Generalizability and Diagnostic Performance of AI Models for Thyroid US.

Background Artificial intelligence (AI) models have improved US assessment of thyroid nodules; however, the lack of generalizability limits the application of these models. Purpose To develop AI models for segmentation and classification of thyroid nodules in US using diverse data sets from nationwide hospitals and multiple vendors, and to measure the impact of the AI models on diagnostic performance. Materials and Methods This retrospective study included consecutive patients with pathologically confirmed thyroid nodules who underwent US using equipment from 12 vendors at 208 hospitals across China from November 2017 to January 2019. The detection, segmentation, and classification models were developed based on the subset or complete set of images. Model performance was evaluated by precision and recall, Dice coefficient, and area under the receiver operating characteristic curve (AUC) analyses. Three scenarios (diagnosis without AI assistance, with freestyle AI assistance, and with rule-based AI assistance) were compared with three senior and three junior radiologists to optimize incorporation of AI into clinical practice. Results A total of 10 023 patients (median age, 46 years [IQR 37-55 years]; 7669 female) were included. The detection, segmentation, and classification models had an average precision, Dice coefficient, and AUC of 0.98 (95% CI: 0.96, 0.99), 0.86 (95% CI: 0.86, 0.87), and 0.90 (95% CI: 0.88, 0.92), respectively. The segmentation model trained on the nationwide data and classification model trained on the mixed vendor data exhibited the best performance, with a Dice coefficient of 0.91 (95% CI: 0.90, 0.91) and AUC of 0.98 (95% CI: 0.97, 1.00), respectively. The AI model outperformed all senior and junior radiologists (P < .05 for all comparisons), and the diagnostic accuracies of all radiologists were improved (P < .05 for all comparisons) with rule-based AI assistance. Conclusion Thyroid US AI models developed from diverse data sets had high diagnostic performance among the Chinese population. Rule-based AI assistance improved the performance of radiologists in thyroid cancer diagnosis. © RSNA, 2023 Supplemental material is available for this article.

Identification of Galectin 9 and its antibacterial function in yellow drum (Nibea albiflora).

Galectins are a family of evolutionarily conserved lectins that contain carbohydrate recognition domains (CRDs) specifically recognizing ß-galactoside. Galectin-9 plays a crucial role in various biological processes during pathogenic infections. In a previous study, galectin-9 was identified as a candidate gene for resistance to Vibrio harveyi disease in yellow drum using a genome-wide association study (GWAS) analysis. In this study, a galectin-9 gene was identified from Nibea albiflora and named YdGal-9. The mRNA transcripts of YdGal-9 were distributed in all the detected tissues and the highest level was found in the kidney. The subcellular localization of YdGal-9-EGFP proteins was observed in both nucleus and cytoplasm in the kidney cells of N. albiflora. The expression of YdGal-9 in the brain increased significantly after infection with Vibrio harveyi. The red blood cells from rabbits, Larimichthys crocea, and N. albiflora were agglutinated by the purified recombinant YdGal-9 proteins. The results of the agglutination activity of deletion mutants of YdGal-9 proved that the conserved sugar binding motifs (H-NPR and WG-EE-) were critical for YdGal-9's agglutination activity. In addition, YdGal-9 killed some gram-negative bacteria by inducing cell wall destruction including Pseudomonas plecoglossicida, Aeromonas hydrophila, Escherichia coli, V. parahemolyticus, V. harveyi, and V. alginolyticus. Taken together, these results suggested that the YdGal-9 protein of N. albiflora played a vital role in fighting bacterial infections.

Molecular Cloning and Functional Characterization of Galectin-1 in Yellow Drum (Nibea albiflora).

Galectins are proteins that are involved in the innate immune response against pathogenic microorganisms. In the present study, the gene expression pattern of galectin-1 (named as NaGal-1) and its function in mediating the defense response to bacterial attack were investigated. The tertiary structure of NaGal-1 protein consists of homodimers and each subunit has one carbohydrate recognition domain. Quantitative RT-PCR analysis indicated that NaGal-1 was ubiquitously distributed in all the detected tissues and highly expressed in the swim-bladder of Nibea albiflora, and its expression could be upregulated by the pathogenic Vibrio harveyi attack in the brain. Expression of NaGal-1 protein in HEK 293T cells was distributed in the cytoplasm as well as in the nucleus. The recombinant NaGal-1 protein by prokaryotic expression could agglutinate red blood cells from rabbit, Larimichthys crocea, and N. albiflora. The agglutination of N. albiflora red blood cells by the recombinant NaGal-1 protein was inhibited by peptidoglycan, lactose, D-galactose, and lipopolysaccharide in certain concentrations. In addition, the recombinant NaGal-1 protein agglutinated and killed some gram-negative bacteria including Edwardsiella tarda, Escherichia coli, Photobacterium phosphoreum, Aeromonas hydrophila, Pseudomonas aeruginosa, and Aeromonas veronii. These results set the stage for further studies of NaGal-1 protein in the innate immunity of N. albiflora.

