Magnetic Resonance Electrical Properties Tomography Based on Modified Physics-Informed Neural Network and Multiconstraints.

This paper presents a novel method based on leveraging physics-informed neural networks for magnetic resonance electrical property tomography (MREPT). MREPT is a noninvasive technique that can retrieve the spatial distribution of electrical properties (EPs) of scanned tissues from measured transmit radiofrequency (RF) in magnetic resonance imaging (MRI) systems. The reconstruction of EP values in MREPT is achieved by solving a partial differential equation derived from Maxwell's equations that lacks a direct solution. Most conventional MREPT methods suffer from artifacts caused by the invalidation of the assumption applied for simplification of the problem and numerical errors caused by numerical differentiation. Existing deep learning-based (DL-based) MREPT methods comprise data-driven methods that need to collect massive datasets for training or model-driven methods that are only validated in trivial cases. Hence we proposed a model-driven method that learns mapping from a measured RF, its spatial gradient and Laplacian to EPs using fully connected networks (FCNNs). The spatial gradient of EP can be computed through the automatic differentiation of FCNNs and the chain rule. FCNNs are optimized using the residual of the central physical equation of convection-reaction MREPT as the loss function (L). To alleviate the ill condition of the problem, we added multiconstraints, including the similarity constraint between permittivity and conductivity and the ℓ1 norm of spatial gradients of permittivity and conductivity, to the L. We demonstrate the proposed method with a three-dimensional realistic head model, a digital phantom simulation, and a practical phantom experiment at a 9.4T animal MRI system.

Functional characterisation of Dof gene family and expression analysis under abiotic stresses and melatonin-mediated tolerance in pitaya (Selenicereus undatus).

DNA binding proteins with one finger (Dof ) transcription factors are essential for seed development and defence against various biotic and abiotic stresses in plants. Genomic analysis of Dof has not been determined yet in pitaya (Selenicereus undatus ). In this study, we have identified 26 Dof gene family members, renamed as HuDof-1 to HuDof-26 , and clustered them into seven subfamilies based on conserved motifs, domains, and phylogenetic analysis. The gene pairs of Dof family members were duplicated by segmental duplications that faced purifying selection, as indicated by the K a /K s ratio values. Promoter regions of HuDof genes contain many cis -acting elements related to phytohormones including abscisic acid, jasmonic acid, gibberellin, temperature, and light. We exposed pitaya plants to different environmental stresses and examined melatonin's influence on Dof gene expression levels. Signifcant expression of HuDof -2 and HuDof -6 were observed in different developmental stages of flower buds, flowers, pericarp, and pulp. Pitaya plants were subjected to abiotic stresses, and transcriptome analysis was carried out to identify the role of Dof gene family members. RNA-sequencing data and reverse transcription quantitative PCR-based expression analysis revealed three putative candidate genes (HuDof -1, HuDof -2, and HuDof -8), which might have diverse roles against the abiotic stresses. Our study provides a theoretical foundation for functional analysis through traditional and modern biotechnological tools for pitaya trait improvement.

A fully automatic parenchyma extraction method for MRI T2* relaxometry of iron loaded liver in transfusion-dependent patients.

PURPOSE: To develop a fully automatic parenchyma extraction method for the T2* relaxometry of iron overload liver. METHODS: A retrospective multicenter collection of liver MR examinations from 177 transfusion-dependent patients was conducted. The proposed method extended a semiautomatic parenchyma extraction algorithm to a fully automatic approach by introducing a modified TransUNet on the R2* (1/T2*) map for liver segmentation. Axial liver slices from 129 patients at 1.5 T were allocated to training (85%) and internal test (15%) sets. Two external test sets separately included 1.5 T data from 20 patients and 3.0 T data from 28 patients. The final T2* measurement was obtained by fitting the average signal of the extracted liver parenchyma. The agreement between T2* measurements using fully and semiautomatic parenchyma extraction methods was assessed using coefficient of variation (CoV) and Bland-Altman plots. RESULTS: Dice of the deep network-based liver segmentation was 0.970 ± 0.019 on the internal dataset, 0.960 ± 0.035 on the external 1.5 T dataset, and 0.958 ± 0.014 on the external 3.0 T dataset. The mean difference bias between T2* measurements of the fully and semiautomatic methods were separately 0.12 (95% CI: -0.37, 0.61) ms, 0.04 (95% CI: -1.0, 1.1) ms, and 0.01 (95% CI: -0.25, 0.23) ms on the three test datasets. The CoVs between the two methods were 4.2%, 4.8% and 2.0% on the internal test set and two external test sets. CONCLUSIONS: The developed fully automatic parenchyma extraction approach provides an efficient and operator-independent T2* measurement for assessing hepatic iron content in clinical practice.

