin+/Vitamin A+). 3D-CHOs were formed using cholangiocytes:HSCs:LECs and kept viable for up to 1 month. Isolated primary cell lines and 3D-CHOs were further characterized by immunofluorescence (IF), qRT-PCR, and transmission electron microscopy. Gene expressions for cholangiocytes (SOX9, CFTR, EpCAM, AE, SCT, SCTR), fibrosis (ACTA2, COL1A1, DESMIN, TGF{beta}1), angiogenesis (PECAM, VEGF, CDH5, vWF), and inflammation (IL-6, TNF-) confirmed PSC phenotypes of 3D-CHOs. Since cholangiocytes develop a neuroendocrine phenotype and express neuromodulators, confocal-IF demonstrated that neurokinin-1 receptor (NK-1R, expressed by cholangiocytes and upregulated in PSC), was localized within CK-19+ cholangiocytes. Moreover, 3D-CHOs from PSC patients confirmed PSC phenotypes with upregulated NK-1R, tachykinin precursor 1, and downregulated membrane metalloendopeptidase. Our viable scaffold-free multiple-cell 3D-CHOs showed superiority as an in vitro model in mimicking PSC in vivo phenotypes compared to 2D cell culture, which can be used in PSC disease-related research.

bioengineering↗

bioRxiv2022

PHF1 compartmentalizes PRC2 at target loci via phase separation

Polycomb repressive complex 2 (PRC2) is central to polycomb repression as it trimethylates lysine 27 on histone H3 (H3K27me3). How PRC2 is recruited to its targets to deposit H3K27me3 remains an open question. Polycomb-like (PCL) proteins, a group of conserved PRC2 accessory proteins, direct PRC2 to its targets. In this report, we demonstrate that a PCL protein named PHF1 forms phase-separated condensates at H3K27me3 loci that recruit PRC2. Combining cellular observation and biochemical reconstitution, we show that the N-terminal domains of PHF1 cooperatively mediate target recognition, the chromo-like domain recruits PRC2, and the intrinsically disordered region (IDR) drives phase separation. Moreover, we reveal that the condensates compartmentalize PRC2, DNA, and nucleosome arrays by phase separation. Luciferase reporter assays confirm that PHF1 phase separation promotes transcription repression, further supporting a role of the condensates in polycomb repression. Based on our findings, we propose that these condensates create favorable microenvironments at the target loci for PRC2 to function.

molecular biology↗

bioRxiv2022

Gaq-PKD/PKCμ regulates the IkB transcription to limit the NF-kB mediated inflammatory response essential for early pregnancy

Decidualization, denoting the transformation of endometrial stromal cells into specialized decidual cells, is a prerequisite for normal embryo implantation and a successful pregnancy in human. Here we demonstrated that knockout of Gaq lead to an aberrantly enhanced inflammatory state during decidualization. Furthermore, we showed that deficiency of Gaq resulted in over-activation of nuclear factor (NF)-{kappa}B signaling, due to the decreased expression of NF{kappa}BIA, which encode the I{kappa}B protein and is the negative regulator for NF{kappa}B. Mechanistically, Gaq deficiency decreased the PKD/PKC phosphorylation levels, so leading to attenuated HDAC5 phosphorylation and thus its nuclear export. Aberrantly high level of nuclear HADC5 retarded histone acetylation to inhibit NF{kappa}BIA transcription during decidualization. Consistently, pharmacological activation of the PKD/PKC or inhibition of the HDAC5 signaling restored the inflammatory state and proper decidual response. Finally, we disclosed that over-active inflammatory state in Gaq deficient decidua deferred the blastocyst hatching and adhesion in vitro, and the decidual expression of Gq was significantly lower in women with recurrent pregnancy loss compared with normal pregnancy. In brief, we showed here that Gq as a key regulator of the inflammatory cytokines expression and decidual homeostasis in response to differentiation cues, which is required for successful implantation and early pregnancy.

cell biology↗

bioRxiv2022

Combined Developmental Toxicity Of Cyhalofop-butyl And Quizalofop-p-ethyl On The Zebrafish (Danio rerio) Embryos

