The added value of ultrasound imaging biomarkers to clinicopathological factors for the prediction of high-risk Oncotype DX recurrence scores in patients with breast cancer.

Background: The Oncotype DX (ODX) recurrence score (RS), a 21-gene assay, has been proven to recognize patients at high risk of recurrence (RS ≥26) who would benefit from chemotherapy. However, it has limited availability and high costs. Our study thus aimed to identify ultrasound (US) imaging biomarkers and develop a prediction model for identifying patients with a high ODX RS. Methods: In this retrospective study, consecutive patients with T1-3N0-1M0 breast cancer who were hormone receptor positive and human epidermal growth factor receptor 2 (HER2) negative who had an available ODX RS were reviewed. Patients treated from May 2012 and December 2015 were placed into a training cohort, and those treated from January 2016 to January 2017 were placed in a validation cohort. Clinicopathologic data were collected, and preoperative US scans were analyzed. Univariable and multivariable regression analyses were performed to evaluate the independent predictors for a high-risk of breast cancer in the training cohort, and a nomogram was developed and evaluated with the area under the receiver operating characteristic curve (AUC), calibration curve, and decision curve analysis (DCA). Results: A total of 363 patients were in the training cohort and 160 in the validation cohort, with the proportion with a high RS (RS 26-100) being 14% and 13.1%, respectively. Echogenic halo, enhanced posterior echo, low level of progesterone receptor (PR), and high Ki-67 index were identified as independent risk factors for high RS (all P values <0.05). The nomogram was constructed based on the combined model, which showed a better discrimination ability than did the clinicopathological model [combined model: AUC =0.95, 95% confidence interval (CI): 0.93-0.97; clinicopathological model: AUC =0.89, 95% CI: 0.86-0.92; P=0.001] and greater clinical benefit according to DCA. Furthermore, the nomogram was found to be effective in the validation cohort (AUC =0.90, 95% CI: 0.84-0.94), especially in patients with stage T1N0M0 disease (AUC =0.91, 95% CI: 0.84-0.95). Conclusions: US features may serve as valuable imaging biomarkers for the prediction of high recurrence risk in patients with T1-3N0-1M0 breast cancer and hormone receptor (HR)-positive and HER2-negative status. A nomogram incorporating PR status, Ki-67 index, and US imaging biomarkers showed a good discrimination ability in the early selection of patients at high risk of recurrence, especially in those with stage T1N0M0 disease.

Five-year Treatment with Tenofovir Alafenamide Achieves High Rates of Viral Suppression, Alanine Aminotransferase Normalization, and Favorable Bone and Renal Safety in Chinese Chronic Hepatitis B Patients.

Background and Aims: After 3-years (144 week) of double-blind treatment in Chinese chronic hepatitis B patients in two ongoing phase 3 studies, tenofovir alafenamide (TAF) showed similar efficacy to tenofovir disoproxil fumarate (TDF), with improved renal and bone safety. In this study, we aimed to report the 5-year results from 2 years into the open-label TAF treatment phase. Methods: All participants completing the 144-week double-blind treatment were eligible to receive open-label TAF 25 mg once daily up to week 384. Serial analysis of viral suppression (hepatitis B virus DNA <29 IU/mL), alanine aminotransferase normalization, serological responses, and safety outcomes at year 5 (week 240) was performed. Results: The open-label phase included 93% (311/334) of the enrolled participants, which included 212 who switched from double-blind TAF to open-label TAF (TAF-TAF) and 99 who switched from double-blind TDF to open-label TAF (TDF-TAF). Baseline characteristics were comparable. Week 240 viral suppression rates were similar between groups [93.4% vs. 93.9%; difference: -1.5%, (95% CI: -6.4 to -3.5), p=0.857]. Alanine aminotransferase normalization and serological response rates were higher in the TAF-TAF group than in the TDF-TAF group. The frequencies of adverse events and laboratory abnormalities were low and similar between groups. Both groups had similar small numerical declines from baseline in estimated glomerular filtration rate at year 5 (week 240, -2.85 mL/min vs. -3.29 mL/min, p=0.910). The greater declines in renal and bone parameters in the TDF-TAF group through week 144 improved after switching to TAF. Conclusions: The 5-year TAF treatment efficacy was high and similar to that of 3-year TDF followed by 2-year TAF in Chinese chronic hepatitis B patients. Favorable effects on bone and renal parameters were sustained with TAF treatment alone and were observed following the switch from TDF to TAF.

