ABSTRACT
Many COVID-19 patients infected by SARS-CoV-2 virus develop pneumonia (called novel coronavirus pneumonia, NCP) and rapidly progress to respiratory failure. However, rapid diagnosis and identification of high-risk patients for early intervention are challenging. Using a large computed tomography (CT) database from 3,777 patients, we developed an AI system that can diagnose NCP and differentiate it from other common pneumonia and normal controls. The AI system can assist radiologists and physicians in performing a quick diagnosis especially when the health system is overloaded. Significantly, our AI system identified important clinical markers that correlated with the NCP lesion properties. Together with the clinical data, our AI system was able to provide accurate clinical prognosis that can aid clinicians to consider appropriate early clinical management and allocate resources appropriately. We have made this AI system available globally to assist the clinicians to combat COVID-19.
Subject(s)
Artificial Intelligence , Coronavirus Infections/diagnosis , Pneumonia, Viral/diagnosis , Tomography, X-Ray Computed , COVID-19 , China , Cohort Studies , Coronavirus Infections/pathology , Coronavirus Infections/therapy , Datasets as Topic , Humans , Lung/pathology , Models, Biological , Pandemics , Pilot Projects , Pneumonia, Viral/pathology , Pneumonia, Viral/therapy , Prognosis , Radiologists , Respiratory Insufficiency/diagnosisABSTRACT
Supersolid, an exotic quantum state of matter that consists of particles forming an incompressible solid structure while simultaneously showing superfluidity of zero viscosity1, is one of the long-standing pursuits in fundamental research2,3. Although the initial report of 4He supersolid turned out to be an artefact4, this intriguing quantum matter has inspired enthusiastic investigations into ultracold quantum gases5-8. Nevertheless, the realization of supersolidity in condensed matter remains elusive. Here we find evidence for a quantum magnetic analogue of supersolid-the spin supersolid-in the recently synthesized triangular-lattice antiferromagnet Na2BaCo(PO4)2 (ref. 9). Notably, a giant magnetocaloric effect related to the spin supersolidity is observed in the demagnetization cooling process, manifesting itself as two prominent valley-like regimes, with the lowest temperature attaining below 100 mK. Not only is there an experimentally determined series of critical fields but the demagnetization cooling profile also shows excellent agreement with the theoretical simulations with an easy-axis Heisenberg model. Neutron diffractions also successfully locate the proposed spin supersolid phases by revealing the coexistence of three-sublattice spin solid order and interlayer incommensurability indicative of the spin superfluidity. Thus, our results reveal a strong entropic effect of the spin supersolid phase in a frustrated quantum magnet and open up a viable and promising avenue for applications in sub-kelvin refrigeration, especially in the context of persistent concerns about helium shortages10,11.
ABSTRACT
Seed dormancy is crucial for optimal plant life-cycle timing. However, domestication has largely diminished seed dormancy in modern cereal cultivars, leading to challenges such as pre-harvest sprouting (PHS) and subsequent declines in yield and quality. Therefore, it is imperative to unravel the molecular mechanisms governing seed dormancy for the development of PHS-resistant varieties. In this study, we screened a mutant of BASIC HELIX-LOOP-HELIX TRANSCRIPTION FACTOR4 (OsbHLH004) with decreased seed dormancy and revealed that OsbHLH004 directly regulates the expression of 9-CIS-EPOXYCAROTENOID DIOXYGENASE3 (OsNCED3) and GIBBERELLIN 2-OXIDASE6 (OsGA2ox6) in rice (Oryza sativa). Additionally, we determined that two phosphatidylethanolamine-binding proteins, MOTHER OF FT AND TFL1 and 2 (OsMFT1 and OsMFT2; hereafter OsMFT1/2) interact with OsbHLH004 and Ideal Plant Architecture 1 (IPA1) to regulate their binding capacities on OsNCED3 and OsGA2ox6, thereby promoting seed dormancy. Intriguingly, FT-INTERACTING PROTEIN1 (OsFTIP1) interacts with OsMFT1/2 and affects their nucleocytoplasmic translocation into the nucleus, where OsMFT1/2-OsbHLH004 and OsMFT1/2-IPA1 antagonistically modulate the expression of OsNCED3 and OsGA2ox6. Our findings reveal that OsFTIP1-mediated inhibition of nuclear translocation of OsMFT1/2 and the dynamic transcriptional modulation of OsNCED3 and OsGA2ox6 by OsMFT1/2-OsbHLH004 and OsMFT1/2-IPA1 complexes in seed dormancy in rice.