Viscoelastic parameters derived from multifrequency MR elastography for depicting hepatic fibrosis and inflammation in chronic viral hepatitis.

OBJECTIVES: The capability of MR elastography (MRE) to differentiate fibrosis and inflammation, and to provide precise diagnoses is crucial, whereas the coexistence of fibrosis and inflammation may obscure the diagnostic accuracy. METHODS: In this retrospective study, from June 2020 to December 2022, chronic viral hepatitis patients who underwent multifrequency MRE (mMRE) were included in, and further divided into, training and validation cohorts. The hepatic viscoelastic parameters [shear wave speed (c) and loss angle (φ) of the complex shear modulus] were obtained from mMRE. The logistic regression and receiver operating characteristic (ROC) curves were generated to evaluate performance of viscoelastic parameters for fibrosis and inflammation. RESULTS: A total of 233 patients were assigned to training cohort and validation cohorts (mean age, 52 years ± 13 (SD); 51 women; training cohort, n = 170 (73%), and validation cohort, n = 63 (27%)). Liver c exhibited superior performance in detecting fibrosis with ROC (95% confidence interval) of ≥ S1 (0.96 (0.92-0.99)), ≥ S2 (0.86 (0.78-0.92)), ≥ S3 (0.89 (0.84-0.95)), and S4 (0.88 (0.83-0.93)). Similarly, φ was effective in diagnosing inflammation with ROC values of ≥ G2 (0.72 (0.63-0.81)), ≥ G3 (0.88 (0.83-0.94)), and G4 (0.92 (0.87-0.98)). And great predictive discrimination for fibrosis and inflammation were shown in validation cohort (all AUCs > 0.75). CONCLUSION: The viscoelastic parameters derived from multifrequency MRE could realize simultaneous detection of hepatic fibrosis and inflammation. CRITICAL RELEVANCE STATEMENT: Fibrosis and inflammation coexist in chronic liver disease which obscures the diagnostic performance of MR elastography, whereas the viscoelastic parameters derived from multifrequency MR elastography could realize simultaneous detection of hepatic fibrosis and inflammation. KEY POINTS: • Hepatic biomechanical parameters derived from multifrequency MR elastography could effectively detect fibrosis and inflammation. • Liver stiffness is useful for detecting fibrosis independent of inflammatory activity. • Fibrosis could affect the diagnostic efficacy of liver viscosity in inflammation, especially in early-grade of inflammation.

High expression of BCAT1 sensitizes AML cells to PARP inhibitor by suppressing DNA damage response.

Previous evidence has confirmed that branched-chain aminotransferase-1 (BCAT1), a key enzyme governing branched-chain amino acid (BCAA) metabolism, has a role in cancer aggression partly by restricting αKG levels and inhibiting the activities of the αKG-dependent enzyme family. The oncogenic role of BCAT1, however, was not fully elucidated in acute myeloid leukemia (AML). In this study, we investigated the clinical significance and biological insight of BCAT1 in AML. Using q-PCR, we analyzed BCAT1 mRNAs in bone marrow samples from 332 patients with newly diagnosed AML. High BCAT1 expression independently predicts poor prognosis in patients with AML. We also established BCAT1 knockout (KO)/over-expressing (OE) AML cell lines to explore the underlying mechanisms. We found that BCAT1 affects cell proliferation and modulates cell cycle, cell apoptosis, and DNA damage/repair process. Additionally, we demonstrated that BCAT1 regulates histone methylation by reducing intracellular αKG levels in AML cells. Moreover, high expression of BCAT1 enhances the sensitivity of AML cells to the Poly (ADP-ribose) polymerase (PARP) inhibitor both in vivo and in vitro. Our study has demonstrated that BCAT1 expression can serve as a reliable predictor for AML patients, and PARP inhibitor BMN673 can be used as an effective treatment strategy for patients with high BCAT1 expression. KEY MESSAGES: High expression of BCAT1 is an independent risk factor for poor prognosis in patients with CN-AML. High BCAT1 expression in AML limits intracellular αKG levels, impairs αKG-dependent histone demethylase activity, and upregulates H3K9me3 levels. H3K9me3 inhibits ATM expression and blocks cellular DNA damage repair process. Increased sensitivity of BCAT1 high expression AML to PARP inhibitors may be used as an effective treatment strategy in AML patients.

