Biology subjects

Chan, J.

Publications and source records attributed to Chan, J..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Oral dosing of the nucleoside analog obeldesivir is efficacious against RSV infection in African green monkeys

Respiratory syncytial virus (RSV) is a significant cause of morbidity and mortality in high-risk populations. Although prophylactic options are available, there are no effective oral therapeutics for RSV infection. Obeldesivir (ODV) is an orally bioavailable prodrug of the nucleoside analog GS-441524, which is converted intracellularly to its active nucleoside triphosphate and inhibits the RSV RNA polymerase. Here we report the potent antiviral activity of ODV against geographically and temporally diverse RSV A and B clinical isolates (EC50: 0.20-0.66 M). Resistance selection studies with ODV and GS-441524 against RSV identified a single amino acid substitution, I777L, in the L polymerase with reduced susceptibility (3.3-3.8-fold) to ODV and GS-441524, indicating a high barrier for resistance development. In an African green monkey RSV infection model, once-daily oral ODV doses of 30 or 90 mg/kg initiated [~]24 hours post-infection significantly reduced log10 viral RNA copies/mLxday area under the curve by 69-92% in the upper and lower respiratory tracts. Together, these preclinical data support the clinical evaluation of ODV for the treatment of RSV infection.

microbiology↗

bioRxiv2025

A Comparative Evaluation of Computational Models for RNA modification detection using Nanopore sequencing with RNA004 Chemistry

Direct RNA sequencing from Oxford Nanopore Technologies (ONT) has become a valuable method for studying RNA modifications such as N6-methyladenosine (m6A), pseudouridine ({psi}), and 5-methylcytosine (m5C). Recent advancements in the RNA004 chemistry substantially reduce sequencing errors compared to previous chemistries (e.g., RNA002), thereby promising enhanced accuracy for epitranscriptomic analysis. In this study, we benchmark the performance of two state-of-the-art RNA modification detection models capable of handling RNA004 data - ONTs Dorado and m6Anet - using two wild-type (WT) cell lines, HEK293T and HeLa, with respective ground truths from GLORI and eTAM-seq, and their paired in vitro transcribed (IVT) RNA as negative controls. We found that under default settings and considering sites with [≥]10% modification ratio and [≥]10X coverage, Dorado has higher recall ([~]0.92) than m6Anet ([~]0.51) for m6A detection. Among the overlapping methylated sites between ground truth and computational predictions, there are high correlations of site-specific m6A modification stoichiometry, with correlation coefficient of [~]0.89 for Dorado-truth comparison and [~]0.72 for m6Anet-truth comparison. However, combined assessment of WT and IVT datasets show that while the per-site false positive rate (FPR) can be lower ([~]8% for Dorado and [~]33% for m6Anet), both computational tools can have high per-site false discovery rate (FDR) of m6A ([~]40% for Dorado and [~]80% for m6Anet) due to the low prevalence of m6A in transcriptome, with a similar trend observed for pseudouridine ([~]95% FDR for Dorado). Additional motif analysis reveals that both Dorado and m6Anet exhibit high heterogeneity of false positive calls across sequence contexts, suggesting that sequence contexts help determine accuracy of specific modification calls. There is also a substantial overlap of false positive calls between the two IVT samples, suggesting a post-filtering strategy to improve modification calling by compiling a set of low-confidence sites with a probabilistic model from several IVT samples across diverse cells/tissues. Our analysis highlights key strengths and limitations of the current generation of m6A detection algorithms and offers insights into optimizing thresholds and interpretability. The IVT datasets generated by the RNA004 chemistry provides a publicly available benchmark resource for further development and refinement of computational methods.

bioinformatics↗

bioRxiv2025

MicroRNA signatures of VO2peak in older adult participants of the Study of Muscle, Mobility and Aging

