Biology subjects

Xu, R.

Publications and source records attributed to Xu, R..

At least 109 records · Page 6Linked to original sources

bioRxiv2023

Viscoelastic Deformability Cytometry: Ultra-high Throughput Platform for Mechanical Phenotyping of Cells in Liquid and Solid Biopsies

Due to the differences in mechanical properties between cancer cells and their benign counterparts, the mechanical characteristics of cells have emerged as a significant feature in diagnosing cancer. Consequently, measuring cell deformability as a means of mechanical phenotyping is promising for both the detection and classification of the disease. However, performing high-throughput single-cell deformability measurements on liquid or solid tissue biopsies remains a significant challenge within a clinical setting. Herein, we introduce an ultra-high throughput viscoelastic-based microfluidic platform to measure the cell mechanical properties at rates of up to 100,000 cells/s. Thanks to the viscoelastic property of the fluid, cells are focused and deformed within the same platform obviating the need for any sheath fluid. We used the presented platform for cell phenotyping in both liquid and solid tumor biopsies, such as identification of malignant lymphocytes in peripheral blood samples and glioblastoma-type cell classification from solid tumor samples. The presented platform has the potential to open new opportunities in the assessment of cancer, enable precise mechanical profiling of rare cells, and facilitate sensitive diagnostic applications.

bioengineering↗

bioRxiv2023

Multimodal single cell-resolved spatial proteomics reveals pancreatic tumor heterogeneity

Despite the advances in antibody-guided cell typing and mass spectrometry-based proteomics, their integration is hindered by challenges for processing rare cells in the heterogeneous tissue context. Here, we introduce Spatial and Cell-type Proteomics (SCPro), which combines multiplexed imaging and flow cytometry with ion exchange-based protein aggregation capture technology to characterize spatial proteome heterogeneity with single cell resolution. The SCPro was employed to explore the pancreatic tumor microenvironment and revealed the spatial alternations of over 5,000 proteins by automatically dissecting up to 100 single cells guided by multi-color imaging of centimeter-scale formalin-fixed, paraffin-embedded tissue slide. To enhance cell-type resolution, we characterized the proteome of 14 different cell types by sorting up to 1,000 cells from the same tumor, which allows us to deconvolute the spatial distribution of immune cell subtypes and leads to the discovery of a novel subtype of regulatory T cells. Together, the SCPro provides a multimodal spatial proteomics approach for profiling tissue proteome heterogeneity.

systems biology↗

bioRxiv2023

Human iPSC-derived microglia sense and dampen hyperexcitability of cortical neurons carrying the epilepsy-associated SCN2A-L1342P mutation

Neuronal hyperexcitability is a hallmark of seizures. It has been recently shown in rodent models of seizures that microglia, the brains resident immune cells, can respond to and modulate neuronal excitability. However, how human microglia interacts with human neurons to regulate hyperexcitability mediated by epilepsy-causing genetic mutation found in human patients remains unknown. The SCN2A genetic locus is responsible for encoding the voltage-gated sodium channel Nav1.2, recognized as one of the leading contributors to monogenic epilepsies. Previously, we demonstrated that the recurring Nav1.2-L1342P mutation identified in patients with epilepsy leads to hyperexcitability in a hiPSC-derived cortical neuron model from a male donor. While microglia play an important role in the brain, these cells originate from a different lineage (yolk sac) and thus are not naturally present in hiPSCs-derived neuronal culture. To study how microglia respond to diseased neurons and influence neuronal excitability, we established a co-culture model comprising hiPSC-derived neurons and microglia. We found that microglia display altered morphology with increased branch length and enhanced calcium signal when co-cultured with neurons carrying the Nav1.2-L1342P mutation. Moreover, the presence of microglia significantly lowers the action potential firing of neurons carrying the mutation. Interestingly, we further demonstrated that the current density of sodium channels in neurons carrying the epilepsy-associated mutation was reduced in the presence of microglia. Taken together, our work reveals a critical role of human iPSCs-derived microglia in sensing and dampening hyperexcitability mediated by an epilepsy-causing mutation present in human neurons, highlighting the importance of neuron-microglia interactions in human pathophysiology. Significance StatementSeizure studies in mouse models have highlighted the role of microglia in modulating neuronal activity, particularly in the promotion or suppression of seizures. However, a gap persists in comprehending the influence of human microglia on intrinsically hyperexcitable neurons carrying epilepsy-associated pathogenic mutations. This research addresses this gap by investigating human microglia and their impact on neuronal functions. Our findings demonstrate that microglia exhibit dynamic morphological alterations and calcium fluctuations in the presence of neurons carrying an epilepsy-associated SCN2A mutation. Furthermore, microglia suppressed the excitability of diseased hyperexcitable neurons, suggesting a potential beneficial role. This study underscores the role of microglia in the regulation of abnormal neuronal activity, providing insights into therapeutic strategies for neurological conditions associated with hyperexcitability.