ABSTRACT
Accurate prediction of protein-ligand binding affinity (PLA) is important for drug discovery. Recent advances in applying graph neural networks have shown great potential for PLA prediction. However, existing methods usually neglect the geometric information (i.e. bond angles), leading to difficulties in accurately distinguishing different molecular structures. In addition, these methods also pose limitations in representing the binding process of protein-ligand complexes. To address these issues, we propose a novel geometry-enhanced mid-fusion network, named GEMF, to learn comprehensive molecular geometry and interaction patterns. Specifically, the GEMF consists of a graph embedding layer, a message passing phase, and a multi-scale fusion module. GEMF can effectively represent protein-ligand complexes as graphs, with graph embeddings based on physicochemical and geometric properties. Moreover, our dual-stream message passing framework models both covalent and non-covalent interactions. In particular, the edge-update mechanism, which is based on line graphs, can fuse both distance and angle information in the covalent branch. In addition, the communication branch consisting of multiple heterogeneous interaction modules is developed to learn intricate interaction patterns. Finally, we fuse the multi-scale features from the covalent, non-covalent, and heterogeneous interaction branches. The extensive experimental results on several benchmarks demonstrate the superiority of GEMF compared with other state-of-the-art methods.
Subject(s)
Neural Networks, Computer , Protein Binding , Proteins , Proteins/chemistry , Proteins/metabolism , Ligands , Algorithms , Computational Biology/methods , Drug Discovery/methodsABSTRACT
Coordinated skills such as speech or dance involve sequences of actions that follow syntactic rules in which transitions between elements depend on the identities and order of past actions. Canary songs consist of repeated syllables called phrases, and the ordering of these phrases follows long-range rules1 in which the choice of what to sing depends on the song structure many seconds prior. The neural substrates that support these long-range correlations are unknown. Here, using miniature head-mounted microscopes and cell-type-specific genetic tools, we observed neural activity in the premotor nucleus HVC2-4 as canaries explored various phrase sequences in their repertoire. We identified neurons that encode past transitions, extending over four phrases and spanning up to four seconds and forty syllables. These neurons preferentially encode past actions rather than future actions, can reflect more than one song history, and are active mostly during the rare phrases that involve history-dependent transitions in song. These findings demonstrate that the dynamics of HVC include 'hidden states' that are not reflected in ongoing behaviour but rather carry information about prior actions. These states provide a possible substrate for the control of syntax transitions governed by long-range rules.
Subject(s)
Canaries/physiology , Neurons/physiology , Singing/physiology , Vocalization, Animal/physiology , Animals , Brain/anatomy & histology , Brain/cytology , Brain/physiology , Canaries/anatomy & histology , Canaries/genetics , Male , Models, Neurological , Psycholinguistics , Time FactorsABSTRACT
Magnetic skyrmions are promising as next-generation information units. Their antiparticle-the antiskyrmion-has also been discovered in chiral magnets. Here we experimentally demonstrate antiskyrmion sliding in response to a pulsed electric current at room temperature without the requirement of an external magnetic field. This is realized by embedding antiskyrmions in helical stripe domains, which naturally provide one-dimensional straight tracks along which antiskyrmion sliding can be easily launched with low current density and without transverse deflection from the antiskyrmion Hall effect. The higher mobility of the antiskyrmions in the background of helical stripes in contrast to the typical ferromagnetic state is a result of intrinsic material parameters and elastic energy of the stripe domain, thereby smearing out the random pinning potential, as supported by micromagnetic simulations. The demonstration and comprehensive understanding of antiskyrmion movement along naturally straight tracks offers a new perspective for (anti)skyrmion application in spintronics.
ABSTRACT
Rice (Oryza sativa) is one of the most important crops worldwide. Heading date is a vital agronomic trait that influences rice yield and adaption to local conditions. Hd3a, a proposed florigen that primarily functions under short-day (SD) conditions, is a mobile flowering signal that promotes the floral transition in rice. Nonetheless, how Hd3a is transported from leaves to the shoot apical meristem (SAM) under SDs remains elusive. Here, we report that FT-INTERACTING PROTEIN9 (OsFTIP9) specifically regulates rice flowering time under SDs by facilitating Hd3a transport from companion cells (CCs) to sieve elements (SEs). Furthermore, we show that the tetratricopeptide repeat (TPR) protein OsTPR075 interacts with both OsFTIP9 and OsFTIP1 and strengthens their respective interactions with Hd3a and the florigen RICE FLOWERING LOCUS T1 (RFT1). This in turn affects the trafficking of Hd3a and RFT1 to the SAM, thus regulating flowering time under SDs and long-day conditions, respectively. Our findings suggest that florigen transport in rice is mediated by different OsFTIPs under different photoperiods and those interactions between OsTPR075 and OsFTIPs are essential for mediating florigen movement from leaves to the SAM.