BackgroundPeak oxygen consumption during exercise (VO2peak), is a direct measure of cardiorespiratory fitness (CF), a key indicator of physical function and overall health. However, the molecular changes that underpin VO2peak variation are not clear. Our objective is to understand the miRNA signatures that relate to VO2peak variation, which could provide insights to novel mechanisms that contribute to low VO2peak. MethodsWe used small RNA sequencing to analyze serum samples from 72 participants (70-79 yrs old, 53% female) of the Study of Muscle, Mobility and Aging (SOMMA). We analyzed samples from individuals with low or high VO2peak (N=18/group) as well as samples from 36 randomly selected participants spanning the entire spectrum of VO2peak. We used LIMMA analysis package for regression analysis and to identify differentially expressed miRNAs. We used receiver operating characteristic curve analysis to evaluate the Area Under the Curve (AUC) and sensitivity and specificity rates. ResultsWe identified 1,055 miRNAs expressed in all serum samples. Expression of 65 miRNAs differed between participants with low and high VO2peak (p < 0.05). After p-value adjustment, expression of 5 miRNAs (miR-1301-3p, -431-5p, -501-5p, -519a-3p, and -18a-3p) remained significantly different (FDR = 0.05). The five miRNAs had AUC ranging from 0.77 to 0.84. The optimal sensitivity and specificity ranged from 70 to 80% and 80 to 90%, respectively. After adjustment for age and sex covariates, 46 miRNAs significantly correlated with VO2peak (p < 0.05) and miR-519a-3p remained significant based on adjusted of p-values. ConclusionsWe identified a miRNA signature of VO2peak in older individuals that might provide insights to novel mechanisms that drive low VO2peak. Future studies will validate the findings in a larger, longitudinal study cohort.

molecular biology↗

bioRxiv2024

Evaluation of subretinally delivered Cas9 ribonucleoproteins in murine and porcine animal models highlights key considerations for therapeutic translation of genetic medicines

Genetic medicines, including CRISPR/Cas technologies, extend tremendous promise for addressing unmet medical need in inherited retinal disorders and other indications; however, there remain challenges for the development of therapeutics. Herein, we evaluate genome editing by engineered Cas9 ribonucleoproteins (eRNP) in vivo via subretinal administration using mouse and pig animal models. Subretinal administration of adenine base editor and double strand break-inducing Cas9 nuclease eRNPs mediate genome editing in both species. Editing occurs in retinal pigmented epithelium (RPE) and photoreceptor cells, with favorable tolerability in both species. Using transgenic reporter strains, we determine that editing primarily occurs close to the site of administration, within the bleb region associated with subretinal injection. Our results show that subretinal administration of eRNPs in mice mediates base editing of up to 12% of the total neural retina, with an average rate of 7% observed at the highest dose tested. In contrast, a substantially lower editing efficiency was observed in minipigs; even with direct quantification of only the treated region, a maximum base editing rate of 1.5%, with an average rate of <1%, was observed. Our data highlight the importance of species consideration in translational studies for genetic medicines targeting the eye and provide an example of a lack of translation between small and larger animal models in the context of subretinal administration of Cas9 eRNPs.

pharmacology and toxicology↗

bioRxiv2024

Finding Salient Multi-Omic Interactomes Relevant to Multiple Biomedical Outcomes using Graph Ensemble Neural Networks

Although multi-omics integration relevant to patient outcome is typically characterized by an analyte interactome, current multi-omic integration methods either (1) model outcome without directly including associations between analytes, (2) model the interactome without directly evaluating the saliency of the model in the context of outcome, or (3) model outcome in a high-dimensional parameter space not suitable for small sample sizes (which are common in multi-omics studies). We introduce Graph Ensemble Neural Network (GENN), a methodology that learns the interactome most predictive of outcome in a low-dimensional parameter space built on complementary attributes for all possible analyte associations (metafeatures). We show that GENN is robust to noise in measurements using a theoretical model, outperforms the predictive performance of existing methods when evaluated on Tegafur drug response in NCI-60 cancer cell line data, and uncovers potentially novel multi-omic mechanisms driving total serum IgE levels in pediatric asthma and patient survival in glioblastomas.

bioinformatics↗

bioRxiv2024

Improving design and normalization of multiplex proteomics study

Advances in multiplex mass spectrometry-based technologies have enabled high-throughput, quantitative proteome profiling of large cohort. However, certain experimental design configurations can amplify sample variability and introduce systematic biases. To address these challenges, we incorporated two novel features in a recent proteogenomic investigation: (1) the inclusion of two reference samples within each mass spectrometry run to serve as internal standards, and (2) the analysis of each specimen as technical replicates across two distinct mass spectrometry runs. Building on these enhancements, we present ProMix, a flexible analytical framework designed to fully leverage these supplementary experimental components. Using both simulated and real-world datasets, we demonstrate the improved performance of ProMix and highlight the advantages conferred by these refined experimental design strategies.

bioinformatics↗

bioRxiv2024

Neutrophils exposed to a cholesterol metabolite secrete extracellular vesicles that promote epithelial-mesenchymal transition and stemness in breast cancer cells.