neuroscience↗

bioRxiv2023

Pan-genome of pear provides insights into the differentiation of fruit quality traits between Asian and European pears

The pear (Pyrus spp.) is a remarkable fruit, well known for its diverse flavors, textures, culinary versatility, and global horticultural importance. However, the genetic diversity responsible for its extensive phenotypic variations remains largely unexplored. Here, we de novo assembled and annotated the genomes of the maternal (PsbM) and paternal (PsbF) lines of the hybrid Yuluxiang pear and constructed the first pear pangenome of 1.15Gb by combining these two genomes with five previously published pear genomes. Using the constructed pangenome, we identified 21,224 gene PAVs and 1,158,812 SNPs in the non-reference genome that were absent in the PsbM reference genome. Compared with SNP markers, we found that PAV-based analysis provides additional insights into the pear population structure. In addition, we also revealed that some genes associated with pear fruit quality traits have differential occurrence frequencies and differential gene expression between Asian and European populations. Moreover, our analysis of the pear pangenome revealed a mutated SNP and an insertion in the promoter region of the gene PsbMGH3.1 potentially enhances sepal shedding in Xuehuali which is vital for pear quality. This research helps further capture the genetic diversity of pear populations and provides valuable genomic resources for accelerating pear breeding.

genomics↗

bioRxiv2023

Chemical proteomic approach for in-depth glycosylation profiling of plasma carcinoembryonic antigen in cancer patients

Carcinoembryonic antigen (CEA) of human plasma is a biomarker of many cancer diseases, and its N-glycosylation accounts for 60% of molecular mass. It is highly desirable to characterize its glycoforms for providing additional dimension of features to increase its performance in prognosis and diagnosis of cancers. However, to systematically characterize its site-specific glycosylation is challenging due to its low abundance. Here, we developed a highly sensitive strategy for in-depth glycosylation profiling of plasma CEA through chemical proteomics combined with multi-enzymatic digestion. A trifunctional probe was utilized to generate covalent bond of plasma CEA and its antibody upon UV irradiation. As low as 1 ng/mL CEA in plasma could be captured and digested with trypsin and chymotrypsin for intact glycopeptide characterization. Twenty six out of 28 potential N-glycosylation sites were well identified, which were the most comprehensive N-glycosylation site characterization of CEA on intact glycopeptide level as far as we known. Importantly, this strategy was applied to the glycosylation analysis of plasma CEA in cancer patients. Differential site-specific glycoforms of plasma CEA were observed in patients with colorectal carcinomas (CRC) and lung cancer. The distributions of site-specific glycoforms were different as the progression of CRC, and most site-specific glycoforms were overexpressed in stage II of CRC. Overall, we established a highly sensitive chemical proteomic method to profile site-specific glycosylation of plasma CEA, which should generally applicable to other well-established cancer glycoprotein biomarkers for improving their cancer diagnosis and monitoring performance. In BriefA chemical proteomic approach for glycosylation profiling of proteins was established for glycosylation characterization of plasma CEA with low abundance. Although CEA has been widely used in diagnosis and prognosis of many cancers, it lacks specificity and sensitivity. We found that the glycosylation of CEA on intact glycopeptide level provided additional dimension of molecular features to improve the performance of CEA in cancer diagnosis and progression. HighlightsO_LIA chemical proteomic approach for glycosylation profiling of proteins with low abundance C_LIO_LIGlycosylation identification of plasma CEA on intact glycopeptide level with high sensitivity and reproducibility C_LIO_LIGlycosylation features of plasma CEA in cancer patients with CRC and lung cancer and in CRC patients at different progression stages C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=147 SRC="FIGDIR/small/558933v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@73b539org.highwire.dtl.DTLVardef@7ed658org.highwire.dtl.DTLVardef@12a3e20org.highwire.dtl.DTLVardef@54a87f_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2023