Mycobacterium marinum mediates regulation of prostaglandin E2 expression on host immune response through cyclooxygenase pathway.

PURPOSE: Investigate the role of COX signaling in activating the PGE2-EP2 pathway. METHODS: Utilized a marine Mycobacterium infection model in zebrafish. Marine mycobacteria were stained with fluorescein isothiocyanate. The COX inhibitor indomethacin, EP2 receptor inhibitor AH6809, EP4 receptor inhibitor AH23848 and clodronate Liposomes were used to investigate the role of COX, EP2, EP4 and macrophage whether participating in combat marine mycobacterial infection. The expression level of the target gene was detected using real-time fluorescence quantitative PCR instrument. RESULTS: The findings revealed that larvae exposed to the COX inhibitor indomethacin or the EP2 receptor inhibitor AH6809 demonstrated a significantly higher mortality rate due to marine mycobacterium infection than those in the control group. Administration of exogenous prostaglandin E2 (PGE2) rescued the survival of zebrafish infected with marine mycobacteria and treated with indomethacin. Additionally, a significant reduction in survival rate was noted in macrophage-depleted zebrafish infected with marine mycobacteria. CONCLUSION: The host may combat marine mycobacterium infection via COX signaling, which activates the PGE2-EP2 pathway and mediates macrophage resistance.

PIM1 attenuates cisplatin-induced AKI by inhibiting Drp1 activation.

Cisplatin, an effective anti-cancer drug, always causes acute kidney injury (AKI) by inducing mitochondrial damage. PIM1 is a serine/threonine kinase, which has been shown to regulate mitochondrial function. However, the role and mechanisms of PIM1 in cisplatin-induced AKI remain unexplored. This study aimed to investigate the effects of PIM1 in cisplatin-induced AKI and its underlying mechanisms. To established Cisplatin-induced AKI model, mice were given a single intraperitoneal injection(20 mg/kg) and BUMPT cells were treated with cisplatin(20 µM). PIM1 inhibitor AZD1208 was used to inhibit PIM1 and PIM1-experssing adenovirus was used to overexpress PIM1. Drp1 inhibitor P110 and pcDNA3-Drp1K38A were used to inhibit the activation of Drp1 and mitochondrial fission. The indicators of renal function, renal morphology, apoptosis and mitochondrial dysfunction were assessed to evaluate cisplatin-induced nephrotoxicity. We observed that PIM1 was activated in cisplatin-induced AKI in vivo and cisplatin-induced tubular cells injury in vitro. PIM1 inhibition aggravated cisplatin-induced AKI in vivo, while PIM1 overexpression attenuated cisplatin-induced kidney injury in vivo and in vitro. Moreover, inhibiting PIM1 exacerbated mitochondrial damage in mice, but overexpressing PIM1 relieved mitochondrial damage in mice and BUMPT cells. In mice and BUMPT cells, inhibiting PIM1 deregulated the expression of p-Drp1S637, overexpressing PIM1 upregulated the ex-pression of p-Drp1S637. And inhibiting Drp1 activity alleviated cell damage in BUMPT cells with PIM1 knockdown or inhibition. This study demonstrated the protective effect of PIM1 in cisplatin-induced AKI, and regulation of Drp1 activation might be the underlying mechanism. Altogether, PIM1 may be a potential therapeutic target for cisplatin-induced AKI.

Nomogram prediction of the 70-gene signature (MammaPrint) binary and quartile categorized risk using medical history, imaging features and clinicopathological data among Chinese breast cancer patients.