Small extracellular vesicles (sEVs) are emerging as critical mediators of intercellular communication in the tumor microenvironment (TME). Here, we investigate the mechanisms by which sEVs derived from neutrophils treated with the cholesterol metabolite, 27-hydroxycholesterol (27HC), influence breast cancer progression. sEVs released from 27HC treated neutrophils enhance epithelial-mesenchymal transition (EMT) and stem-like properties in breast cancer cells, resulting in loss of adherence, increased migratory capacity and resistance to cytotoxic chemotherapy. Decreased microRNAs (miRs) within the sEVs resulted in activation of the WNT/{beta}-catenin signaling pathway in recipient cells and suggest that this may be a predominant pathway for stem-like phenotype and EMT. Our findings underscore a novel mechanism by which 27HC-modulated neutrophils contribute to breast cancer pathophysiology through EV-mediated intercellular communication, suggesting potential therapeutic targets in cancer treatment.

cancer biology↗

bioRxiv2024

Horizontal transfer of nuclear DNA in transmissible cancer

Although somatic cell genomes are usually entirely clonally inherited, nuclear DNA exchange between cells of an organism can occur sporadically by cell fusion, phagocytosis or other mechanisms1-3. This phenomenon has long been noted in the context of cancer, where it could be envisaged that DNA horizontal transfer plays a functional role in disease evolution4-13. However, an understanding of the frequency and significance of this process in naturally occurring tumours is lacking. The host-tumour genetic discordance of transmissible cancers, malignant clones which pass between animals as allogeneic grafts, provides an opportunity to investigate this. We screened for host-to-tumour horizontal transfer of nuclear DNA in 174 tumours from three transmissible cancers affecting dogs and Tasmanian devils, and detected a single instance in the canine transmissible venereal tumour (CTVT). This involved introduction of a 15-megabase dicentric genetic element, composed of 11 rearranged fragments of six chromosomes, to a CTVT sublineage occurring in Asia around 2,000 years ago. The element forms the short arm of a small submetacentric chromosome, and derives from a dog with ancestry associated with the ancient Middle East. The introduced DNA fragment is transcriptionally active and has adopted the expression profile of CTVT. Its 143 genes do not, however, confer any obvious advantage to its spatially restricted CTVT sublineage. Our findings indicate that nuclear DNA horizontal transfer, although likely a rare event in tumour evolution, provides a viable mechanism for the acquisition of genetic material in naturally occurring cancer genomes.

cancer biology↗

bioRxiv2024

APP-KI mice do not display the hallmark age-dependent cognitive decline of amyloid diseases

APP knock-in (KI) mice serve as an exciting new model system to understand amyloid beta (A{beta}) pathology, overcoming many of the limitations of previous overexpression-based model systems. The APPSAA mouse model (containing the humanized APP with three familial Alzheimers disease mutations) and the APPWT control are the first commercially available APP KI mice within the United States. While APPSAA mice have been shown to develop progressive A{beta} pathology and neuroinflammation, behavioral changes, particularly in cognitive functions, have yet to be described. Therefore, we performed an in-depth longitudinal study over 12 months, assessing cognition in these two strains, as well as assessments of motor and GI function. We surprisingly note no overt, progressive cognitive impairment or motor deficits. However, we do observe a significant increase in fecal output in APPSAA mice compared to APPWT at 12 months old. These data provide a baseline for these models behavioral attributes. HighlightsO_LIAPPSAA and APPWT knock-in mice do not display age related cognitive decline C_LIO_LIFecal output appears altered by APP genotype, but no other measure of GI function is impacted. C_LIO_LIBoth genotypes behave equally in motor function tests C_LI

neuroscience↗

bioRxiv2024

Magnetically Steered Cell Therapy For Functional Restoration Of Intraocular Pressure Control In Open-Angle Glaucoma