Studies on competitive adsorption characteristics of bisphenol A and 17α-ethinylestradiol on thermoplastic polyurethane by site energy distribution theory.

Compound pollution of microplastics and estrogens is a growing ecotoxicological problem in aquatic environments. The adsorption isothermal properties of bisphenol A (BPA) and 17α-ethinyl estradiol (EE2) on polyamide (TPU) in monosolute and bisolute systems were studied. Under the same adsorption concentration (1-4 mg L-1), EE2 had a greater adsorption capacity than BPA in the monsolute system. Compared to the energy distribution features of the adsorption sites of EE2 and BPA, the BPA adsorption sites were located in the higher energy area and were more evenly distributed than those of EE2, while the quantity of BPA adsorption sites was less than that of EE2. In the bisolute system, the average site energy, site energy inhomogeneity, and adsorption site numbers of BPA increased by 1.674, -17.166, and 16.793%, respectively. In comparison, the average site energy, site energy inhomogeneity, and adsorption sites numbers of EE2 increased by 2.267, 4.416, and 8.585%, respectively. The results showed that BPA and EE2 had a cooperative effect on the competitive adsorption of TPU. XPS analysis showed that BPA and EE2 had electron transfer on TPU, although the chemisorption effects and hydrogen bonds between BPA and TPU were more significant. Comparing the changes in the relative functional group content of TPU in monosolute and bisolute systems, BPA and EE2 were synergistically absorbed on TPU. This study can provide a theoretical reference for the study of competitive adsorption between coexisting organic pollutants.

The severity of portal hypertension by a non-invasive assessment: acoustic structure quantification analysis of liver parenchyma.

BACKGROUND: Acoustic structure quantification (ASQ) has been applied to evaluate liver histologic changes by analyzing the speckle pattern seen on B-mode ultrasound. We aimed to assess the severity of portal hypertension (PHT) through hepatic ultrasonography. METHODS: Sixty patients diagnosed with PHT and underwent surgical treatment with portosystemic shunts were enrolled. Portal pressure (PP) was measured intraoperatively. Patients were divided into subgroups according to the severity of gastroesophageal varices and Child-Pugh class. Three difference ratio (Cm2) values on ASQ histogram mode were analyzed for their relationships with PP, degree of gastroesophageal varices and Child-Pugh liver function. Thirty healthy volunteers matched with the patients for gender and age were enrolled as controls. Comparisons among groups and correlation of the parameters with PP were analyzed. Area under the receive operating characteristic curve was used to evaluate the predicting value of ASQ parameters. RESULTS: In the patients, the ASQ parameters peak Cm2 (Cm2max), mean Cm2 (Cm2mean) and the highest occurred Cm2 value of the obtained red curve (RmaxCm2) were all greatly increased (P < 0.0001, P < 0.0001, P = 0.027). Multiple comparisons indicated that, regardless of Child-Pugh class and degree of gastroesophageal varices, the patients had significantly increased Cm2max and Cm2mean compared with the controls (all P < 0.0001). No differences among subgroups were observed. Cm2max was significantly statistically correlated with PP (r = 0.3505, P < 0.01), degree of varices (r = 0.4998, P < 0.0001). Youden's index for Cm2max with a cut-off value of 140.3 for predicting the presence of PHT, gastroesophageal varices and liver function equal to or worse than Child-Pugh class B were 0.8, 0.91 and 0.84, respectively. CONCLUSIONS: ASQ analysis of ultrasonographic images may have a role in the evaluation of the severity of PHT by detecting liver histologic changes in the speckle pattern caused by cirrhosis.

Identification of upregulated NF-κB inhibitor alpha and IRAK3 targeting lncRNA following intracranial aneurysm rupture-induced subarachnoid hemorrhage.