Subject(s)
Florigen , Oryza , Florigen/metabolism , Flowers/metabolism , Gene Expression Regulation, Plant/genetics , Oryza/metabolism , Photoperiod , Plant Proteins/genetics , Plant Proteins/metabolism , Tetratricopeptide RepeatABSTRACT
Intervertebral disk degeneration (IDD) is a significant cause of low back pain, characterized by excessive senescence and apoptosis of nucleus pulposus cells (NPCs). However, the precise mechanisms behind this senescence and apoptosis remain unclear. This study aimed to investigate the role of T-box transcription factor T (Tbxt) in IDD both in vitro and in vivo, using a hydrogen peroxide (H2O2)-induced NPCs senescence and apoptosis model, as well as a rat acupuncture IDD model. First, the expression of p16 and cleaved-caspase 3 significantly increased in degenerated human NPCs, accompanied by a decrease in Tbxt expression. Knockdown of Tbxt exacerbated senescence and apoptosis in the H2O2-induced NPCs degeneration model. Conversely, upregulation of Tbxt alleviated these effects induced by H2O2. Mechanistically, bioinformatic analysis revealed that the direct downstream target genes of Tbxt were highly enriched in autophagy-related pathways, and overexpression of Tbxt significantly activated autophagy in NPCs. Moreover, the administration of the autophagy inhibitor, 3-methyladenine, impeded the impact of Tbxt on the processes of senescence and apoptosis in NPCs. Further investigation revealed that Tbxt enhances autophagy by facilitating the transcription of ATG7 through its interaction with a specific motif within the promoter region. In conclusion, this study suggests that Tbxt mitigates H2O2-induced senescence and apoptosis of NPCs by activating ATG7-mediated autophagy.NEW & NOTEWORTHY This study investigates the role of Tbxt in IDD. The results demonstrate that knockdown of Tbxt exacerbates H2O2-induced senescence and apoptosis in NPCs and IDD, whereas upregulation of Tbxt significantly protects against IDD both in vivo and in vitro. Mechanistically, in the nucleus, Tbxt enhances the transcription of ATG7, leading to increased expression of ATG7 protein levels. This, in turn, promotes elevated autophagy levels, ultimately alleviating IDD.
Subject(s)
Apoptosis , Autophagy-Related Protein 7 , Autophagy , Cellular Senescence , Intervertebral Disc Degeneration , Nucleus Pulposus , Rats, Sprague-Dawley , Nucleus Pulposus/metabolism , Nucleus Pulposus/pathology , Autophagy/drug effects , Intervertebral Disc Degeneration/pathology , Intervertebral Disc Degeneration/metabolism , Intervertebral Disc Degeneration/genetics , Autophagy-Related Protein 7/metabolism , Autophagy-Related Protein 7/genetics , Animals , Cellular Senescence/drug effects , Humans , Rats , Male , Female , Adult , Middle Aged , Hydrogen Peroxide/toxicity , Hydrogen Peroxide/pharmacology , Hydrogen Peroxide/metabolism , Cells, CulturedABSTRACT
Metabolic dysfunction of the extracellular matrix (ECM) is one of the primary causes of intervertebral disc degeneration (IVDD). Previous studies have demonstrated that the transcription factor Brachyury (Bry) has the potential to promote the synthesis of collagen II and aggrecan, while the specific mechanism is still unknown. In this study, we used a lipopolysaccharide (LPS)-induced model of nucleus pulposus cell (NPC) degeneration and a rat acupuncture IVDD model to elucidate the precise mechanism through which Bry affects collagen II and aggrecan synthesis in vitro and in vivo. First, we confirmed Bry expression decreased in degenerated human nucleus pulposus (NP) cells (NPCs). Knockdown of Bry exacerbated the decrease in collagen II and aggrecan expression in the lipopolysaccharide (LPS)-induced NPCs degeneration in vitro model. Bioinformatic analysis indicated that Smad3 may participate in the regulatory pathway of ECM synthesis regulated by Bry. Chromatin immunoprecipitation followed by quantitative polymerase chain reaction (ChIP-qPCR) and luciferase reporter gene assays demonstrated that Bry enhances the transcription of Smad3 by interacting with a specific motif on the promoter region. In addition, Western blot and reverse transcription-qPCR assays demonstrated that Smad3 positively regulates the expression of aggrecan and collagen II in NPCs. The following rescue experiments revealed that Bry-mediated regulation of ECM synthesis is partially dependent on Smad3 phosphorylation. Finally, the findings from the in vivo rat acupuncture-induced IVDD model were consistent with those obtained from in vitro assays. In conclusion, this study reveals that Bry positively regulates the synthesis of collagen II and aggrecan in NP through transcriptional activation of Smad3.NEW & NOTEWORTHY Mechanically, in the nucleus, Bry enhances the transcription of Smad3, leading to increased expression of Smad3 protein levels; in the cytoplasm, elevated substrate levels further lead to an increase in the phosphorylation of Smad3, thereby regulating collagen II and aggrecan expression. Further in vivo experiments provide additional evidence that Bry can alleviate IVDD through this mechanism.