Trabecular meshwork (TM) cell therapy has been proposed as a next-generation treatment for elevated intraocular pressure (IOP) in glaucoma, the most common cause of irreversible blindness. Using a magnetic cell steering technique with excellent efficiency and tissue-specific targeting, we delivered two types of cells into a mouse model of glaucoma: either human adipose-derived mesenchymal stem cells (hAMSCs) or induced pluripotent cell derivatives (iPSC-TM cells). We observed a 4.5 [3.1, 6.0] mmHg or 27% reduction in intraocular pressure (IOP) for nine months after a single dose of only 1500 magnetically-steered hAMSCs, explained by increased outflow through the conventional pathway and associated with an higher TM cellularity. iPSC-TM cells were also effective, but less so, showing only a 1.9 [0.4, 3.3] mmHg or 13% IOP reduction and increased risk of tumorigenicity. In both cases, injected cells remained detectable in the iridocorneal angle three weeks post-transplantation. Based on the locations of the delivered cells, the mechanism of IOP lowering is most likely paracrine signaling. We conclude that magnetically-steered hAMSC cell therapy has potential for long-term treatment of ocular hypertension in glaucoma. One Sentence SummaryA novel magnetic cell therapy provided effective intraocular pressure reduction in a mouse model, motivating future translational studies.

bioengineering↗

bioRxiv2024

Functional Characterisation of the ATOH1 Molecular Subtype Indicates a Pro-Metastatic Role in Small Cell Lung Cancer

Molecular subtypes of Small Cell Lung Cancer (SCLC) have been described based on differential expression of transcription factors (TFs) ASCL1, NEUROD1, POU2F3 and immune-related genes. We previously reported an additional subtype based on expression of the neurogenic TF ATOH1 within our SCLC Circulating tumour cell- Derived eXplant (CDX) model biobank. Here we show that ATOH1 protein was detected in 7/81 preclinical models and 16/102 clinical samples of SCLC. In CDX models, ATOH1 directly regulated neurogenesis and differentiation programs consistent with roles in normal tissues. In ex vivo cultures of ATOH1-positive CDX, ATOH1 was required for cell survival. In vivo, ATOH1 depletion slowed tumour growth and suppressed liver metastasis. Our data validate ATOH1 as a bona fide oncogenic driver of SCLC with tumour cell survival and pro-metastatic functions. Further investigation to explore ATOH1 driven vulnerabilities for targeted treatment with predictive biomarkers is warranted.

cancer biology↗

bioRxiv2023

Cardiac Molecular Analysis Reveals Aging-Associated Metabolic Alterations Promoting Glycosaminoglycans Accumulation Via Hexosamine Biosynthetic Pathway

Age is a prominent risk factor for cardiometabolic disease, and often leads to heart structural and functional changes. However, precise molecular mechanisms underlying cardiac remodeling and dysfunction resulting from physiological aging per se remain elusive. Understanding these mechanisms requires biological models with optimal translation to humans. Previous research demonstrated that baboons undergo age-related reduction in ejection fraction and increased heart sphericity, mirroring changes observed in humans. The goal of this study was to identify early cardiac molecular alterations that precede functional adaptations, shedding light on the regulation of age-associated changes. We performed unbiased transcriptomics of left ventricle (LV) samples from female baboons aged 7.5-22.1 years (human equivalent [~]30-88 years). Weighted-gene correlation network and pathway enrichment analyses were performed to identify potential age-associated mechanisms in LV, with histological validation. Myocardial modules of transcripts negatively associated with age were primarily enriched for cardiac metabolism, including oxidative phosphorylation, tricarboxylic acid cycle, glycolysis, and fatty-acid {beta}-oxidation. Transcripts positively correlated with age suggest upregulation of glucose uptake, pentose phosphate pathway, and hexosamine biosynthetic pathway (HBP), indicating a metabolic shift towards glucose-dependent anabolic pathways. Upregulation of HBP commonly results in increased glycosaminoglycan precursor synthesis. Transcripts involved in glycosaminoglycan synthesis, modification, and intermediate metabolism were also upregulated in older animals, while glycosaminoglycan degradation transcripts were downregulated with age. These alterations would promote glycosaminoglycan accumulation, which was verified histologically. Upregulation of extracellular matrix (ECM)-induced signaling pathways temporally coincided with glycosaminoglycan accumulation. We found a subsequent upregulation of cardiac hypertrophy-related pathways and an increase in cardiomyocyte width. Overall, our findings revealed a transcriptional shift in metabolism from catabolic to anabolic pathways that leads to ECM glycosaminoglycan accumulation through HBP prior to upregulation of transcripts of cardiac hypertrophy-related pathways. This study illuminates cellular mechanisms that precede development of cardiac hypertrophy, providing novel potential targets to remediate age-related cardiac diseases.