Accurate single-molecule spot detection for image-based spatial transcriptomics with weakly supervised deep learning

Image-based spatial transcriptomics methods enable transcriptome-scale gene expression measurements with spatial information but require complex, manually-tuned analysis pipelines. We present Polaris, an analysis pipeline for image-based spatial transcriptomics that combines deep learning models for cell segmentation and spot detection with a probabilistic gene decoder to quantify single-cell gene expression accurately. Polaris offers a unifying, turnkey solution for analyzing spatial transcriptomics data from MERFSIH, seqFISH, or ISS experiments. Polaris is available through the DeepCell software library (https://github.com/vanvalenlab/deepcell-spots) and https://www.deepcell.org.

bioinformatics↗

bioRxiv2023

PRO-LDM: Protein Sequence Generation with Conditional Latent Diffusion Models

AbstractsDeep learning-driven protein design holds enormous potential despite the complexities in sequences and structures. Recent developments in diffusion models yielded success in structure design, but awaits progress in sequence design and are computationally demanding. Here we present PRO-LDM: an efficient framework combining design fidelity and computational efficiency, utilizing the diffusion model in latent space to design proteins with property tuning. The model employs a joint autoencoder to capture latent variable distributions and generate meaningful embeddings from sequences. PRO-LDM (1) learns representations from biological features in natural proteins at both amino-acid and sequence level; (2) generates native-like new sequences with enhanced diversity; and (3) conditionally designs new proteins with tailored properties or functions. The out-of-distribution design enables sampling notably different sequences by adjusting classifier guidance strength. Our model presents a feasible pathway and an integratable tool to extract physicochemical and evolutionary information embedded within primary sequences, for protein design and optimization.

bioengineering↗

bioRxiv2023

Multiple pathways for glucose phosphate transport and utilization support growth of Cryptosporidium parvum

Cryptosporidium parvum is an obligate intracellular parasite with a highly reduced mitochondrion that lacks the TCA cycle and the ability to generate ATP, making the parasite reliant on glycolysis. Genetic ablation experiments demonstrated that neither of the two putative glucose transporters CpGT1 and CpGT2 were essential for growth. Surprisingly, hexokinase was also dispensable for parasite growth while the downstream enzyme aldolase was required, suggesting the parasite has an alternative way of obtaining phosphorylated hexose. Complementation studies in E. coli support a role for direct transport of glucose-6-phosphate from the host cell by the parasite transporters CpGT1 and CpGT2, thus bypassing a requirement for hexokinase. Additionally, the parasite obtains phosphorylated glucose from amylopectin stores that are released by the action of the essential enzyme glycogen phosphorylase. Collectively, these findings reveal that C. parvum relies on multiple pathways to obtain phosphorylated glucose both for glycolysis and to restore carbohydrate reserves.

microbiology↗

bioRxiv2023

Glycochenodeoxycholic acid and ceramide suppress the antiviral effect of 25-hydroxycholesterol against human norovirus infection in human intestinal enteroids