BACKGROUND: This study was performed to identify genes and lncRNAs involved in the pathogenesis of subarachnoid hemorrhage (SAH) from ruptured intracranial aneurysm (RIA). METHODS: Microarray GSE36791 was downloaded from Gene Expression Omnibus (GEO) database followed by the identification of significantly different expressed RNAs (DERs, including lncRNA and mRNA) between patients with SAH and healthy individuals. Then, the functional analyses of DEmRNAs were conducted and weighted gene co-expression network analysis (WGCNA) was also performed to extract the modules associated with SAH. Following, the lncRNA-mRNA co-expression network was constructed and the gene set enrichment analysis (GSEA) was performed to screen key RNA biomarkers involved in the pathogenesis of SAH from RIA. We also verified the results in a bigger dataset GSE7337. RESULTS: Totally, 561 DERs, including 25 DElncRNAs and 536 DEmRNAs, were identified. Functional analysis revealed that the DEmRNAs were mainly associated with immune response-associated GO-BP terms and KEGG pathways. Moreover, there were 6 modules significantly positive-correlated with SAH. The lncRNA-mRNA co-expression network contained 2 lncRNAs (LINC00265 and LINC00937) and 169 mRNAs. The GSEA analysis showed that these two lncRNAs were associated with three pathways (cytokine-cytokine receptor interaction, neurotrophin signaling pathway, and apoptosis). Additionally, IRAK3 and NFKBIA involved in the neurotrophin signaling pathway and apoptosis while IL1R2, IL18RAP and IL18R1 was associated with cytokine-cytokine receptor interaction pathway. The expression levels of these genes have the same trend in GSE36791 and GSE7337. CONCLUSION: LINC00265 and LINC00937 may be implicated with the pathogenesis of SAH from RIA. They were involved in three important regulatory pathways. 5 mRNAs played important roles in the three pathways.

In vivo ultraosound elastographic evaluation of the age-related change of human lens nuclear stiffness.

BACKGROUND: To evaluate the age-related changes in the stiffness of the human lens nucleus in vivo. METHODS: A total of 78 volunteers with best-corrected visual acuity of 20/20with a mean ± standard deviation intraocular pressure (IOP) of 16 ± 2.5 mmHg were divided into 3 groups of 26. The mean ages of Groups A, B and C were 81 ± 5.5, 44 ± 3.2 and 21 ± 2.5 years, with mean axial lengths of 23.8 ± 0.5 mm, 23.8 ± 0.4 mm and 23.9 ± 0.3 mm, respectively. Using an elastographer, the ultrasound echolucency and elastic strain rate of the lens nucleus of one eye, selected randomly, of each subject were measured three times. The strain rate of the lens cortex could not be assessed. The qualitative differences in the strain rates across the groups were assessed, and differences in the strain rate ratios of the lens nuclei across groups were analysed by one-way ANOVA. RESULTS: The strain rates of the lens nuclei of Group A were much lower than those in Groups B and C, as assessed qualitatively; the elastograph images of the lens nuclei of the older group showed a blue colour.The strain rate ratios of the lens nuclei of Groups A, B and C were 0.02 ± 0.08, 0.69 ± 0.12 and 1.95 ± 0.85, respectively. The differences in the lens nucleus strain rate ratios across the groups were statistically significant, with p-values < 0.05. CONCLUSIONS: Ultrasound elastography demonstrated in vivo that an older age is associated with a statistically significantly lower lens nucleus strain rate ratio and therefore a markedly higher lens nuclear stiffness.

Single-Nucleotide Resolution Analysis of 5-Hydroxymethylcytosine in DNA by Enzyme-Mediated Deamination in Combination with Sequencing.