BACKGROUND: The 70-gene signature (70-GS, MammaPrint) test has been recommended by the main guidelines to evaluate prognosis and chemotherapy benefit of hormonal receptor positive human epidermal receptor 2 negative (HR + /Her2-) early breast cancer (BC). However, this expensive assay is not always accessible and affordable worldwide. Based on our previous study, we established nomogram models to predict the binary and quartile categorized risk of 70-GS. METHODS: We retrospectively analyzed a consecutive cohort of 150 female patients with HR + /Her2- BC and eligible 70-GS test. Comparison of 40 parameters including the patients' medical history risk factors, imaging features and clinicopathological characteristics was performed between patients with high risk (N = 62) and low risk (N = 88) of 70-GS test, whereas risk calculations from established models including Clinical Treatment Score Post-5 years (CTS5), Immunohistochemistry 3 (IHC3) and Nottingham Prognostic Index (NPI) were also compared between high vs low binary risk of 70-GS and among ultra-high (N = 12), high (N = 50), low (N = 65) and ultra-low (N = 23) quartile categorized risk of 70-GS. The data of 150 patients were randomly split by 4:1 ratio with training set of 120 patients and testing set 30 patients. Univariate analyses and multivariate logistic regression were performed to establish the two nomogram models to predict the the binary and quartile categorized risk of 70-GS. RESULTS: Compared to 70-GS low-risk patients, the high-risk patients had significantly less cardiovascular co-morbidity (p = 0.034), more grade 3 BC (p = 0.006), lower progesterone receptor (PR) positive percentage (p = 0.007), more Ki67 high BC (≥ 20%, p < 0.001) and no significant differences in all the imaging parameters of ultrasound and mammogram. The IHC3 risk and the NPI calculated score significantly correlated with both the binary and quartile categorized 70-GS risk classifications (both p < 0.001). The area under curve (AUC) of receiver-operating curve (ROC) of nomogram for binary risk prediction were 0.826 (C-index 0.903, 0.799-1.000) for training and 0.737 (C-index 0.785, 0.700-0.870) for validation dataset respectively. The AUC of ROC of nomogram for quartile risk prediction was 0.870 (C-index 0.854, 0.746-0.962) for training and 0.592 (C-index 0.769, 0.703-0.835) for testing set. The prediction accuracy of the nomogram for quartile categorized risk groups were 55.0% (likelihood ratio tests, p < 0.001) and 53.3% (p = 0.04) for training and validation, which more than double the baseline probability of 25%. CONCLUSIONS: To our knowledge, we are the first to establish easy-to-use nomograms to predict the individualized binary (high vs low) and the quartile categorized (ultra-high, high, low and ultra-low) risk classification of 70-GS test with fair performance, which might provide information for treatment choice for those who have no access to the 70-GS testing.

A Comparative Investigation of Machine Learning Algorithms for Pore-Influenced Fatigue Life Prediction of Additively Manufactured Inconel 718 Based on a Small Dataset.

Fatigue life prediction of Inconel 718 fabricated by laser powder bed fusion was investigated using a miniature specimen tests method and machine learning algorithms. A small dataset-based machine learning framework integrating thirteen kinds of algorithms was constructed to predict the pore-influenced fatigue life. The method of selecting random seeds was employed to evaluate the performance of the algorithms, and then the ranking of various machine learning algorithms for predicting pore-influenced fatigue life on small datasets was obtained by verifying the prediction model twenty or thirty times. The results showed that among the thirteen popular machine learning algorithms investigated, the adaptive boosting algorithm from the boosting category exhibited the best fitting accuracy for fatigue life prediction of the additively manufactured Inconel 718 using the small dataset, followed by the decision tree algorithm in the nonlinear category. The investigation also found that DT, RF, GBDT, and XGBOOST algorithms could effectively predict the fatigue life of the additively manufactured Inconel 718 within the range of 1 × 105 cycles on a small dataset compared to others. These results not only demonstrate the capability of using small dataset-based machine learning techniques to predict fatigue life but also may guide the selection of algorithms that minimize performance evaluation costs when predicting fatigue life.