The human intestinal enteroid (HIE) cell culture system with the support of glycine-conjugated bile acid glycochenodeoxycholic acid (GCDCA) and ceramide (C2) facilitate successful replication of several norovirus strains. Here we investigate how the presence of GCDCA/C2 impacts gene expression of norovirus-infected HIE and the impact of 25 hydroxycholesterol (25-HC), a key regulator of cholesterol homeostasis and bile acid production on norovirus replication. In absence of GCDCA/C2, 0.01 and 0.1 M 25-HC suppressed virus (GII.4 Sydney[P16]) replication by 1.3 log and 1.1 log respectively (p<0.05). In the presence of GCDCA/C2, 5 M 25-HC was required to achieve a 1 log decrease (p<0.05) in viral titers demonstrating that 25-HC restricts norovirus replication in HIE. RNA sequence analysis showed that during human norovirus infection, 25-HC downregulated expression of genes (CYP3A4, APOB, APOA1, and ABCG1) involved in cholesterol metabolism and transport as well as interferon stimulated genes such as ISG15 and IFIT1. GCDCA/C2 counteracts the suppressive effect of 25-HC expression of some genes related to these pathways including APOA4 and CYP27A1 however, other cholesterol genes such as APOA1 were further suppressed in the presence of GCDCA/C2. ImportanceNorovirus is the leading cause of epidemic and endemic acute gastroenteritis worldwide and currently, there are no effective therapeutic strategies against this highly contagious pathogen. Our study provides insights into the effect of bile during norovirus infection, highlight the role of the cholesterol/oxysterol pathways during human norovirus replication, and demonstrate the potential utility of oxysterols in developing norovirus therapeutics.

genetics↗

bioRxiv2023

Microbiota produced indole metabolites disrupt host cell mitochondrial energy production and inhibit Cryptosporidium parvum growth

Cryptosporidiosis is a leading cause of life-threatening diarrhea in young children in resource-poor settings. Susceptibility rapidly declines with age, associated with changes in the microbiota. To explore microbial influences on susceptibility, we screened 85 microbiota- associated metabolites enriched in the adult gut for their effects on C. parvum growth in vitro. We identified eight inhibitory metabolites in three main classes: secondary bile salts/acids, a vitamin B6 precursor, and indoles. Growth restriction of C. parvum by indoles did not depend on the host aryl hydrocarbon receptor (AhR) pathway. Instead, treatment impaired host mitochondrial function and reduced total cellular ATP, as well as directly reduced the membrane potential in the parasite mitosome, a degenerate mitochondria. Oral administration of indoles, or reconstitution of the gut microbiota with indole producing bacteria, delayed life cycle progression of the parasite in vitro and reduced severity of C. parvum infection in mice. Collectively, these findings indicate that microbiota metabolites contribute to colonization resistance to Cryptosporidium infection.

microbiology↗

bioRxiv2023

C-type natriuretic peptide improves maternally aged oocytes quality by inhibiting excessive PINK1/Parkin-mediated mitophagy

The overall oocyte quality declines with ageing, and this effect is strongly associated with a higher reactive oxygen species (ROS) level and the resultant oxidative damage. C-type natriuretic peptide (CNP) is a well-characterized physiological meiotic inhibitor that has been successfully used to improve immature oocyte quality during in vitro maturation (IVM). However, the underlying roles of CNP in maternally aged oocytes have not been reported. Here, we found that the age-related reduction in the serum CNP concentration was highly correlated with decreased oocyte quality. Treatment with exogenous CNP promoted follicle growth and ovulation in aged mice and enhanced meiotic competency and fertilization ability. Interestingly, the cytoplasmic maturation of aged oocytes was thoroughly improved by CNP treatment, as assessed by spindle/chromosome morphology and redistribution of organelles (mitochondria, the endoplasmic reticulum [ER], cortical granules [CGs], and the Golgi apparatus). CNP treatment also ameliorated DNA damage and apoptosis caused by ROS accumulation in aged oocytes. Importantly, oocyte RNA-seq revealed that the beneficial effect of CNP on aged oocytes was mediated by restoration of mitochondrial oxidative phosphorylation, eliminating excessive mitophagy. CNP reversed the defective phenotypes in aged oocytes by alleviating oxidative damage and suppressing excessive PINK1/Parkin-mediated mitophagy. Mechanistically, CNP functioned as a cAMP/PKA pathway modulator to decrease PINK1 stability and inhibit Parkin recruitment. In summary, our results demonstrated that CNP supplementation constitutes an alternative therapeutic approach for advanced maternal age-related oocyte deterioration and may improve the overall success rates of clinically assisted reproduction in older women.

