Biology subjects

Fan, B.

Publications and source records attributed to Fan, B..

At least 19 recordsLinked to original sources

bioRxiv2026

Phagocytic activity of perivascular cell promotes CNS injury pathology

Injury, stroke, and neurological diseases cause persistent accumulation of cellular debris that deteriorates lesion microenvironment and impedes central nervous system (CNS) repair. Debris clearance in the injured CNS has long been attributed primarily to microglia and infiltrating macrophages. Here, we identify perivascular cells as previously unrecognized phagocytes that expand after injury and exhibit robust phagocytic activity. Perivascular cell phagocytosis is conserved across multiple mouse models of CNS injury and human stroke lesions. These cells exhibit key hallmarks of phagocytosis, including LC3-associated phagocytosis for efficient lysosomal degradation. Mechanistically, phosphatidylserine serves as the eat-me signal and Axl mediates myelin debris uptake. Myelin phagocytosis drives perivascular cell proliferation, fibrosis and lesion progression. Genetic deletion of Axl in perivascular cells or pharmacological inhibition with the FDA-approved Axl inhibitor Gilteritinib reduces pathology and improves functional recovery after spinal cord injury. Together, these findings establish Axl-dependent perivascular cell phagocytosis as a therapeutic target for CNS repair.

neuroscience↗

bioRxiv2026

FLD Is Required for N-Hydroxypipecolic Acid Accumulation and Associated Growth Defects in Arabidopsis pmr4 Mutant

The Arabidopsis mutants lacking the pathogen-inducible callose synthase POWDERY MILDEW RESISTANCE 4 (PMR4)/GLUCAN SYNTHASE-LIKE 5 (GSL5) exhibit enhanced disease resistance accompanied by reduced growth, spontaneous necrosis, and premature senescence. This autoimmune phenotype of pmr4 is associated with a high accumulation of N-hydroxypipecolic acid (NHP) and a moderate increase in salicylic acid. We previously reported three suppressors of pmr4 (spm), PAD4 and the NHP biosynthetic genes ALD1 and FMO1, whose loss-of-function mutations abolish NHP accumulation and completely suppress the growth defects of pmr4, demonstrating that NHP is critical to the autoimmune growth phenotype. Here, we characterize a fourth suppressor, spm4, which similarly fully suppresses the growth defects of pmr4. Map-based cloning and molecular genetic analyses revealed that spm4 carries a mutation in FLOWERING LOCUS D (FLD). Reintroduction of a wild-type FLD allele into the pmr4 spm4 background restored both NHP accumulation and the characteristic growth defects of pmr4. Conversely, independent FLD loss-of-function alleles generated by CRISPR/Cas-mediated genome editing suppressed NHP accumulation and rescued the autoimmune growth defects of pmr4, confirming that FLD is required for manifestation of the pmr4 phenotype. Beyond its established role in flowering-time regulation, FLD has been implicated in plant immunity, particularly in systemic acquired resistance (SAR), although the mechanistic basis of its immune function remains poorly understood. Our findings identify FLD as an essential positive regulator of NHP accumulation, thereby providing a mechanistic link between FLD-dependent epigenetic regulation, NHP-mediated signaling, and SAR.

plant biology↗

bioRxiv2026

Coronavirus envelope protein drives iron sensing disorder by hijacking the TAp73-FDXR axis

Iron overload is increasingly recognized as a critical contributor to coronavirus pathogenesis1, yet the underlying induction mechanisms remain unclear. Here, we uncover a fundamental pathway by which coronavirus drives IRP1 RNA-binding activity to induce iron accumulation2 via targeting the TAp73-FDXR axis. Specifically, coronavirus infection represses transcription of FDXR (encoding the key rate-limiting enzyme in host iron-sulfur cluster synthesis3), thereby impairing host iron-sulfur cluster generation to trigger the functional conversion of the cytosolic aconitase 1 (ACO1) into iron-regulatory protein 1 (IRP1)4, ultimately leading to the hosts persistently false perception of iron deficiency. We identify TAp73 as the primary transcription factor governing FDXR expression, and demonstrate that the coronavirus envelope protein (CoV-E) orchestrates TAp73 nuclear export. Subsequently, CoV-E binds TAp73 through a critical valine residue within its C-terminal PBM domain, inducing the K48-linked ubiquitination and proteasomal degradation of TAp73. Furthermore, we developed a CoV-E-targeting molecule, DPTP-FC, which blocks CoV-E-TAp73 interaction via forming steric hindrance and effectively alleviates iron accumulation and tissue damage caused by PEDV, PDCoV, and SARS-CoV-2 infection. Our study reveals the central role of the TAp73-FDXR axis in CoV-induced iron accumulation, highlighting CoV-E as an attractive antiviral target and DPTP-FC as a promising therapeutic candidate.