Subject(s)
Aggrecans , Extracellular Matrix , Fetal Proteins , Gene Expression Regulation , Nucleus Pulposus , Smad3 Protein , Adult , Animals , Female , Humans , Male , Middle Aged , Rats , Aggrecans/metabolism , Aggrecans/genetics , Cells, Cultured , Collagen Type II/metabolism , Collagen Type II/genetics , Extracellular Matrix/metabolism , Fetal Proteins/genetics , Fetal Proteins/metabolism , Intervertebral Disc Degeneration/genetics , Intervertebral Disc Degeneration/metabolism , Intervertebral Disc Degeneration/pathology , Nucleus Pulposus/metabolism , Nucleus Pulposus/pathology , Rats, Sprague-Dawley , Smad3 Protein/metabolism , Smad3 Protein/genetics , T-Box Domain Proteins/genetics , T-Box Domain Proteins/metabolismABSTRACT
To deal with the shortage and high price of helium-3 resources, adiabatic demagnetization refrigeration technology as an alternative to helium-3-based refrigeration technology has received much attention. The magnetism and ultralow-temperature magnetocaloric effect (MCE) of the EuB4O7 compound have been investigated. The results of magnetic and quasi-adiabatic demagnetization measurements suggest the absence of a magnetic order above 0.4 K for EuB4O7. The dipolar interaction between the nearest-neighbor Eu atoms has a characteristic energy of about 800 mK, which may induce a large MCE. The maximum magnetic entropy change reaches 22.8, 36.2, and 47.6 J·kg-1 K-1 at µ0H = 0-10 kOe, 0-20 kOe, and 0-50 kOe, respectively. Measurements by a quasi-adiabatic demagnetization device show that the lowest temperature achievable (289 mK) for polycrystalline EuB4O7 is lower than that (362 mK) for the commercial refrigerant Gd3Ga5O12 (GGG) single crystals. The hold time is more than 70 min below 700 mK, with an environment temperature of 2 K, proving that EuB4O7 exhibits superior cooling performance.
ABSTRACT
Atherosclerosis (AS) is a common cause of coronary heart disease and stroke. The delivery of exogenous H2S and in situ production of O2 within atherosclerotic plaques can help suppress inflammatory cell infiltration and alleviate disease progression. However, the uncontrolled release of gas donors hinders achieving effective drug concentrations and causes toxic effects. Herein, diallyl trisulfide (DATS)-loaded metal-organic cage (MOC)-68-doped MnO2 nanoparticles are developed as a microenvironment-responsive nanodrug with the capacity for the in situ co-delivery of H2S and O2 to inflammatory cells within plaques. This nanomedicine exhibited excellent monodispersity and stability and protected DATS from degradation in the circulation. In vitro studies showed that the nanomedicine reduced macrophage polarization toward an inflammatory phenotype and inhibited the formation of foam cells, while suppressing the expression of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and interleukin-1ß. In a mouse model of ApoE-/- genotype, the nanomedicine reduces the plaque burden, inflammatory infiltration, and hypoxic conditions within the plaques. Furthermore, the treatment process and therapeutic effects can be monitored by magnetic resonance image (MRI), in real time upon Mn2+ release from the acidic- and H2O2- microenvironment-responsive MnO2 nanoparticles. The DATS-loaded MOC-68-doped MnO2-based nanodrug holds great promise as a novel theranostic platform for AS.