molecular biology↗

bioRxiv2023

A Novel Semi-automated Proofreading and Mesh Error Detection Pipeline for Neuron Extension

AO_SCPLOWBSTRACTC_SCPLOWThe immense scale and complexity of neuronal electron microscopy (EM) datasets pose significant challenges in data processing, validation, and interpretation, necessitating the development of efficient, automated, and scalable error-detection methodologies. This paper proposes a novel approach that employs mesh processing techniques to identify potential error locations near neuronal tips. Error detection at tips is a particularly important challenge since these errors usually indicate that many synapses are falsely split from their parent neuron, injuring the integrity of the connectomic reconstruction. Additionally, we draw implications and results from an implementation of this error detection in a semi-automated proofreading pipeline. Manual proofreading is a laborious, costly, and currently necessary method for identifying the errors in the machine learning based segmentation of neural tissue. This approach streamlines the process of proofreading by systematically highlighting areas likely to contain inaccuracies and guiding proofreaders towards potential continuations, accelerating the rate at which errors are corrected.

neuroscience↗

bioRxiv2023

Multi-omics Analysis of Aging Liver Reveals Changes in Endoplasmic Stress and Degradation Pathways in Female Nonhuman Primates

The liver is critical for functions that support metabolism, immunity, digestion, detoxification, and vitamin storage. Aging is associated with severity and poor prognosis of various liver diseases such as nonalcoholic fatty liver disease (NAFLD). Previous studies have used multi-omic approaches to study liver diseases or to examine the effects of aging on the liver. However, to date, no studies have used an integrated omics approach to investigate aging-associated molecular changes in the livers of healthy female nonhuman primates. The goal of this study was to identify molecular changes associated with healthy aging in the livers of female baboons (Papio sp., n=35) by integrating multiple omics data types (transcriptomics, proteomics, metabolomics) from samples across the adult age span. To integrate omics data, we performed unbiased weighted gene co-expression network analysis (WGCNA), and the results revealed 3 modules containing 3,149 genes and 33 proteins were positively correlated with age, and 2 modules containing 37 genes and 216 proteins were negatively correlated with age. Pathway enrichment analysis showed that unfolded protein response (UPR) and endoplasmic reticulum (ER) stress were positively associated with age, whereas xenobiotic metabolism and melatonin and serotonin degradation pathways were negatively associated with age. The findings of our study suggest that UPR and a reduction in reactive oxygen species generated from serotonin degradation could protect the liver from oxidative stress during the aging process in healthy female baboons.

molecular biology↗

bioRxiv2023

Maternal Under-Nutrition During Pregnancy Alters the Molecular Response to Over-Nutrition in Multiple Organs and Tissues in Juvenile Offspring

Previous studies suggest that mismatch between fetal and postnatal nutrition predisposes individuals to metabolic diseases. We examined whether NHP juvenile offspring of pregnancies with maternal undernutrition (MUN) had altered response to a high-fat, high-carbohydrate diet plus sugar drink challenge (HFCS) compared with controls (CON). Pregnant baboons were fed ad libitum (CON) or 30% calorie reduction from 0.16 gestation through lactation, and weaned offspring fed chow diet ad libitum. Offspring of MUN were growth restricted at birth. At [~]4.5y offspring received a 7-week HFCS challenge. Baseline and HFCS gene expression in liver, omental fat, and skeletal muscle, liver glycogen content, and fat cell size were quantified. MUN offspring had lower BMI and liver glycogen compared with CON. Pathway analysis showed differences for skeletal muscle and liver, including hepatic splicing and unfolded protein response. MUN offspring consumed more sugar drink than CON. After HFCS, MUN BMIs were similar to CON. Liver showed coordinated response to HFCS in CON but not MUN. Pathway and liver glycogen differences between MUN and CON at baseline indicate in utero programming persists in MUN juveniles. MUN catchup growth during HFCS suggests increased risk of obesity, diabetes, and cardiovascular disease. Greater sugar drink consumption in MUN demonstrates altered appetitive drive due to programming. Differences in blood leptin concentrations, omental adipocyte cell size, liver glycogen content, and tissue-specific molecular response to HFCS challenge suggest MUN significantly impacts juvenile offspring ability to manage an energy rich diet. O_FIG O_LINKSMALLFIG WIDTH=172 HEIGHT=200 SRC="FIGDIR/small/548121v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@b15085org.highwire.dtl.DTLVardef@11d4c1dorg.highwire.dtl.DTLVardef@704209org.highwire.dtl.DTLVardef@1ff9791_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2023