developmental biology↗

bioRxiv2023

Proline provides a nitrogen source in the retinal pigment epithelium to synthesize and export amino acids for the neural retina

It is known that metabolic defects in the retinal pigment epithelium (RPE) can cause degeneration of its neighboring photoreceptors in the retina, leading to retinal degenerative diseases such as age-related macular degeneration. However, how RPE metabolism supports the health of the neural retina remains unclear. The retina requires exogenous nitrogen sources for protein synthesis, neurotransmission, and energy metabolism. Using 15N tracing coupled with mass spectrometry, we found human RPE can utilize the nitrogen in proline to produce and export 13 amino acids, including glutamate, aspartate, glutamine, alanine and serine. Similarly, we found this proline nitrogen utilization in the mouse RPE/Cho but not in the neural retina of explant cultures. Co-culture of human RPE with the retina showed that the retina can take up the amino acids, especially glutamate, aspartate and glutamine, generated from proline nitrogen in the RPE. Intravenous delivery of 15N proline in vivo demonstrated 15N-derived amino acids appear earlier in the RPE before the retina. We also found proline dehydrogenase (PRODH), the key enzyme in proline catabolism, is highly enriched in the RPE but not the retina. The deletion of PRODH blocks proline nitrogen utilization in RPE and the import of proline nitrogen-derived amino acids in the retina. Our findings highlight the importance of RPE metabolism in supporting nitrogen sources for the retina, providing insight into understanding the mechanisms of the retinal metabolic ecosystem and RPE-initiated retinal degenerative diseases.

biochemistry↗

bioRxiv2023

Computational ranking-assisted identification of Plexin-B2 in homotypic and heterotypic clustering of circulating tumor cells in breast cancer metastasis

Metastasis is the cause of over 90% of all deaths associated with breast cancer, yet the strategies to predict cancer spreading based on primary tumor profiles and therefore prevent metastasis are egregiously limited. As rare precursor cells to metastasis, circulating tumor cells (CTCs) in multicellular clusters in the blood are 20-50 times more likely to produce viable metastasis than single CTCs. However, the molecular mechanisms underlying various CTC clusters, such as homotypic tumor cell clusters and heterotypic tumor-immune cell clusters, are yet to be fully elucidated. Combining machine learning-assisted computational ranking with experimental demonstration to assess cell adhesion candidates, we identified a transmembrane protein Plexin- B2 (PB2) as a new therapeutic target that drives the formation of both homotypic and heterotypic CTC clusters. High PB2 expression in human primary tumors predicts an unfavorable distant metastasis-free survival and is enriched in CTC clusters compared to single CTCs in advanced breast cancers. Loss of PB2 reduces formation of homotypic tumor cell clusters as well as heterotypic tumor-myeloid cell clusters in triple-negative breast cancer. Interactions between PB2 and its ligand Sema4C on tumor cells promote homotypic cluster formation, and PB2 binding with Sema4A on myeloid cells (monocytes) drives heterotypic CTC cluster formation, suggesting that metastasizing tumor cells hijack the PB2/Sema family axis to promote lung metastasis in breast cancer. Additionally, using a global proteomic analysis, we identified novel downstream effectors of the PB2 pathway associated with cancer stemness, cell cycling, and tumor cell clustering in breast cancer. Thus, PB2 is a novel therapeutic target for preventing new metastasis.