Targeting PRMT9-mediated arginine methylation suppresses cancer stem cell maintenance and elicits cGAS-mediated anticancer immunity.

Current anticancer therapies cannot eliminate all cancer cells, which hijack normal arginine methylation as a means to promote their maintenance via unknown mechanisms. Here we show that targeting protein arginine N-methyltransferase 9 (PRMT9), whose activities are elevated in blasts and leukemia stem cells (LSCs) from patients with acute myeloid leukemia (AML), eliminates disease via cancer-intrinsic mechanisms and cancer-extrinsic type I interferon (IFN)-associated immunity. PRMT9 ablation in AML cells decreased the arginine methylation of regulators of RNA translation and the DNA damage response, suppressing cell survival. Notably, PRMT9 inhibition promoted DNA damage and activated cyclic GMP-AMP synthase, which underlies the type I IFN response. Genetically activating cyclic GMP-AMP synthase in AML cells blocked leukemogenesis. We also report synergy of a PRMT9 inhibitor with anti-programmed cell death protein 1 in eradicating AML. Overall, we conclude that PRMT9 functions in survival and immune evasion of both LSCs and non-LSCs; targeting PRMT9 may represent a potential anticancer strategy.

Three-Dimensional Multifrequency MR Elastography for Microvascular Invasion and Prognosis Assessment in Hepatocellular Carcinoma.

BACKGROUND: Pretreatment identification of microvascular invasion (MVI) in hepatocellular carcinoma (HCC) is important when selecting treatment strategies. PURPOSE: To improve models for predicting MVI and recurrence-free survival (RFS) by developing nomograms containing three-dimensional (3D) MR elastography (MRE). STUDY TYPE: Prospective. POPULATION: 188 patients with HCC, divided into a training cohort (n = 150) and a validation cohort (n = 38). In the training cohort, 106/150 patients completed a 2-year follow-up. FIELD STRENGTH/SEQUENCE: 1.5T 3D multifrequency MRE with a single-shot spin-echo echo planar imaging sequence, and 3.0T multiparametric MRI (mp-MRI), consisting of diffusion-weighted echo planar imaging, T2-weighted fast spin echo, in-phase out-of-phase T1-weighted fast spoiled gradient-recalled dual-echo and dynamic contrast-enhanced gradient echo sequences. ASSESSMENT: Multivariable analysis was used to identify the independent predictors for MVI and RFS. Nomograms were constructed for visualization. Models for predicting MVI and RFS were built using mp-MRI parameters and a combination of mp-MRI and 3D MRE predictors. STATISTICAL TESTS: Student's t-test, Mann-Whitney U test, chi-squared or Fisher's exact tests, multivariable analysis, area under the receiver operating characteristic curve (AUC), DeLong test, Kaplan-Meier analysis and log rank tests. P < 0.05 was considered significant. RESULTS: Tumor c and liver c were independent predictors of MVI and RFS, respectively. Adding tumor c significantly improved the diagnostic performance of mp-MRI (AUC increased from 0.70 to 0.87) for MVI detection. Of the 106 patients in the training cohort who completed the 2-year follow up, 34 experienced recurrence. RFS was shorter for patients with MVI-positive histology than MVI-negative histology (27.1 months vs. >40 months). The MVI predicted by the 3D MRE model yielded similar results (26.9 months vs. >40 months). The MVI and RFS nomograms of the histologic-MVI and model-predicted MVI-positive showed good predictive performance. DATA CONCLUSION: Biomechanical properties of 3D MRE were biomarkers for MVI and RFS. MVI and RFS nomograms were established. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Etoposide combined with cytarabine and pegfilgrastim for poorly mobilizing patients with multiple myeloma and lymphoma: A prospective multicentre study.