The report of the existence of 5-hydroxymethylcytosine (hm5C) in mammalian genomes is a milestone discovery. hm5C is now generally viewed as the sixth base of DNA with important functions on epigenetic regulation. The in-depth investigation of the biological functions of hm5C requires elucidating the distribution patterns of hm5C in genomes, better in single-nucleotide resolution. It was reported that the cytosine deaminases of the APOBEC (apolipoprotein B mRNA-editing catalytic polypeptide-like) family are nucleic acid editing enzymes and can deaminate cytosine (C) to form uracil (U). Particularly, a subfamily of APOBEC (APOBEC3A) can efficiently deaminate both C and 5-methylcytosine (m5C). In the current study, we identified that APOBEC3A protein can effectively deaminate C, m5C, and hm5C but shows no observable deamination activity toward glycosylated hm5C (ß-glucosyl-5-hydroxymethyl-2'-deoxycytidine, ghm5C) by using the restriction enzyme-based assay and liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) analysis. By virtue of the differential deamination activity of APOBEC3A toward C, m5C, and ghm5C in conjugation with sequencing, we developed the single-nucleotide resolution analysis of hm5C in DNA. In this analytical strategy, the original C and m5C in DNA will be deaminated by APOBEC3A to form U and thymine (T), both of which will read as T during sequencing, while ghm5C is resistant to deamination and will read as C during sequencing. Therefore, the remaining C in the sequence context only could come from original hm5C, which offers the single-nucleotide resolution analysis of hm5C in DNA. This APOBEC3A-mediated deamination sequencing (AMD-seq) is straightforward and involves no bisulfite treatment, which avoids the substantial degradation of DNA. Future application of this strategy can be performed for the reliable mapping of hm5C in genome-wide scale at the single-nucleotide resolution.

Effects of female sex hormones on expression of the Ang-(1-7)/Mas-R/nNOS pathways in rat brain.

Female sex hormones are considered to reduce the risk of ischemic stroke. As a part of the renin-angiotensin system, angiotensin-(1-7) [Ang-(1-7)] has recently been reported to play a role in protecting neuronal tissues from ischemic stroke. Thus, we examined the effects of female sex hormones on the levels of Ang-(1-7) and its downstream pathways in the brain. Female rats were ovariectomized and 17ß-estradiol (17ß-EST), progesterone (PGR), or a combination of 17ß-EST plus PGR were administered. Our data demonstrated that lack of female sex hormones significantly decreased the levels of Ang-(1-7) in the cerebral cortex and hippocampal CA1 area. Also, we observed a linear relationship between cortex levels of Ang-(1-7) and plasma brain natriuretic peptide levels (as an indicator for risk of ischemic stroke). We further showed that lack of female sex hormones decreased the expression of Ang-(1-7), Mas-receptor (Mas-R), and neuronal nitric oxide synthase (nNOS). Overall, our findings show for the first time that Ang-(1-7) and Mas-R/nNOS in the cortex are influenced by circulating 17ß-EST and (or) PGR, whereas Ang-(1-7) and its pathways in the hippocampal CA1 area are primarily altered by 17ß-EST. This suggests that female sex hormones play a role in regulating the expression of Ang-(1-7) and its pathways during ischemic brain injuries.

Homemade Chinese herbal fumigation eye patch prevents myopia in children and adolescents.

OBJECTIVE: To demonstrate the clinical efficacy of a homemade Chinese herbal fumigation eye patch in the prevention and treatment of myopia in children and adolescents. METHODS: In this retrospective study, participants were grouped according to different intervention methods. A primary school was selected, wherein 50 myopic students in each grade and a total of 300 from the 6 grades were selected as the observation group. According to the 1:1 matching principle, another 300 myopic students matched with the uncorrected visual acuity (UCVA), gender, and class were selected as the control group. The observation group was treated with the Chinese herbal fumigation patch, once daily between 12:00 and 13:00, 10-15 min/time, for 30 consecutive days. The control group did not get any intervention measures. The UCVA, diopter (D), and axial length (AXL) of both groups were recorded on the 1st, 15th, and 30th day after enrollment. RESULTS: Six hundred children and adolescents, including 324 males and 276 females with an average age of (8.8±2.3) years and UCVA of (4.51±0.37), were included, with none lost to follow up. No statistical significance was determined in pre-interventional TCM syndrome distribution, D and AXL between groups (all P > 0.05). Univariate analysis identified that the UCVA of the observation group changed with time (P < 0.05), presenting a linear trend (P < 0.05). In the control group, the changes in UCVA, D, and AXL over time were also statistically significant (all P < 0.05), and the reverse changes showed a linear trend with statistical significance (all P < 0.05). Multivariate analysis determined the presence of statistical inter-group differences in UCVA, D, and AXL (all P < 0.05), as well as an interaction between grouping and time. CONCLUSIONS: The homemade Chinese herbal fumigation eye patch can improve UCVA, delaying D deterioration and preventing eye axial lengthening among myopic children and adolescents, with clinical popularization value.