ABSTRACT
INTRODUCTION: Acute pulmonary vein reconnection (PVR) via epicardial fibers can be found during observation period after PV isolation, the characteristics and related factors have not been fully studied. We aimed to investigate the prevalence, locations, electrogram characteristics, and ablation parameters related to acute epicardial pulmonary vein reconnection (AEPVR). METHODS: Acute PVR was monitored during observation period after PV isolation. AEPVRs were mapped and distinguished from endocardial conduction gaps. The clinical, electrophysiological characteristics and lesion set parameters were compared between patients with and without PVR. They were also compared among AEPVR, gap-related reconnection, and epicardial PVR in repeat procedures. RESULTS: A total of 56.1% acute PVR were AEPVR, which required a longer waiting period (p < .001) than endocardial gap. The majority of AEPVR were connections from the posterior PV carina to the left atrial posterior wall, followed by late manifestation of intercaval bundle conduction from the right anterior carina to right atrium. AEPVR was similar to epicardial PVR in redo procedures in distribution and electrogram characteristics. Smaller atrium (p < .001), lower impedance drop (p = .039), and ablation index (p = .028) on the posterior wall were independently associated with presence of AEPVR, while lower interlesion distance (p = .043) was the only predictor for AEPVR in acute PVR. An integrated model containing multiple lesion set parameters had the highest predictive ability for AEPVR in receiver operating characteristics analysis. CONCLUSIONS: Epicardial reconduction accounted for the majority of acute PVR. AEPVR was associated with anatomic characteristics and multiple ablation-related parameters, which could be explained by nondurable transmural lesion or late manifestation of conduction through intercaval bundle.
Subject(s)
Atrial Fibrillation , Catheter Ablation , Pulmonary Veins , Humans , Atrial Fibrillation/surgery , Treatment Outcome , Pulmonary Veins/surgery , Catheter Ablation/adverse effects , Catheter Ablation/methods , Heart Rate , RecurrenceABSTRACT
The in vivo functions of SerpinB2 in tumor cells and tumor-associated macrophages (TAMs) during breast cancer development and metastasis remain elusive. SerpinB2-deficient MMTV-PyMT mice (PyMTSB2-/-) were previously produced to explore the biological roles of SerpinB2 in breast cancer. Compared with MMTV-PyMT wild-type (PyMTWT) mice, PyMTSB2-/- mice showed delayed tumor progression and reduced CK8 + tumor cell dissemination to lymph nodes. RNA-Seq data revealed significantly enriched genes associated with inflammatory responses, especially upregulated M1 and downregulated M2 macrophage marker genes in PyMTSB2-/- tumors. Decreased CD206+M2 and increased NOS2+M1 markers were detected in the primary tumors and metastatic lymph nodes of PyMTSB2-/- mice. In an in vitro study, SerpinB2 knockdown decreased the sphere formation and migration of MDA-MB-231 cells and suppressed protumorigenic M2 polarization of RAW264.7 cells. The combination of low SerpinB2, high NOS2, and low CD206 expression was favorable for survival in patients with breast cancer, as assessed in the BreastMark dataset. Our study demonstrates that SerpinB2 deficiency delays mammary tumor development and metastasis in PyMTWT mice, along with reduced sphere formation and migration abilities of tumor cells and decreased macrophage protumorigenic polarization.
Subject(s)
Breast Neoplasms , Plasminogen Activator Inhibitor 2 , Animals , Female , Humans , Mice , Breast Neoplasms/pathology , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cell Line, Tumor , Cell Movement/genetics , Macrophages/metabolism , Mammary Neoplasms, Experimental/pathology , Mammary Neoplasms, Experimental/genetics , Mice, Knockout , Nitric Oxide Synthase Type II/metabolism , Nitric Oxide Synthase Type II/genetics , Plasminogen Activator Inhibitor 2/genetics , Plasminogen Activator Inhibitor 2/metabolism , Plasminogen Activator Inhibitor 2/deficiency , RAW 264.7 Cells , Tumor-Associated Macrophages/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolismABSTRACT
Nucleus pulposus (NP) degeneration is characterized by the decreased cellularity of nucleus pulposus cells (NPCs) and diminished content of hydrophilic extracellular matrix (ECM). Overexpression of brachyury has been reported to reverse the degenerated NPCs into healthy phenotypes. However, the direct correlation between brachyury and ECM has not been fully elucidated. This study revealed that brachyury expression decreased in human degenerated NP tissues and Lipopolysaccharide (LPS)-induced degenerated rat NPCs model. In vitro and in vivo experiments further showed that brachyury deficiency suppressed the synthesis of aggrecan and collagen II in NP. Mechanistically, ChIP-qPCR assays demonstrated that brachyury bound to the promoter region of aggrecan in NPCs. Furthermore, luciferase reporter assays revealed that brachyury transcriptionally activated aggrecan expression through binding with a novel specific motif. In rat in vivo model, brachyury overexpression partially reversed the degenerative phenotype. In conclusion, brachyury positively regulated ECM synthesis via directly promoting aggrecan transcription in NPCs. Accordingly, it may be helpful to be developed into a promising therapeutic target for NP degeneration.