microbiology↗

bioRxiv2026

Calcium transient detection and segmentation with the astronomically motivated algorithm for background estimation and transient segmentation (Astro-BEATS)

SignificanceFluorescence-based Ca2+-imaging is a powerful tool for studying localized neuronal activity, including miniature Synaptic Calcium Transients, providing real-time insights into synaptic activity. These transients induce only subtle changes in the fluorescence signal, often barely above baseline, which poses a significant challenge for automated synaptic transient detection and segmentation. AimDetecting astronomical transients similarly requires efficient algorithms that will remain robust over a large field of view with varying noise properties. We leverage techniques used in astronomical transient detection for miniature Synaptic Calcium Transient detection in fluorescence microscopy. ApproachWe present Astro-BEATS, an automatic miniature Synaptic Calcium Transient segmentation algorithm that incorporates image estimation and source-finding techniques used in astronomy and designed for Ca2+-imaging videos. Astro-BEATS uses the Rolling Hough Transform filament detector to construct an estimate of the expected (transient-free) fluorescence signal of both the dendritic foreground and the background. Subtracting this baseline signal yields difference images displaying transient signals. We use Density-Based Spatial Clustering of Applications with Noise to find sources clustered in spatial and temporal space. ResultsAstro-BEATS outperforms current threshold-based approaches for synaptic Ca2+ transient detection and segmentation. The produced segmentation masks can be used to train a supervised deep learning algorithm for improved synaptic Ca2+ transient detection in Ca2+-imaging data. The speed of Astro-BEATS and its applicability to previously unseen datasets without re-optimization makes it particularly useful for generating training datasets for deep learning-based approaches. ConclusionAstro-BEATS greatly reduces the time needed for the annotation of synaptic Ca2+ transient and removes the significant overhead of human expert annotation, enabling consistent analysis of new Ca2+-imaging datasets.

bioinformatics↗

bioRxiv2025

Oncogenic KRAS regulates secretion of extracellular vesicles and surface membrane charge via regulation of phosphatidylserine in pancreatic cancer

Extracellular vesicles (EVs) have the potential to be used as a liquid biopsy for cancer detection and treatment response assessment. Although the potential of EVs as disease-specific biomarkers has been promising, the rapid and specific enrichment of EVs from body fluids in the clinical setting remains challenging. To address this limitation, we developed a Microfluidic Electrophoresis (MEP) device, that allows label-free enrichment of EVs based on charge from the serum of patients with pancreatic cancer (PaCa). The ability of MEP to enrich anionic EVs was validated using cell line-derived EVs and PaCa serum-derived EVs. We observed a positive correlation between the KRAS status, secretion of EVs, and net negative zeta potential ({zeta}-potential) of EVs. Further analyses identified phosphatidylserine (PS) and extraluminal DNA as molecular determinants of the enhanced anionic nature of PaCa-derived EVs. Overall, this work introduces a new microfluidic device to enrich cancer EVs in circulation with potential for further rapid detection of PaCa.

bioengineering↗

bioRxiv2024

Deep learning uncovers sequence-specific amplification bias in multi-template PCR

Multi-template polymerase chain reaction is a key step in many amplicon sequencing protocols enabling parallel amplification of diverse DNA molecules sharing common adapters in applications, ranging as wide as quantitative molecular biology and DNA data storage. However, this process results in a skewed amplicon abundance, due to sequence-specific amplification biases. In this study, one-dimensional convolutional neural networks (1D-CNNs) were trained on synthetic DNA pools to learn the PCR amplification efficiency of individual templates. These 1D-CNN models can predict poorly amplifying templates based solely on sequence information, achieving an AUROC/AUPRC of up to 0.88/0.44 with very imbalanced prevalence of 2%, thereby greatly outperforming baseline models relying only on GC content and nucleotide frequency as predictors. A new, general-purpose framework for interpreting deep learning models, termed CluMo provides mechanistic insights into the amplification biases. Most strikingly, specific amplification reactions were identified as suffering from adaptor-template self-priming a mechanism previously disregarded in PCR.