Development and validation of a nomogram for discriminating between benign and malignant breast masses by conventional ultrasound and dual-mode elastography: a multicenter study.

Background: This study developed and validated an ultrasound nomogram based on conventional ultrasound and dual-mode elastography to differentiate breast masses. Methods: The data of 234 patients were collected before they underwent breast mass puncture or surgery at 4 different centers between 2016 and 2021. Patients were divided into 5 datasets: internal validation and development sets from the same hospital, and external validation sets from the 3 other hospitals. In the development cohort, age and 294 different ultrasound and elastography features were obtained from ultrasound images. Univariate logistic regression and least absolute shrinkage and selection operator (LASSO) regression were used for data reduction and visualization. Multivariable logistic regression analysis was used to develop the prediction model and ultrasound nomogram. Receiver operating characteristic (ROC) curve analysis, calibration curves, integrated discrimination improvement, and the net reclassification index were used to evaluate nomogram performance; decision curve analysis (DCA) and clinical impact curves were used to estimate clinical usefulness. Results: In the development cohort, margin, posterior features, shape, vascularity, (the mean shear wave elastography value of 1.5 mm surrounding tissues in a breast mass) divided by (the mean shear wave elastography value of the breast mass)-shell mean/A mean1.5(E), (the ratio of strain elastography of adipose tissue near a breast mass) divided by [the ratio of strain elastography of (the breast mass adds the 1.5 mm surrounding tissues in the breast mass)]-B/A'1.5 were selected as predictors in multivariable logistic regression analysis, comprising Model 1. Among the 5 cohorts, Model 1 performed best, with areas under the curve (AUC) of 0.92, 0.84, 0.87, 0.93, and 0.89, respectively. The AUCs were 0.90, 0.82, 0.83, 0.91, and 0.85, respectively, in Model 2 (margin + posterior features + shape + vascularity) and 0.80, 0.76, 0.77, 0.87, and 0.80, respectively, in Model 3 [shell mean/A mean1.5(E) + B/A'1.5]. Conclusions: Our ultrasound nomograms facilitate exposure to the features and visualization of breast cancer. Shell mean/A mean1.5(E), B/A'1.5 integrated with margin, posterior features, shape, and vascularity are superior at identifying breast cancer, and are worthy of further clinical investigation.

Virtual elastography ultrasound via generative adversarial network for breast cancer diagnosis.

Elastography ultrasound (EUS) imaging is a vital ultrasound imaging modality. The current use of EUS faces many challenges, such as vulnerability to subjective manipulation, echo signal attenuation, and unknown risks of elastic pressure in certain delicate tissues. The hardware requirement of EUS also hinders the trend of miniaturization of ultrasound equipment. Here we show a cost-efficient solution by designing a deep neural network to synthesize virtual EUS (V-EUS) from conventional B-mode images. A total of 4580 breast tumor cases were collected from 15 medical centers, including a main cohort with 2501 cases for model establishment, an external dataset with 1730 cases and a portable dataset with 349 cases for testing. In the task of differentiating benign and malignant breast tumors, there is no significant difference between V-EUS and real EUS on high-end ultrasound, while the diagnostic performance of pocket-sized ultrasound can be improved by about 5% after V-EUS is equipped.

Artificial neural network aided non-invasive grading evaluation of hepatic fibrosis by duplex ultrasonography.

BACKGROUND: Artificial neural networks (ANNs) are widely studied for evaluating diseases. This paper discusses the intelligence mode of an ANN in grading the diagnosis of liver fibrosis by duplex ultrasonogaphy. METHODS: 239 patients who were confirmed as having liver fibrosis or cirrhosis by ultrasound guided liver biopsy were investigated in this study. We quantified ultrasonographic parameters as significant parameters using a data optimization procedure applied to an ANN. 179 patients were typed at random as the training group; 60 additional patients were consequently enrolled as the validating group. Performance of the ANN was evaluated according to accuracy, sensitivity, specificity, Youden's index and receiver operating characteristic (ROC) analysis. RESULTS: 5 ultrasonographic parameters; i.e., the liver parenchyma, thickness of spleen, hepatic vein (HV) waveform, hepatic artery pulsatile index (HAPI) and HV damping index (HVDI), were enrolled as the input neurons in the ANN model. The sensitivity, specificity and accuracy of the ANN model for quantitative diagnosis of liver fibrosis were 95.0%, 85.0% and 88.3%, respectively. The Youden's index (YI) was 0.80. CONCLUSIONS: The established ANN model had good sensitivity and specificity in quantitative diagnosis of hepatic fibrosis or liver cirrhosis. Our study suggests that the ANN model based on duplex ultrasound may help non-invasive grading diagnosis of liver fibrosis in clinical practice.