A chemotherapy-based mobilization regimen in patients who mobilize poorly, based on etoposide, cytarabine and pegfilgrastim (EAP), has recently been introduced. The aim of this prospective study was to investigate the efficacy and safety of the EAP regimen in patients with poorly mobilizing multiple myeloma (MM) or lymphoma. This single-arm clinical trial was performed at eight public hospitals in China and was registered as a clinical trial (NCT05510089). The inclusion criteria were; (1) diagnosis of MM or lymphoma, (2) defined as a 'poor mobilizer' and (3) aged 18-75 years. The EAP regimen consisted of etoposide 75 mg/m2 /day on days 1-2, cytarabine 300 mg/m2 every 12 h on days 1-2 and pegfilgrastim 6 mg on day 6. The primary endpoint of the study was the ratio of patients achieving adequate mobilization (≥2.0 × 106 CD34+ cells/kg). From 1 September 2022 to 15 August 2023, a total of 58 patients were enrolled, 53 (91.4%) achieved adequate mobilization, while 41 (70.7%) achieved optimal mobilization with a median number of cumulative collected CD34+ cells was 9.2 (range 2.1-92.7) × 106 /kg and the median number of apheresis per patient of 1.2. The median time from administration of the EAP regimen to the first apheresis was 12 days. Approximately 8.6% of patients required plerixa for rescue, which was successful. Twelve (20.7%) of the 58 patients suffered grade 2-3 infections, while 25 (43.1%) required platelet transfusions. The duration of neutrophil and platelet engraftment was 11 days. In conclusion, these results suggest that the EAP mobilization regimen might be a promising option for poorly mobilizing patients with MM or lymphoma.

Principal component analysis-assisted zirconium-based metal-organic frameworks/DNA biosensor for the analysis of various phosphates.

Considering the diversity of phosphates and their pivotal roles in physiological processes, detection of various phosphates related to their metabolism is urgent but challenging. Herein, we design a biosensor with zirconium-based MOFs (Zr-MOFs) and fluorophore-modified single-stranded DNA (F-ssDNA) for the analysis of phosphates. Relying on the interaction between Zr clusters and phosphate backbone, F-ssDNA is anchored on the surface of Zr-MOFs, inducing fluorescence resonance energy transfer (FRET) and subsequently quenching the fluorescence of F-ssDNA. Meanwhile, phosphates with different numbers of phosphate groups, molecular structures and coordination environments are able to adjust the FRET between Zr-MOFs and F-ssDNA via a site-occupying effect, recovering the fluorescence of F-ssDNA in distinct cases, which may result in diverse fluorescence signals. Consequently, seventeen phosphates and four phosphate mixtures are discriminated with the assistance of principal component analysis. These results provide new insight into the application of Zr-MOFs and broaden the path for the development of analytical methods for phosphates.

Fumarate Hydratase-Deficient Renal Cell Carcinoma With Predominant Tubulocystic Features Mimics Tubulocystic Renal Cell Carcinoma.

CONTEXT.­: Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) rarely exhibits a predominant tubulocystic architecture with few other components. RCC with pure tubules and cysts lined by eosinophilic tumor cells with prominent nucleoli would raise the diagnosis of tubulocystic RCC. It is important to differentiate the 2 entities because they lead to different outcomes. OBJECTIVE.­: To address the concern, a multicenter study was implemented to explore useful clinicopathologic features in differentiation between tubulocystic FH-deficient RCC and tubulocystic RCC. DESIGN.­: Clinical factors included age, sex, tumor size, and outcome. Morphologic factors included cell morphology, presence or absence of a nontubulocystic component, and stromal findings. Immunohistochemistry, fluorescence in situ hybridization, and next-generation sequencing were performed to explore the protein expression and molecular profiles of the 2 entities. RESULTS.­: We evaluated 6 patients with tubulocystic RCC and 10 patients with tubulocystic FH-deficient RCC. Tubulocystic RCC exhibited a small size (<4.0 cm, pT1a), low Ki-67 index (<5%), retained FH, and negative 2SC expression. Tubulocystic FH-deficient RCC had a relatively large size and a high Ki-67 index. Perinucleolar haloes, loss of FH, and 2SC positivity were always observed. Pure tubulocystic architecture was not observed in FH-deficient RCC, because focal nontubulocystic components can always be seen. CONCLUSIONS.­: We emphasized multiple sectioning to identify a nontubulocystic architecture to exclude tubulocystic RCC. Moreover, tumor size, FH/2SC staining, and the Ki-67 index can differentiate tubulocystic FH-deficient RCC from tubulocystic RCC. The diagnosis of tubulocystic RCC was not recommended in renal mass biopsy because of the limited tissues sampled.