molecular biology↗

bioRxiv2024

Quantitative Analysis of Miniature Synaptic Calcium Transients Using Positive Unlabeled Deep Learning

Ca2+ imaging methods are widely used for studying cellular activity in the brain, allowing detailed analysis of dynamic processes across various scales. Enhanced by high-contrast optical microscopy and fluorescent Ca2+ sensors, this technique can be used to reveal localized Ca2+ fluctuations within neurons, including in sub-cellular compartments, such as the dendritic shaft or spines. Despite advances in Ca2+ sensors, the analysis of miniature Synaptic Calcium Transients (mSCTs), characterized by variability in morphology and low signal-to-noise ratios, remains challenging. Traditional threshold-based methods struggle with the detection and segmentation of these small, dynamic events. Deep learning (DL) approaches offer promising solutions but are limited by the need for large annotated datasets. Positive Unlabeled (PU) learning addresses this limitation by leveraging unlabeled instances to increase dataset size and enhance performance. This approach is particularly useful in the case of mSCTs that are scarce and small, associated with a very small proportion of the foreground pixels. PU learning significantly increases the effective size of the training dataset, improving model performance. Here, we present a PU learning-based strategy for detecting and segmenting mSCTs. We evaluate the performance of two 3D deep learning models, StarDist-3D and 3D U-Net, which are well established for the segmentation of small volumetric structures in microscopy datasets. By integrating PU learning, we enhance the 3D U-Nets performance, demonstrating significant gains over traditional methods. This work pioneers the application of PU learning in Ca2+ imaging analysis, offering a robust framework for mSCT detection and segmentation. We also demonstrate how this quantitative analysis pipeline can be used for subsequent mSCTs feature analysis. We characterize morphological and kinetic changes of mSCTs associated with the application of chemical long-term potentiation (cLTP) stimulation in cultured rat hippocampal neurons. Our data-driven approach shows that a cLTP-inducing stimulus leads to the emergence of new active dendritic regions and differently affects mSCTs subtypes.

bioinformatics↗

bioRxiv2024

Detecting Genetic Interactions with Visible Neural Networks

Non-linear interactions among single nucleotide polymorphisms (SNPs), genes, and pathways play an important role in human diseases, but identifying these interactions is a challenging task. Neural networks are state-of-the-art predictors in many domains due to their ability to analyze big data and model complex patterns, including non-linear interactions. In genetics, visible neural networks are gaining popularity as they provide insight into the most important SNPs, genes and pathways for prediction. Visible neural networks use prior knowledge (e.g. gene and pathway annotations) to define the connections between nodes in the network, making them sparse and interpretable. Currently, most of these networks provide measures for the importance of SNPs, genes, and pathways but lack details on the nature of the interactions. In this paper, we explore different methods to detect non-linear interactions with visible neural networks. We adapted and sped up existing methods, created a comprehensive benchmark with simulated data from GAMETES and EpiGEN, and demonstrated that these methods can extract multiple types of interactions from trained visible neural networks. Finally, we applied these methods to a genome-wide case-control study of inflammatory bowel disease and found high consistency of the epistasis pairs candidates between the interpretation methods. The follow-up association test on these candidate pairs identified seven significant epistasis pairs.

bioinformatics↗

bioRxiv2023

The Natural Products Discovery Center: Release of the First 8490 Sequenced Strains for Exploring Actinobacteria Biosynthetic Diversity

Actinobacteria, the bacterial phylum most renowned for natural product discovery, has been established as a valuable source for drug discovery and biotechnology but is underrepresented within accessible genome and strain collections. Herein, we introduce the Natural Products Discovery Center (NPDC), featuring 122,449 strains assembled over eight decades, the genomes of the first 8490 NPDC strains (7142 Actinobacteria), and the online NPDC Portal making both strains and genomes publicly available. A comparative survey of RefSeq and NPDC Actinobacteria highlights the taxonomic and biosynthetic diversity within the NPDC collection, including three new genera, hundreds of new species, and [~]7000 new gene cluster families. Selected examples demonstrate how the NPDC Portals strain metadata, genomes, and biosynthetic gene clusters can be leveraged using genome mining approaches. Our findings underscore the ongoing significance of Actinobacteria in natural product discovery, and the NPDC serves as an unparalleled resource for both Actinobacteria strains and genomes.