Influence of Percutaneous Drainage Surgery and the Interval to Perform Laparoscopic Cholecystectomy on Acute Cholecystitis through Genetic Algorithm-Based Contrast-Enhanced Ultrasound Imaging.

To discuss the optimal interval time between genetic algorithm-based ultrasound imaging-guided percutaneous drainage surgery (PTGD) and laparoscopic cholecystectomy (LC), 64 cholecystitis patients were selected as the research objects and evenly divided into experimental group (intelligent algorithm was adopted to recognize patients' ultrasonic images) and control group (professional doctors carried out diagnosis). 92 acute cholecystitis patients undergoing PTGD were divided into three groups. 30 out of the 92 patients received LC within 2 months and were defined as the early group. 32 were performed with LC within 2 to 4 months and were defined as the metaphase group. 28 underwent LC over 4 months and were defined as the late-stage group. The average operation time, the transition from LC to laparotomy, the average postoperative hospital stay, and the incidence of complications of the three groups were compared. The results revealed that the comparison of the diagnostic accuracy and comprehensive effectiveness between experimental group and control group demonstrated that the differences were statistically significant (P < 0.05). When the optimal interval of implementing LC after PTGD was realized, the corresponding values of the early group were 88.5 minutes, 16.67%, 8.13 days, and 13.75%. Those of the metaphase group were 49.91 minutes, 3.13%, 4.97 days, and 9.52%. Those of the late stage group were 68.78 minutes, 10.71%, 7.09 days, and 11.96%. To sum up, the diagnostic accuracy and comprehensive effectiveness of intelligent algorithm were higher than those of conventional ultrasound, and the optimal interval time of implementing LC after PTGD was 2 to 4 months.

Study on the role of immune­related genes after intracranial subarachnoid hemorrhage.

We aimed to screen the feature genes related to subarachnoid hemorrhage (SAH). The datasets (GSE73378 and GSE36791) were downloaded from National Center for Biotechnology Information database. Limma package in R was used to screen the differentially expressed genes (DEGs). Single sample gene set enrichment analysis algorithm was used to evaluate the type of immune infiltration. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were used to analyze function of DEGs. The support vector machine (SVM) was used to constructed classifier, which was evaluated using receiver operating characteristic curves. The E­TABM­421 was used to verify the DEGs related to immunity and the classifier. Seven types of immune cells with significant differences were screened, such as activated CD8 T cell and center memory CD4 T cell. We then obtained 408 DEGs related to immune cell. Subsequently, 10 overlapped KEGG pathways related to the DEGs were obtained, such as hematopoietic cell lineage, NOD­like receptor signaling pathway and T cell receptor signaling pathway. Finally, 9 DEGs related to immune cells (CCL5, CD27, CD3D, CREB5, FYN, ITPR3, TAB1, NCR3 and S1PR5) were screened to constructed SVM classifier. The area under the curve was 0.865 in training dataset and the AUC was 0.75 in the validation set. A SVM classifier based on the 9 DEGs (CCL5, CD27, CD3D, CREB5, FYN, ITPR3, TAB1, NCR3 and S1PR5) related to immune cells might effectively identify SAH patients or healthy people.

Practical and Scalable Manufacturing Process for the Key Intermediate of Poly(ADP-Ribose) Polymerase Inhibitor Olaparib.

Olaparib (Lynparza) is a potent, highly selective inhibitor of poly(ADP-ribose)polymerase enzymes, approved by the U.S. FDA and EMA for the treatment of ovarian cancer. Herein, we report a practical, economical, and scalable process for the synthesis of 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid, a key intermediate for olaparib. The low-cost industrial byproduct phthalhydrazide was used as the starting material to construct the phthalazinone moiety, which allowed access to the key intermediate by the Negishi coupling reaction. Optimization of each step has enabled the development of an environmentally benign and robust process with effective control of impurities.

Bioinspired therapeutic platform based on extracellular vesicles for prevention of arterial wall remodeling in hypertension.