Subject(s)
Intervertebral Disc Degeneration , Nucleus Pulposus , Animals , Humans , Rats , Aggrecans/genetics , Aggrecans/metabolism , Extracellular Matrix/metabolism , Intervertebral Disc Degeneration/metabolism , Nucleus Pulposus/metabolismABSTRACT
Parkinson's Disease (PD) is characterized by the loss of dopaminergic neurons, with ferroptosis playing a significant role. Salidroside (SAL) has shown neuroprotective potential, this study aims to explore its capacity to mitigate ferroptosis in PD, focusing on the modulation of the Nuclear Factor E2-Related Factor 2 (Nrf2)/ Glutathione Peroxidase 4 (GPX4) pathway. Male C57BL/6 mice were subjected to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce PD-like symptoms, followed by SAL and Nrf2 inhibitor administration. Then behavioral tests, immunohistochemical staining, transmission electron microscopy, and Western blot analysis were conducted to assess motor functions, pathological changes, ferroptosis, and related protein expressions. In vitro, SH-SY5Y cells were treated with erastin to induce ferroptosis to assess the protective effects of SAL. Additionally, A53T-α-synuclein (α-syn) was used to stimulate the PD model, SAL and a Nrf2 inhibitor (ML385) was utilized to elucidate the role of the Nrf2/GPX4 pathway in mitigating ferroptosis in PD. In vivo, SAL significantly improved motor functions and reduced the expression of α-syn, while increasing tyrosine hydroxylase (TH) expression of PD mice. Additionally, SAL treatment notably enhanced the levels of antioxidants and reduced MDA and iron content in the substantia nigra of PD mice. In vitro, SAL treatment increased the TH, GPX4, Nrf2 expression, and mitochondrial membrane potential whereas alleviated ferroptosis through the Nrf2/GPX4 pathway, as evidenced in erastin-induced and α-syn overexpressing SH-SY5Y cells. While these effects were reversed upon Nrf2 inhibition. SAL demonstrates significant potential in mitigating PD pathology and ferroptosis, positioning the Nrf2/GPX4 pathway as a promising therapeutic target. However, future studies should focus on the long-term effects of SAL, its pharmacokinetics, addressing the multifactorial nature of PD pathogenesis.
Subject(s)
Ferroptosis , Glucosides , Neuroblastoma , Parkinson Disease , Phenols , Male , Humans , Mice , Animals , NF-E2-Related Factor 2/metabolism , Signal Transduction , Mice, Inbred C57BLABSTRACT
OBJECTIVES: To explore the performance of multiparametric MRI-based radiomics in discriminating different human epidermal growth factor receptor 2 (HER2) expressing statuses (i.e., HER2-overexpressing, HER2-low-expressing, and HER2-zero-expressing) in breast cancer. METHODS: A total of 771 breast cancer patients from two institutions were retrospectively studied. Five-hundred-eighty-one patients from Institution I were divided into a training dataset (n1 = 407) and an independent validation dataset (n1 = 174); 190 patients from Institution II formed the external validation dataset. All patients were categorized into HER2-overexpressing, HER2-low-expressing, and HER2-zero-expressing groups based on pathologic examination. Multiparametric (including T2-weighted imaging with fat suppression [T2WI-FS], diffusion-weighted imaging [DWI], apparent diffusion coefficient [ADC], and dynamic contrast-enhanced [DCE]) MRI-based radiomics features were extracted and then selected from the training dataset using the least absolute shrinkage and selection operator (LASSO) regression. Three predictive models to discriminate HER2-overexpressing vs. others, HER2-low expressing vs. others, and HER2-zero-expressing vs. others were developed based on the selected features. The model performance was evaluated using the area under the receiver operating characteristic curve (AUC). RESULTS: Eleven radiomics features from DWI, ADC, and DCE; one radiomics feature from DWI; and 17 radiomics features from DWI, ADC, and DCE were selected to build three predictive models, respectively. In training, independent validation, and external validation datasets, radiomics models achieved AUCs of 0.809, 0.737, and 0.725 in differentiating HER2-overexpressing from others; 0.779, 0.778, and 0.782 in differentiating HER2-low-expressing from others; and 0.889, 0.867, and 0.813 in differentiating HER2-zero-expressing from others, respectively. CONCLUSIONS: Multiparametric MRI-based radiomics model may preoperatively predict HER2 statuses in breast cancer patients. CLINICAL RELEVANCE STATEMENT: The MRI-based radiomics models could be used to noninvasively identify the new three-classification of HER2 expressing status in breast cancer, which is helpful to the decision-making for HER2-target therapies. KEY POINTS: ⢠Detecting HER2-overexpressing, HER2-low-expressing, and HER2-zero-expressing status in breast cancer patients is crucial for determining candidates for anti-HER2 therapy. ⢠Radiomics features from multiparametric MRI significantly differed among HER2-overexpressing, HER2-low expressing, and HER2-zero-expressing breast cancers. ⢠Multiparametric MRI-based radiomics could preoperatively evaluate three different HER2-expressing statuses and help to determine potential candidates for anti-HER2 therapy in breast cancer patients.