Unveiling camouflaged and partially occluded colorectal polyps: Introducing CPSNet for accurate colon polyp segmentation.

BACKGROUND: Segmenting colorectal polyps presents a significant challenge due to the diverse variations in their size, shape, texture, and intricate backgrounds. Particularly demanding are the so-called "camouflaged" polyps, which are partially concealed by surrounding tissues or fluids, adding complexity to their detection. METHODS: We present CPSNet, an innovative model designed for camouflaged polyp segmentation. CPSNet incorporates three key modules: the Deep Multi-Scale-Feature Fusion Module, the Camouflaged Object Detection Module, and the Multi-Scale Feature Enhancement Module. These modules work collaboratively to improve the segmentation process, enhancing both robustness and accuracy. RESULTS: Our experiments confirm the effectiveness of CPSNet. When compared to state-of-the-art methods in colon polyp segmentation, CPSNet consistently outperforms the competition. Particularly noteworthy is its performance on the ETIS-LaribPolypDB dataset, where CPSNet achieved a remarkable 2.3% increase in the Dice coefficient compared to the Polyp-PVT model. CONCLUSION: In summary, CPSNet marks a significant advancement in the field of colorectal polyp segmentation. Its innovative approach, encompassing multi-scale feature fusion, camouflaged object detection, and feature enhancement, holds considerable promise for clinical applications.

Venetoclax plus daunorubicin and cytarabine in newly diagnosed acute myeloid leukemia patients: A propensity score-matched analysis.

Venetoclax plus 3 + 7 daunorubicin and cytarabine chemotherapy (DAV) has shown safety and efficacy in eligible patients with newly diagnosed acute myeloid leukemia (AML). However, there are no direct comparisons between DAV and 3 + 7 daunorubicin and cytarabine chemotherapy (DA) alone. We performed a propensity score-matched analysis to compare the outcomes of DAV group with historical DA group and identify the clinical and molecular characteristics of patients who might benefit from the DAV regimen. The DAV group had a higher Complete remission (CR) rate than the DA group (90% vs. 55%, p = 0.008). 25 (96%) patients in the DAV group had a higher MRD-negative CRc rate compared with 13 (62%) patients in the DA group (p = 0.006). After a median follow-up duration of 19.15 (IQR 17.13-21.67) months, the DAV group had an improved overall survival (p = 0.001) and event-free survival (p = 0.069), but not disease-free survival (p = 0.136). Collectively, DAV regimen induced high CR rates and deep MRD-negative CRc rates after one cycle of induction therapy, as well as prolonged the overall survival, in young adult patients with AML who were eligible for intensive chemotherapy. The addition of venetoclax to intensive chemotherapy should be considered in the future to achieve better survival advantages in eligible AML patients.

DHCR24-mediated sterol homeostasis during spermatogenesis is required for sperm mitochondrial sheath formation and impacts male fertility over time.

Desmosterol and cholesterol are essential lipid components of the sperm plasma membrane. Cholesterol efflux is required for capacitation, a process through which sperm acquire fertilizing ability. In this study, using a transgenic mouse model overexpressing 24-dehydrocholesterol reductase (DHCR24), an enzyme in the sterol biosynthesis pathway responsible for the conversion of desmosterol to cholesterol, we show that disruption of sterol homeostasis during spermatogenesis led to defective sperm morphology characterized by incomplete mitochondrial packing in the midpiece, reduced sperm count and motility, and a decline in male fertility with increasing paternal age, without changes in body fat composition. Sperm depleted of desmosterol exhibit inefficiency in the acrosome reaction, metabolic dysfunction, and an inability to fertilize the egg. These findings provide molecular insights into sterol homeostasis for sperm capacitation and its impact on male fertility.

Gilteritinib-based combination therapy in adult relapsed/refractory FLT3-mutated acute myeloid leukaemia.