Aryloxyphenoxypropionate herbicides have the characteristics of high efficiency, low toxicity, and safety to subsequent crops, and occupy an important position in the world herbicide market. Cyhalofop-butyl and quizalofop-p-ethyl are two representative herbicides, which are widely used in weed control. However, there is limited information on their combined toxicity to aquatic organisms. In this study, the developmental toxicity of cyhalofop-butyl and quizalofop-p-ethyl exposure in combination on zebrafish embryos was valuated to better understand the interaction between the that. The 96 h-LC50 (50% lethal concentration) of cyhalofop-butyl and quizalofop-p-ethyl on zebrafish embryos were 0.637 mg{middle dot}L-1 and 0.248 mg{middle dot}L-1, respectively. The combined effect of cyhalofop-butyl and quizalofop-p-ethyl was an antagonistic effect, and the 96 h-LC50 of zebrafish embryos was 1.043 mg{middle dot}L-1. Morphologically distinct pericardial edema and yolk cysts were observed after combined exposure, with significant effects on body length and heart rate in zebrafish embryos. At the same time, the mRNA levels of gene related to apoptosis and cardiac development also changed significantly. Therefore, we speculate that changes in genes related to apoptosis and cardiac development should be responsible for the abnormal development during embryonic development following co-exposure of cyhalofop-butyl and quizalofop-p-ethyl. HighlightsO_LICombined exposure caused deformities in zebrafish. C_LIO_LICombined exposure caused apoptosis in zebrafish. C_LIO_LICombined exposure altered the expression of apoptosis and cardiac-related genes in zebrafish. C_LI

pharmacology and toxicology↗

bioRxiv2022

Nimbolide Targets RNF114 to Induce the Trapping of PARP1 and Poly-ADP-Ribosylation-Dependent DNA Repair Factors

PARP1 is an abundant nuclear enzyme that is critically involved in DNA damage response. Its main enzymatic function is to catalyze a protein post-translational modification known as poly-ADP-ribosylation (PARylation). Despite the tremendous progresses of PARP1 inhibitors (PARPi) in the clinic, the basic mechanism of action of PARPi is poorly understood. Recent studies point to PARP1 trapping as a key factor driving the cytotoxic and immunomodulatory functions of PARPi. However, the molecular underpinnings of PARP1 trapping remain elusive. Here, using an unbiased, quantitative proteomic screen, we identified RING finger protein 114 (RNF114), as a PARylation-dependent, ubiquitin E3 ligase involved in DNA damage response. Upon sensing DNA damage, RNF114 was recruited, in a PAR-dependent manner, to the DNA lesions, where it specifically targeted PARylated-PARP1 for ubiquitin-proteasomal degradation. The blockade of this pathway interfered with the removal of PARP1 from the DNA damage site, leading to profound PARP1 trapping. We show that a natural product, Nimbolide, targeted RNF114 to block the degradation and removal of PARylated-PARP1 from DNA lesions. Unlike conventional PARPi, nimbolide treatment induced the trapping of both PARP1 and PARylation-dependent DNA repair factors. This unique mechanism of action of nimbolide translated into its superior cytotoxic effects against BRCA-deficient cancers. Furthermore, we demonstrated that, as a super trapper of both PARylated-PARP1 and PARylation-dependent DNA repair factors, nimbolide was able to overcome the intrinsic and acquired resistance to PARPi. Finally, we showed that nimbolide treatment activated innate immune signaling and was able to synergize with various cytotoxic agents. These results point to the exciting possibility of targeting homologous recombination-deficient cancers using nimbolide and its analogs.

cancer biology↗

bioRxiv2022

Brief Report: Prognostic relevance of 3q amplification in squamous cell carcinoma of the lung

IntroductionAmplification of 3q is the most common genetic alteration identified in squamous cell carcinoma of the lung (LUSC) with the most frequent amplified region being 3q26-3q28. MethodsIn this analysis, we aim to describe the prognostic relevance of 3q by focusing on a minimal common region (MCR) of amplification within 3q constituted by 25 genes. We analyzed 511 cases of LUSC from The Cancer Genome Atlas (TCGA) and included 476 in the final analysis. ResultsWe identified a 25-gene MCR that was amplified in 221 (44.3%) cases and was associated with better disease specific-survival (DSS) (NR versus 9.25 years; 95% CI [5.24-NR]; log-rank p=0.011) and a progression-free interval (PFI) of 8 years (95% CI [5.1-NR]) versus 4.9 years (95% [3.5-NR]) (Log-rank p=0.020). Multivariable analysis revealed MCR amplification was associated with improved DSS and PFI. ConclusionAmplification of the 25-gene MCR within 3q was present in 44% of this cohort mainly composed of Caucasian patients with early-stage LUSC. This analysis is a strong indicator of the prognostic relevance of the 25-gene MCR within 3q. We are further evaluating its prognostic relevance in a racially diverse patient population with advanced LUSC.

genomics↗