cancer biology↗

bioRxiv2023

Leptospira transcriptome sequencing using long-read technology reveals unannotated transcripts and potential polyadenylation of mRNA molecules

Leptospirosis caused by the spirochete bacteria Leptospira is an emerging zoonosis that causes life-threatening disease in humans and animals. However, a detailed understanding of Leptospiras RNA profiles is limited. In this study, we sequenced and analyzed the transcriptome of multiple Leptospira serovars using Oxford Nanopore Technologies direct cDNA and direct RNA sequencing methods. We identified several operon transcriptional units, novel RNA coding regions, and evidence of potential posttranscriptional polyadenylation in the Leptospira transcriptome. Some coding regions of multiple RNA molecules that have not been previously annotated could be potential sRNA or ncRNA molecules that support gene expression regulation purposes in Leptospira. Many of the relative positions of these unannotated RNA coding regions were consistent in their neighboring coding regions across the reference genomes of two pathogenic Leptospira analyzed in this study. Besides, the majority of the unannotated coding regions and operon transcriptional units were not detected in the nonpathogenic Leptospira, suggesting potential virulence-related functions for these RNA molecules coding regions. Overall, our study confirms the utility of ONTs sequencing in studying prokaryotic transcriptome profiles and offers a tool to improve our understanding of the structural composition of RNA molecules and prokaryotic polyadenylation. However, the findings from our study also warrant that the presence of homopolymers of adenine bases in the transcripts may interfere with the interpretation of bacterial transcriptome profiles. Carefully designed experiments are needed to unravel the role of the features described in this study in Leptospira virulence and pathogenesis. Author SummaryLeptospirosis caused by the spirochete bacteria, Leptospira, is recognized as one of the most widespread zoonotic diseases. Leptospirosis is a neglected disease and has been estimated to cause over one million annual human clinical cases and over 60,000 deaths. Leptospira are maintained in the renal tubules of asymptomatic animal reservoirs, and in contaminated environments, such as soil and water. Studying gene expression profiles is an important component of bacterial pathogenesis studies, and a number of methods are available to do it. Our study compared various transcriptome sequencing methods using one of the latest next generation sequencing tools (Oxford Nanopore Technologies) and evaluated the compositions of RNA in different Leptospiras transcriptomes. We identified many previously undescribed and potentially significant features within the Leptospira transcriptome that may contribute to the virulence and pathogenesis of Leptospira sp. Our findings lead to new opportunities for researchers to sequence prokaryotic RNA molecules and to unravel many regulatory mechanisms.

microbiology↗

bioRxiv2023

Coordinated transformation of object representations across human visual cortex

Our brain constructs increasingly sophisticated representations along the ventral visual pathway to support object recognition. To understand how these representations unfold over time, we recorded human intracranial electroencephalography responses to 120 object images at five consecutive stages of the ventral pathway from V1 to occipitotemporal areas. Using representational similarity analysis, we confirmed that response patterns were more strongly driven by low-order stimulus properties at early stages and high-order category information at late stages, respectively. Interestingly, response patterns also became less stimulus-driven and more categorical at all stages over time, from [~]100 to 200 ms post-stimulus. During this period, we found significant noise correlation between single-trial response patterns across stages, indicating tight inter-areal coupling. Thus, multi-areal recurrent processes may be essential in building high-order object representations.

neuroscience↗

bioRxiv2023

Single-cell transcriptomic landscape deciphers novel olfactory neuroblastoma subtypes and intratumoral heterogeneity