microbiology↗

bioRxiv2022

LSR Targets YAP to Modulate Intestinal Paneth Cell Differentiation

Lipolysis-stimulated lipoprotein receptor (LSR) is a multi-functional protein that is best known for its roles in assembly of epithelial tricellular tight junctions and hepatic clearance of lipoproteins. Here, we investigated whether LSR contributes to intestinal epithelium homeostasis and pathogenesis of intestinal disease. By using multiple conditional deletion mouse models and ex vivo cultured organoids, we find that LSR elimination in intestinal stem cells results in disappearance of Paneth cell without affecting the differentiation of other cell lineages. Mechanistic studies reveal that LSR deficiency increases abundance and nuclear localization of YAP by modulating its phosphorylation and proteasomal degradation. Using gain- and loss-of-function studies we show that LSR protects against necrotizing enterocolitis through enhancement of Paneth cell differentiation in small intestinal epithelium. Thus, this study identifies LSR as an upstream negative regulator of YAP activity, an essential factor for Paneth cell differentiation, and a potential novel therapeutic target for inflammatory bowel disease.

cell biology↗

bioRxiv2022

Environment-wide and epigenome-wide association study of adiposity in "Children of 1997" birth cohort

BackgroundIncreasing childhood adiposity is a global issue requiring potentially local solutions to ensure it does not continue into adulthood. We systematically identified potentially modifiable targets of adiposity at the onset and end of puberty in Hong Kong the most economically developed major Chinese city. MethodsWe conducted an environment-wide association study (EWAS) and an epigenome-wide association study of adiposity to systematically assess associations with body mass index (BMI) and waist-hip ratio (WHR) in Hong Kongs population-representative "Children of 1997" birth cohort. Univariable linear regression was used to select exposures related to adiposity at ~11.5 years (BMI n[≤]7,119, WHR n=5,691) and ~17.6 years (n = 3,618) at Bonferroni-corrected significance, and multivariable linear regression to adjust for potential confounders followed by replication (n=308) and CpG by CpG analysis (n=286) at ~23 years. Findings were compared with evidence from randomized controlled trials (RCTs) and Mendelian randomization (MR) studies. ResultsAt ~11.5 and ~17.6 years the EWAS identified 14 and 37 exposures associated with BMI, as well as seven and 12 associated with WHR respectively. Most exposures had directionally consistent associations at ~23 years. Maternal second-hand smoking, maternal weight, and birth weight were consistently associated with adiposity. Diet (including dairy intake and artificially sweetened beverages), physical activity, snoring, binge eating, and earlier puberty were positively associated with BMI at ~17.6 years, while eating before sleep was inversely associated with BMI at ~17.6 years. Findings for birth weight, dairy intake, binge eating, and possibly earlier puberty are consistent with available evidence from RCTs or MR studies We found 21 CpGs related to BMI and 18 to WHR. ConclusionsThese novel insights into potentially modifiable factors associated with adiposity at the outset and the end of puberty could, if causal, inform future interventions to improve population health in Hong Kong and similar Chinese settings. FundingThis study was supported by the Health and Medical Research Fund Research Fellowship, Food and Health Bureau, Hong Kong SAR Government (#04180097). The DNA extraction was supported by CFS-HKU1.

genetics↗

bioRxiv2022

A Small Subset of Cytosolic dsRNAs Must Be Edited by ADAR1 to Evade MDA5-Mediated Autoimmunity

The innate immune system detects viral infection via pattern recognition receptors and induces defense reactions such as production of type I interferon1. One such receptor, MDA5, is activated upon the recognition of double-stranded RNAs (dsRNAs) that are often produced during viral replication2. Endogenous dsRNAs evade MDA5 activation through RNA editing by ADAR1, thus preventing autoimmunity3-5. Among the large number of endogenous dsRNAs, the key substrates whose editing is critical to evade MDA5 activation (termed as immunogenic dsRNAs) remain elusive. Here we reveal the identity of human immunogenic dsRNAs, a surprisingly small fraction of all cellular dsRNAs, to fill the gap in the ADAR1-dsRNA-MDA5 axis. We found that, in contrast to previous findings6,7, the immunogenic dsRNAs were highly enriched in mRNAs and depleted of introns, an expected indication of bona fide substrates of cytosolic MDA5. The immunogenic dsRNAs, in contrast to non-immunogenic dsRNAs, tended to have shorter loop between the stems, which may facilitate dsRNA formation. They also tended to be enriched at the GWAS signals of common inflammatory diseases, implying that they are truly immunogenic. We validated the MDA5-dependent immunogenicity of the dsRNAs, which was dampened following ADAR1-mediated RNA editing. We anticipate that a focused analysis of immunogenic dsRNAs will greatly facilitate the understanding and treatment of cancer and inflammatory diseases in which the important roles of dsRNA editing and sensing continue to be revealed8-13.