ABSTRACT
OBJECTIVES: To determine the value of conventional DWI, continuous-time random walk (CTRW), fractional order calculus (FROC), and stretched exponential model (SEM) in discriminating human epidermal growth factor receptor 2 (HER2) status of breast cancer (BC). METHODS: This prospective study included 158 women who underwent DWI, CTRW, FROC, and SEM and were pathologically categorized into the HER2-zero-expressing group (n = 10), HER2-low-expressing group (n = 86), and HER2-overexpressing group (n = 62). Nine diffusion parameters, namely ADC, αCTRW, ßCTRW, DCTRW, ßFROC, DFROC, µFROC, αSEM, and DDCSEM of the primary tumor, were derived from four diffusion models. These diffusion metrics and clinicopathologic features were compared between groups. Logistic regression was used to determine the optimal diffusion metrics and clinicopathologic variables for classifying the HER2-expressing statuses. Receiver operating characteristic (ROC) curves were used to evaluate their discriminative ability. RESULTS: The estrogen receptor (ER) status, progesterone receptor (PR) status, and tumor size differed between HER2-low-expressing and HER2-overexpressing groups (p < 0.001 to p = 0.009). The αCTRW, DCTRW, ßFROC, DFROC, µFROC, αSEM, and DDCSEM were significantly lower in HER2-low-expressing BCs than those in HER2-overexpressing BCs (p < 0.001 to p = 0.01). Further multivariable logistic regression analysis showed that the αCTRW was the single best discriminative metric, with an area under the curve (AUC) being higher than that of ADC (0.802 vs. 0.610, p < 0.05); the addition of ER status, PR status, and tumor size to the αCTRW improved the AUC to 0.877. CONCLUSIONS: The αCTRW could help discriminate the HER2-low-expressing and HER2-overexpressing BCs. CLINICAL RELEVANCE STATEMENT: Human epidermal growth factor receptor 2 (HER2)-low-expressing breast cancer (BC) might also benefit from the HER2-targeted therapy. Prediction of HER2-low-expressing BC or HER2-overexpressing BC is crucial for appropriate management. Advanced continuous-time random walk diffusion MRI offers a solution to this clinical issue. KEY POINTS: ⢠Human epidermal receptor 2 (HER2)-low-expressing BC had lower αCTRW, DCTRW, ßFROC, DFROC, µFROC, αSEM, and DDCSEM values compared with HER2-overexpressing breast cancer. ⢠The αCTRW was the single best diffusion metric (AUC = 0.802) for discrimination between the HER2-low-expressing and HER2-overexpressing breast cancers. ⢠The addition of αCTRW to the clinicopathologic features (estrogen receptor status, progesterone receptor status, and tumor size) further improved the discriminative ability.