Olfactory neuroblastoma (ONB) is an uncommon malignant tumor known to originate from the olfactory epithelial. The complex tumor ecosystem of this pathology remained unclear. Here, we explored the cellular components with ONB tumors based on scRNA profiles of 96,325 single-cells derived from 10 tumors and 1 olfactory mucosa sample. We discovered 11 major cell types, including 6 immune cell, 3 stromal cell subtypes and epithelial cluster in the tumor microenvironment (TME), and identified 5 common expression programs from malignant epithelial cells. We analyzed subclusters of TME and the interactions among different cell types in the TME. An innovative three-classification of ONB was established via scRNA analysis. Markers for categorizing tumor samples into new subtypes were elucidated. Different responses towards certain chemotherapy regimens could be inferred according to the molecular features of three tumor types. Relative abundance of immunosuppressive TAMs indicated the benefits of immunotherapies targeting myeloid cells.

cancer biology↗

bioRxiv2023

Tissue-specific sex difference in mouse eye and brain metabolome under fed and fasted states

PurposeVisual physiology and various ocular diseases demonstrate sexual dimorphisms; however, how sex influences metabolism in different eye tissues remains undetermined. This study aims to address common and tissue-specific sex differences in metabolism in the retina, retinal pigment epithelium (RPE), lens and brain under fed and fasted conditions. MethodsAfter ad libitum fed or deprived of food for 18 hours, mouse eye tissues (retina, RPE/choroid, and lens), brain, and plasma were harvested for targeted metabolomics. The data were analyzed with both Partial least squares-discriminant analysis (PLS-DA) and Volcano Plot analysis. ResultsAmong 133 metabolites that cover major metabolic pathways, we found 9-45 metabolites that are sex-different in different tissues under the fed state and 6-18 metabolites under the fasted state. Among these sex-different metabolites, 33 were changed in two or more tissues, and 64 were tissue-specific. Pantothenic acid, hypotaurine and 4-hydroxyproline were the top commonly changed metabolites. Lens and retina had the most tissue-specific sex-different metabolites enriched in the metabolism of amino acid, nucleotide, lipids and TCA cycle. Lens and brain had more similar sex-different metabolites than other occular tissues. Female RPE and female brain were more sensitive to fasting with more reduced metabolites in amino acid metabolism, TCA cycle and glycolysis. The plasma had the least sex-different metabolites with very few overlapping changes with tissues. ConclusionSex has a strong influence on eye and brain metabolism in tissue-specific and metabolic state-specific manners. Our findings may implicate the sexual dimorphisms in eye physiology and susceptibility to ocular diseases.

biochemistry↗

bioRxiv2022

Elimusertib outperforms standard of care chemotherapy in preclinical patient-derived pediatric solid tumor models

The small molecule inhibitor of ataxia telangiectasia and Rad3-related protein (ATR), elimusertib, is currently being tested clinically in various cancer entities in adults and children. Its preclinical anti-tumor activity in pediatric malignancies, however, is largely unknown. We here assessed the preclinical activity of elimusertib in >40 cell lines and >30 patient-derived xenograft (PDX) models derived from common pediatric solid tumor entities. Detailed in vitro and in vivo molecular characterization of the treated models enabled the evaluation of response biomarkers. Pronounced objective response rates were observed for elimusertib monotherapy in PDX, when treated with a regimen currently used in clinical trials. Strikingly, elimusertib outperformed standard of care chemotherapies, particularly in alveolar rhabdomysarcoma PDX. Thus, elimusertib has strong preclinical anti-tumor activity in pediatric solid tumor models, which may translate to clinically meaningful responses in patients. Statement of translational relevanceElimusertib is a small molecule inhibitor of ATR. ATR inhibitors have shown promising results as anticancer agents in adult cancers, but there is limited information on their effectiveness in pediatric solid tumors. Using a cohort of 32 patient-derived xenografts from pediatric solid tumors, we here evaluated the therapeutic potential of elimusertib in vivo. Elimusertib reduced tumor volume growth in all samples. Elimusertib had very limited toxicity and was potent even in tumors with preexisting chemoresistance. Our preclinical data indicates that elimusertib is a safe and potent therapeutic option for pediatric solid tumors. This data may serve as a rationale for the development of pediatric clinical trials for ATR inhibitors.

cancer biology↗