genetics↗

bioRxiv2021

Annulment of antagonism shifts properties that are beneficial to plants in two-member consortia of Bacillus velezensis

Bacillus spp. strains that are beneficial to plants are widely used in commercial biofertilizers and biocontrol agents for sustainable agriculture. Generally, functional Bacillus strains are applied as single strain communities since the principles of synthetic microbial consortia constructed with Bacillus strains remain largely unclear. Here, we demonstrated that the mutual compatibility directly affects the survival and function of two-member consortia composed of B. velezensis SQR9 and FZB42 in the rhizosphere. A mutation in the global regulator Spo0A of SQR9 markedly reduced the boundary phenotype with wild-type FZB42, and the combined use of the SQR9{triangleup}spo0A mutant and FZB42 improved biofilm formation, root colonization and the production of secondary metabolites that are beneficial to plants. We further confirmed the correlation between the swarm discrimination phenotype between the two consortia members and the effects that are beneficial to plants in a greenhouse experiment. Our results provide evidence that social interactions among bacteria could be an influencing factor in achieving a desired community-level function. IMPORTANCEBacillus velezensis is one of the most widely applied bacteria in biofertilizers in China and Europe. Additionally, the molecular mechanisms of plant growth promotion and disease suppression by representative model strains are well established, such as B. velezensis SQR9 and FZB42. However, it remains extremely challenging to design efficient consortia based on these model strains. Here, we showed that swarm discrimination phenotype is one of the major determinants affects the performance of two-member Bacillus consortia in vitro and in the rhizosphere. Deletion in global regulatory gene spo0A of SQR9 reduced the strength of boundary formation with FZB42, result in the improved plant growth promotion performance of dual consortium. This knowledge provides new insights into efficient probiotics consortia design in Bacillus.

microbiology↗

bioRxiv2021

Anomalous low impedance for small platinum microelectrodes

ObjectiveElectrical measurement of the activity of individual neurons is a primary goal for many invasive neural electrodes. Making these "single unit" measurements requires that we fabricate electrodes small enough so that only a few neurons contribute to the signal, but not so small that the impedance of the electrode creates overwhelming noise or signal attenuation. Thus, neuroelectrode design often must strike a balance between electrode size and electrode impedance, where the impedance is often assumed to scale linearly with electrode area. Approach and main resultsHere we study how impedance scales with neural electrode area and find that the 1 kHz impedance of Pt electrodes (but not Au electrodes) transitions from scaling with area (r-2) to scaling with perimeter (r-1) when the electrode radius falls below 10 microns. This effect can be explained by the transition from planar to spherical diffusion behavior previously reported for electrochemical microelectrodes. Significance: These results provide important intuition for designing small, single unit recording electrodes. Specifically, for materials where the impedance is dominated by a pseudo-capacitance that is associated with a diffusion limited process, the total impedance will scale with perimeter rather than area when the electrode size becomes comparable with the diffusion layer thickness. For Pt electrodes this transition occurs around 10 um radius electrodes. At even lower frequencies (1 Hz) impedance approaches a constant. This transition to r-1 scaling implies that electrodes with a pseudo-capacitance can be made smaller than one might expect before thermal noise or voltage division limits the ability to acquire high-quality single-unit recordings.

bioengineering↗

bioRxiv2020

Nitazoxanide and JIB-04 have broad-spectrum antiviral activity and inhibit SARS-CoV-2 replication in cell culture and coronavirus pathogenesis in a pig model