Subject(s)
Breast Neoplasms , Receptor, ErbB-2 , Female , Humans , Breast Neoplasms/pathology , Prospective Studies , Receptors, Progesterone , Diffusion Magnetic Resonance Imaging , Receptors, Estrogen/metabolismABSTRACT
BACKGROUND. Breast cancer HER2 expression has been redefined using a three-tiered system, with HER2-zero cancers considered ineligible for HER2-targeted therapy, HER2-low cancers considered candidates for novel HER2-targeted drugs, and HER2-positive cancers treated with traditional HER2-targeted medications. OBJECTIVE. The purpose of this study was to assess MRI radiomics models for a three-tiered classification of HER2 expression of breast cancer. METHODS. This retrospective study included 592 patients with pathologically confirmed breast cancer (mean age, 47.0 ± 18.0 [SD] years) who underwent breast MRI at either of a health system's two hospitals from April 2016 through June 2022. Three-tiered HER2 status was pathologically determined. Radiologists assessed the conventional MRI features of tumors and manually segmented the tumors on multiparametric sequences (T2-weighted images, DWI, ADC maps, and T1-weighted delayed contrast-enhanced images) to extract radiomics features. Least absolute shrinkage and selection operator analysis was used to develop two radiomics signatures, to differentiate HER2-zero cancers from HER2-low or HER2-positive cancers (task 1) as well as to differentiate HER2-low cancers from HER2-positive cancers (task 2). Patients from hospital 1 were randomly assigned to a discovery set (task 1: n = 376; task 2: n = 335) or an internal validation set (task 1: n = 161; task 2: n = 143); patients from hospital 2 formed an external validation set (task 1: n = 55; task 2: n = 50). Multivariable logistic regression analysis was used to create nomograms combining radiomics signatures with clinicopathologic and conventional MRI features. RESULTS. AUC, sensitivity, and specificity in the discovery, internal validation, and external validation sets were as follows: for task 1, 0.89, 99.4%, and 69.0%; 0.86, 98.6%, and 76.5%; and 0.78, 100.0%, and 0.0%, respectively; for task 2, 0.77, 93.8%, and 32.3%; 0.75, 92.9%, and 6.8%; and 0.77, 97.0%, and 29.4%, respectively. For task 1, no nomogram was created because no clinicopathologic or conventional MRI feature was associated with HER2 status independent of the MRI radiomics signature. For task 2, a nomogram including an MRI radiomics signature and three pathologic features (histologic grade of III, high Ki-67 index, and positive progesterone receptor status) that were independently associated with HER2-low expression had an AUC of 0.87, 0.83, and 0.80 in the three sets. CONCLUSION. MRI radiomics features were used to differentiate HER2-zero from HER2-low cancers or HER2-positives cancers as well as to differentiate HER2-low cancers from HER2-positive cancers. CLINICAL IMPACT. MRI radiomics may help select patients for novel or traditional HER2-targeted therapies, particularly those patients with ambiguous results of immunohistochemical staining results or limited access to fluorescence in situ hybridization.
Subject(s)
Breast Neoplasms , Magnetic Resonance Imaging , Receptor, ErbB-2 , Humans , Breast Neoplasms/diagnostic imaging , Breast Neoplasms/pathology , Female , Middle Aged , Magnetic Resonance Imaging/methods , Retrospective Studies , Receptor, ErbB-2/metabolism , Adult , Aged , Diagnosis, Differential , Image Interpretation, Computer-Assisted/methods , RadiomicsABSTRACT
BACKGROUND: Contrast-induced encephalopathy (CIE) is a rare complication during or after angiography, usually transient and reversible. CIE diagnosis is challenging due to the absence of no formal diagnostic criteria. CIE can mimic stroke symptoms, including visual disturbances, seizures, confusion, coma, and focal neurological deficits. This case reports neurological deficit reversal in a CIE patient due to the embolization of an intracranial aneurysm, the second angiographic procedure in six days. CASE PRESENTATION: A 77-year-old woman was admitted to the hospital for headaches. The cerebral computed tomography (CT) scan indicated a subarachnoid hemorrhage. The first digital subtraction angiography (DSA) identified an aneurysm of 4 mm ∗ 3 mm in size in the M1 segment of the right middle cerebral artery (MCA). Then, embolization surgery was performed for the cerebral aneurysm, which was successful. However, the patient had post-operative headaches, slurred speech, epilepsy, limb weakness, and delirium post-procedure. The non-contrast cerebral CT indicated widespread edema in the right cerebral hemisphere. The patient was diagnosed with CIE and treated with symptomatic supportive therapy. Eventually, the patient's neurological deficits and cerebral edema improved significantly. CONCLUSIONS: The current case emphasized the importance of early diagnosis and symptomatic treatment of CIE. Thus, CIE should be the first consideration during the differential diagnosis of a patient having acute neurological impairment after repeated DSA.