Background matching can reduce responsiveness of jumping spiders to stimuli in motion

Motion and camouflage were previously considered to be mutually exclusive, as sudden movements can be easily detected. Background matching, for instance, is a well-known, effective camouflage strategy where the color and pattern of a stationary animal match its surrounding background. However, background matching may lose its efficacy when the animal moves, as the boundaries of the animal become more defined against its background. Recent evidence shows otherwise, as camouflaged objects can be less detectable than uncamouflaged objects even while in motion. Here, we explored if the detectability of computer-generated stimuli varies with the speed of motion, background (matching and unmatching) and size of stimuli in six species of jumping spiders (Araneae: Salticidae). Our results showed that in general, the responsiveness of all six salticid species tested decreased with increasing stimulus speed regardless of whether the stimuli were conspicuousness or camouflaged. Importantly, salticid responses to camouflaged stimuli were significantly lower compared to conspicuous stimuli. There were significant differences in motion detectability across species when the stimuli were conspicuous, suggesting differences in visual acuity in closely related species of jumping spiders. Furthermore, small stimuli elicited significantly lower responses than large stimuli across species and speeds. Our results thus suggest that background matching is effective even when stimuli are in motion, reducing the detectability of moving stimuli. Summary StatementContrary to belief, stimuli in motion can remain camouflaged against their backgrounds. Using computer-generated stimuli, we show that smaller and faster stimuli against camouflaged background elicit lower responses from jumping spiders.

animal behavior and cognition↗

bioRxiv2023

Charting spatial ligand-target activity using Renoir

The advancement of single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics has enabled the inference of cellular interactions in a tissue microenvironment. Despite the development of cell-cell interaction inference methods, there is a lack of methods capable of mapping the influence of ligands on downstream target genes across a spatial topology with specific cell type composition, with the potential to shed light on niche-specific relationship between ligands and their downstream targets. Here we present Renoir for charting the ligand-target activities across a spatial topology and delineating spatial communication niches harboring specific ligand-target activities. Renoir also spatially maps pathway-level activity of ligand-target genesets and identifies domain-specific ligand-target activities. Across spatial datasets with varying resolution (spot to single-cell) ranging from development to disease, Renoir inferred cellular niches with distinct ligand-target interactions, spatially mapped pathway activities, and identified context-specific novel cell-cell interactions. Renoir uncovers biological insights and therapeutically-relevant cellular crosstalk from spatial transcriptomics data.

bioinformatics↗

bioRxiv2023

Pan-cancer analysis of the ion permeome reveals functional regulators of glioblastoma aggression

Ion channels, transporters, and other ion-permeating proteins, collectively comprising the ion permeome (IP), are common drug targets. However, their roles in cancer are understudied. Our integrative pan-cancer analysis shows that IP genes display highly-elevated expression patterns in subsets of cancer samples significantly more often than expected transcriptome-wide. To enable target identification, we identified 410 survival-associated IP genes in 29 cancer types using a machine learning approach. Notably, GJB2 and SCN9A show prominent expression in neoplastic cells and associate with poor prognosis in glioblastoma (GBM), the most common and aggressive brain cancer. GJB2 or SCN9A knockdown in patient-derived GBM cells induces transcriptome-wide changes involving neural projection and proliferation pathways, impairs cell viability and tumor sphere formation, mitigates tunneling nanotube formation, and extends the survival of GBM-bearing mice. Thus, aberrant activation of IP genes appears as a pan-cancer feature of tumor heterogeneity that can be exploited for mechanistic insights and therapy development.

cancer biology↗