Arterial stiffness due to the vessel remodeling is closely linked to raised blood pressure, and its physiopathologic mechanism is still not fully understood. We here aimed to explore whether extracellular vesicle (EV) mediated intercellular communication between endothelium and smooth muscle cell contribute to the blood vessel remodeling under hypertension. We here revealed that the arterial endothelial cells robustly secreted EV, which in turn could be circulated and/or directly taken up by the subendothelial smooth muscle cells (SMC). Under hypertension, the EV secretion increased and the miRNA profile changed significantly mainly due to the raised mechanical force and subsequent enhanced reactive oxygen species generation. Among the miRNA cargos in the EV, miR-320d/423-5p were found increased most significantly. In vivo delivery of miR-320d/423-5p mimics via engineered EV increased their expression in arterial vessels, recapitulating the phenotype in hypertension. In contrast, therapeutic delivery of miR-320d/423-5p inhibitors via engineered EV alleviated the phenotype in spontaneous hypertension rat model. Together, we have found that the injured endothelium due to the raised mechanical force in hypertension contributes to the arterial wall remodeling via the secreted EV. Our study has not only provided novel insights on the mechanism of hypertension associated blood vessel wall remodeling, but also shed light on therapeutic intervention of hypertension associated vascular diseases.

Novel Human Artificial Intelligence Hybrid Framework Pinpoints Thyroid Nodule Malignancy and Identifies Overlooked Second-Order Ultrasonographic Features.

We present a Human Artificial Intelligence Hybrid (HAIbrid) integrating framework that reweights Thyroid Imaging Reporting and Data System (TIRADS) features and the malignancy score predicted by a convolutional neural network (CNN) for nodule malignancy stratification and diagnosis. We defined extra ultrasonographical features from color Doppler images to explore malignancy-relevant features. We proposed Gated Attentional Factorization Machine (GAFM) to identify second-order interacting features trained via a 10 fold distribution-balanced stratified cross-validation scheme on ultrasound images of 3002 nodules all finally characterized by postoperative pathology (1270 malignant ones), retrospectively collected from 131 hospitals. Our GAFM-HAIbrid model demonstrated significant improvements in Area Under the Curve (AUC) value (p-value < 10−5), reaching about 0.92 over the standalone CNN (~0.87) and senior radiologists (~0.86), and identified a second-order vascularity localization and morphological pattern which was overlooked if only first-order features were considered. We validated the advantages of the integration framework on an already-trained commercial CNN system and our findings using an extra set of ultrasound images of 500 nodules. Our HAIbrid framework allows natural integration to clinical workflow for thyroid nodule malignancy risk stratification and diagnosis, and the proposed GAFM-HAIbrid model may help identify novel diagnosis-relevant second-order features beyond ultrasonography.

Comprehensive Risk System Based on Shear Wave Elastography and BI-RADS Categories in Assessing Axillary Lymph Node Metastasis of Invasive Breast Cancer-A Multicenter Study.

Purpose: To develop a risk stratification system that can predict axillary lymph node (LN) metastasis in invasive breast cancer based on the combination of shear wave elastography (SWE) and conventional ultrasound. Materials and Methods: A total of 619 participants pathologically diagnosed with invasive breast cancer underwent breast ultrasound examinations were recruited from a multicenter of 17 hospitals in China from August 2016 to August 2017. Conventional ultrasound and SWE features were compared between positive and negative LN metastasis groups. The regression equation, the weighting, and the counting methods were used to predict axillary LN metastasis. The sensitivity, specificity, and the areas under the receiver operating characteristic curve (AUC) were calculated. Results: A significant difference was found in the Breast Imaging Reporting and Data System (BI-RADS) category, the "stiff rim" sign, minimum elastic modulus of the internal tumor and peritumor region of 3 mm between positive and negative LN groups (p < 0.05 for all). There was no significant difference in the diagnostic performance of the regression equation, the weighting, and the counting methods (p > 0.05 for all). Using the counting method, a 0-4 grade risk stratification system based on the four characteristics was established, which yielded an AUC of 0.656 (95% CI, 0.617-0.693, p < 0.001), a sensitivity of 54.60% (95% CI, 46.9%-62.1%), and a specificity of 68.99% (95% CI, 64.5%-73.3%) in predicting axillary LN metastasis. Conclusion: A 0-4 grade risk stratification system was developed based on SWE characteristics and BI-RADS categories, and this system has the potential to predict axillary LN metastases in invasive breast cancer.