Gilteritinib, a potent FMS-like tyrosine kinase 3 (FLT3) inhibitor, was approved for relapsed/refractory (R/R) FLT3-mutated acute myeloid leukaemia (AML) patients but still showed limited efficacy. Here, we retrospectively analysed the efficacy and safety of different gilteritinib-based combination therapies (gilteritinib plus hypomethylating agent and venetoclax, G + HMA + VEN; gilteritinib plus HMA, G + HMA; gilteritinib plus venetoclax, G + VEN) in 33 R/R FLT3-mutated AML patients. The composite complete response (CRc) and modified CRc (mCRc) rates were 66.7% (12/18) and 88.9% (16/18) in patients received G + HMA + VEN, which was higher compared with that in G + HMA (CRc: 18.2%, 2/11; mCRc: 45.5%, 5/11) or G + VEN (CRc: 50.0%, 2/4; mCRc: 50.0%, 2/4). The median overall survival (OS) for G + HMA + VEN, G + HMA and G + VEN treatment was not reached, 160.0 days and 231.0 days. The median duration of remission (DOR) for G + HMA + VEN, G + HMA and G + VEN treatment was not reached, 82.0 days and 77.0 days. Four patients in the G + HMA + VEN group received alloHSCT after remission exhibited prolonged median DOR. The most common grade 3/4 adverse events were cytopenia, febrile neutropenia and pulmonary infection; there were no differences among the three groups. In conclusion, our data demonstrated promising response of G + HMA + VEN combination therapy in R/R FLT3-mutated AML, and it may be considered an effective therapy bridge to transplantation.

Phosphoproteomic Characterization and Kinase Signature Predict Response to Venetoclax Plus 3+7 Chemotherapy in Acute Myeloid Leukemia.

Resistance to chemotherapy remains a formidable obstacle in acute myeloid leukemia (AML) therapeutic management, necessitating the exploration of optimal strategies to maximize therapeutic benefits. Venetoclax with 3+7 daunorubicin and cytarabine (DAV regimen) in young adult de novo AML patients is evaluated. 90% of treated patients achieved complete remission, underscoring the potential of this regimen as a compelling therapeutic intervention. To elucidate underlying mechanisms governing response to DAV in AML, quantitative phosphoproteomics to discern distinct molecular signatures characterizing a subset of DAV-sensitive patients is used. Cluster analysis reveals an enrichment of phosphoproteins implicated in chromatin organization and RNA processing within DAV-susceptible and DA-resistant AML patients. Furthermore, kinase activity profiling identifies AURKB as a candidate indicator of DAV regimen efficacy in DA-resistant AML due to AURKB activation. Intriguingly, AML cells overexpressing AURKB exhibit attenuated MCL-1 expression, rendering them receptive to DAV treatment and maintaining them resistant to DA treatment. Moreover, the dataset delineates a shared kinase, AKT1, associated with DAV response. Notably, AKT1 inhibition augments the antileukemic efficacy of DAV treatment in AML. Overall, this phosphoproteomic study identifies the role of AURKB as a predictive biomarker for DA, but not DAV, resistance and proposes a promising strategy to counteract therapy resistance in AML.

Predicting the pathological invasiveness in patients with a solitary pulmonary nodule via Shapley additive explanations interpretation of a tree-based machine learning radiomics model: a multicenter study.

Background: Radiomics models could help assess the benign and malignant invasiveness and prognosis of pulmonary nodules. However, the lack of interpretability limits application of these models. We thus aimed to construct and validate an interpretable and generalized computed tomography (CT) radiomics model to evaluate the pathological invasiveness in patients with a solitary pulmonary nodule in order to improve the management of these patients. Methods: We retrospectively enrolled 248 patients with CT-diagnosed solitary pulmonary nodules. Radiomic features were extracted from nodular region and perinodular regions of 3 and 5 mm. After coarse-to-fine feature selection, the radiomics score (radscore) was calculated using the least absolute shrinkage and selection operator logistic method. Univariate and multivariate logistic regression analyses were performed to determine the invasiveness-related clinicoradiological factors. The clinical-radiomics model was then constructed using the logistic and extreme gradient boosting (XGBoost) algorithms. The Shapley additive explanations (SHAP) method was then used to explain the contributions of the features. After removing batch effects with the ComBat algorithm, we assessed the generalization of the explainable clinical-radiomics model in two independent external validation cohorts (n=147 and n=149). Results: The clinical-radiomic XGBoost model integrating the radscore, CT value, nodule length, and crescent sign demonstrated better predictive performance than did the clinical-radiomics logistic model in assessing pulmonary nodule invasiveness, with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.889 [95% confidence interval (CI), 0.848-0.927] in the training cohort. The SHAP algorithm illustrates the contribution of each feature in the final model. The specific model decision process was visualized using a tree-based decision heatmap. Satisfactory generalization performance was shown with AUCs of 0.889 (95% CI, 0.823-0.942) and 0.915 (95% CI, 0.851-0.963) in the two external validation cohorts. Conclusions: An interpretable and generalized clinical-radiomics model for predicting pulmonary nodule invasibility was constructed to help clinicians determine the invasiveness of pulmonary nodules and devise assessment strategies in an easily understandable manner.