Pathogenic coronaviruses represent a major threat to global public health. Here, using a recombinant reporter virus-based compound screening approach, we identified several small-molecule inhibitors that potently block the replication of the newly emerged severe acute respiratory syndrome virus 2 (SARS-CoV-2). Among them, JIB-04 inhibited SARS-CoV-2 replication in Vero E6 cells with an EC50 of 695 nM, with a specificity index of greater than 1,000. JIB-04 showed in vitro antiviral activity in multiple cell types against several DNA and RNA viruses, including porcine coronavirus transmissible gastroenteritis virus. In an in vivo porcine model of coronavirus infection, administration of JIB-04 reduced virus infection and associated tissue pathology, which resulted in improved weight gain and survival. These results highlight the potential utility of JIB-04 as an antiviral agent against SARS-CoV-2 and other viral pathogens.

microbiology↗

bioRxiv2020

Sputtered porous Pt for wafer-scale manufacture of low-impedance flexible microelectrodes

Recording electrical activity from individual cells in vivo is a key technology for basic neuroscience and has growing clinical applications. To maximize the number of independent recording channels as well as the longevity, and quality of these recordings, researchers often turn to small and flexible electrodes that minimize tissue damage and can isolate signals from individual neurons. One challenge when creating these small electrodes, however, is to maintain a low interfacial impedance by applying a surface coating that is stable in tissue and does not significantly complicate the fabrication process. Here we use a high-pressure Pt sputtering process to create low-impedance electrodes at the wafer scale using standard microfabrication equipment. Direct-sputtered Pt provides a reliable and well-controlled porous coating that reduces the electrode impedance by 5-9 fold compared to flat Pt and is compatible with the microfabrication technologies used to create flexible electrodes. These porous Pt electrodes show reduced thermal noise that matches theoretical predictions. In addition, we show that these electrodes can be implanted into rat cortex, record single unit activity, and be removed all without disrupting the integrity of the coating. We also demonstrate that the shape of the electrode (in addition to the surface area) has a significant effect on the electrode impedance when the feature sizes are on the order of tens of microns. Overall, porous Pt represents a promising method for manufacturing low-impedance electrodes that can be seamlessly integrated into existing processes for producing flexible neural probes.

bioengineering↗

bioRxiv2019

Impact of ultrasonography on identifying noninvasive prenatal screening false-negative aneuploidy

PurposeTo evaluate the impact of ultrasonography (US) on identifying noninvasive prenatal screening (NIPS) false-negative aneuploidy.\n\nMethodsAnalysis of large population-based NIPS false-negative aneuploidy data comprising karyotypes, clinical outcomes, and US results.\n\nResultsFrom December 2010 to July 2018, a total of 3,320,457 pregnancies were screened by NIPS performed in BGI; among them, 69 NIPS false-negative aneuploidy cases with informed consent were confirmed, and US examination data for 48 cases were not available. Of the 21 cases with US results, 19 (90.5%) had various abnormalities on ultrasound, and 2 (9.5%) cases were shown to be normal on ultrasound. Additionally, 6 out of 7 live born fetuses (approximately 85.7%) were found to have abnormalities on ultrasound. Ventricular septal defects constituted the most frequently observed ultrasound abnormality type among the 21 NIPS false-negative aneuploidy cases.\n\nConclusionNIPS has expanded rapidly worldwide and now accounts for a large proportion of prenatal screening tests in China. This study suggests that abnormal US findings should not be neglected, even when NIPS produces a negative result. Combining NIPS with an US examination can further reduce the incidence of livebirths with aneuploidy.

genetics↗

bioRxiv2018

Isoform switching as a mechanism of acquired resistance to isocitrate dehydrogenase inhibition

Somatic mutations in cytosolic or mitochondrial isoforms of isocitrate dehydrogenase (IDH1 or IDH2, respectively) contribute to oncogenesis via production of the metabolite 2-hydroxyglutarate (2HG). Isoform-selective IDH inhibitors suppress 2HG production and induce clinical responses in patients with IDH1- and IDH2-mutant malignancies. Despite the promising activity of IDH inhibitors, the mechanisms that mediate resistance to IDH inhibition are poorly understood. Here, we describe four clinical cases that identify mutant IDH isoform switching, either from mutant IDH1 to mutant IDH2 or vice versa, as a mechanism of acquired clinical resistance to IDH inhibition in solid and liquid tumors.\n\nSignificanceIDH-mutant cancers can develop resistance to isoform-selective IDH inhibition by \"isoform switching\" from mutant IDH1 to mutant IDH2 or vice versa, thereby restoring 2-hydroxyglutarate (2HG) production by the tumor. These findings underscore a role for continued 2HG production in tumor progression and suggest therapeutic strategies to prevent or overcome resistance.

cancer biology↗