Engineering plants using diverse CRISPR-associated proteins and deregulation of genome-edited crops.

The CRISPR/Cas system comprises RNA-guided nucleases, the target specificity of which is directed by Watson-Crick base pairing of target loci with single guide (sg)RNA to induce the desired edits. CRISPR-associated proteins and other engineered nucleases are opening new avenues of research in crops to induce heritable mutations. Here, we review the diversity of CRISPR-associated proteins and strategies to deregulate genome-edited (GEd) crops by considering them to be close to natural processes. This technology ensures yield without penalties, advances plant breeding, and guarantees manipulation of the genome for desirable traits. DNA-free and off-target-free GEd crops with defined characteristics can help to achieve sustainable global food security under a changing climate, but need alignment of international regulations to operate in existing supply chains.

The safety and effectiveness of clopidogrel versus aspirin in Kawasaki disease with mild-to-moderate liver injury.

Kawasaki disease can be combined with liver injury. As a mainstay treatment for Kawasaki disease, aspirin may cause liver injury. This study aimed to compare the safety and effectiveness of clopidogrel versus aspirin in Kawasaki disease with mild-to-moderate liver injury. This study retrospectively analysed 166 children with Kawasaki disease combined with mild-to-moderate liver injury. The children treated with clopidogrel were less likely to have aggravated liver injury than those treated with aspirin (n = 2/100 vs. n = 13/66, P < 0.001). The initial alanine aminotransferase value of the clopidogrel group was higher (131.5 [98.5, 167.5] vs. 96 [72, 133], P < 0.001), while the time of alanine aminotransferase recovery to normal was similar (5 [4, 7] vs. 4 [3, 7], P = 0.179). No significant fever differences observed between groups: 7.5 [6, 9] for aspirin vs. 7 [6, 8] for clopidogrel group, P = 0.064. The probability of nonresponse to intravenous immunoglobulin (n = 29/100 vs. n = 30/66, P = 0.030) and the days of hospitalization (n = 6 [4, 9] vs. n = 7 [5, 10], P = 0.007) in the clopidogrel group were less than those in the aspirin group. In conclusion, the application of clopidogrel is potentially superior to aspirin in Kawasaki disease combined with mild-to-moderate liver injury.

Identification of a novel NPM1 mutation in acute myeloid leukemia.

Nucleophosmin (NPM1) is a widely expressed nucleocytoplasmic shuttling protein with prominent nucleolar localization. It is estimated that 25-35% of adult patients with acute myeloid leukemia (AML) carry NPM1 mutations. The classic NPM1 type A mutation occurs in exon 12, which accounts for 75-80% of adult patients with NPM1-mutated AML. It produces an additional leucine and valine-rich nuclear export signal (NES) at the C-terminus, and causes aberrant cytoplasmic dislocation of NPM1 protein. Notably, emerging evidence indicates that besides the classic type A mutation, rare mutants occurring in other exons may also lead to the imbalance of the nucleocytoplasmic shuttle of NPM1. Identification of novel non-type A mutants is crucial for the diagnosis, prognosis, risk stratification and disease monitoring of potential target populations. Here we reported a novel NPM1 mutation in exon 5 identified from a de novo AML patient. Similar to the classic type A mutation, the exon 5 mutation had the NPM1 mutant bound to exportin-1 and directed the mutant into the cytoplasm by generating an additional NES sequence, resulting in aberrant cytoplasmic dislocation of NPM1 protein, which could be reversed by exportin-1 inhibitor leptomycin B. Our findings strongly support that besides the exon 12 mutation, the exon 5 mutant is another NPM1 "born to be exported" mutant critical for leukemogenesis. Therefore, similar to the classic type A mutation, the identification of our novel NPM1 mutation is beneficial for clinical laboratory diagnosis, genetic risk assessment and MRD monitoring.