Can we skip technetium-99 m sestamibi scintigraphy in pediatric primary hyperparathyroidism patients with positive neck ultrasound results?

BACKGROUND: Parathyroidectomy is the only curative treatment for primary hyperparathyroidism (PHPT). Ultrasound (US) and technetium-99 m sestamibi (99mTc-MIBI) scintigraphy are recommended as the first-line localization imaging modalities for PHPT in adults, but the value of preoperative imaging in pediatric patients has not been reported. OBJECTIVE: To evaluate the added value of 99mTc-MIBI scintigraphy in pediatric PHPT patients with positive ultrasound results. MATERIALS AND METHODS: Pediatric patients (≤18 years old) who were diagnosed with PHPT and underwent surgical treatment in Peking Union Medical College Hospital between January 2003 and January 2021 were included in this study. Demographic and clinical characteristics, preoperative localization US, 99mTc-MIBI scintigraphy and pathology results were collected. Preoperative localization results were evaluated by comparison with surgical and pathological findings. RESULTS: There were 32 pediatric PHPT patients with median age of 14.7 ± 2.5 years who all proved to have single-gland disease without ectopic lesions. The median lesion size was 2.85 cm (range 1.0-5.8 cm). All patients underwent US and 99mTc-MIBI scintigraphy. Neck US demonstrated 100% sensitivity. Of 32 patients with a positive US, 99mTc-MIBI scintigraphy was concordant in 30 (93.8%). In 2 patients (6.3%), US reported suspected multigland disease, which was correctly diagnosed by 99mTc-MIBI scintigraphy as single lesions. CONCLUSION: In pediatric PHPT patients, US achieved high sensitivity for preoperative localization. 99mTc-MIBI scintigraphy for pediatric patients with positive US results would not increase the sensitivity. Implementation of 99mTc-MIBI scintigraphy could increase the specificity in pediatric patients with multigland disease suspected by US.

Predicting multigland disease in primary hyperparathyroidism using ultrasound and clinical features.

Background: The identification of multigland disease (MGD) in primary hyperparathyroidism (PHPT) patients is essential for minimally invasive surgical decision-making. Objective: To develop a nomogram based on ultrasound (US) findings and clinical factors to predict MGD in PHPT patients. Materials and methods: Patients with PHPT who had surgery between March 2021 and January 2022 were consecutively enrolled to this study. Biochemical and clinicopathological data were recorded. US images were analyzed to extract US features for prediction. Logistic regression analyses were used to identify MGD risk factors. A nomogram was constructed based on these factors and its performance evaluated by area under the receiver operating characteristic curve (AUC), calibration curve, Hosmer-Lemeshow tests, and decision curve analysis (DCA). Results: A total of 102 PHPT patients were included; 82 (80.4%) had single-gland disease (SGD) and 20 (19.6%) had MGD. Using multivariate analyses, MGD was positively correlated with age (odds ratio (OR) = 1.033, 95% confidence interval (CI): 0.190-4.047), PTH levels (OR = 1.001, 95% CI: 1.000-1.002), multiple endocrine neoplasia type 1 (MEN1) (OR = 29.730, 95% CI: 3.089-836.785), US size (OR = 1.198, 95% CI: 0.647-2.088), and US texture (cystic-solid) (OR = 5.357, 95% CI: 0.499-62.912). MGD was negatively correlated with gender (OR = 0.985, 95% CI: 0.190-4.047), calcium levels (OR = 0.453, 95% CI: 0.070-2.448), and symptoms (yes) (OR = 0.935, 95% CI: 0.257-13.365). The nomogram showed good discrimination with an AUC = 0.77 (0.68-0.85) and good agreement in predicting MGD in PHPT patients. Also, 65 points was recommended as a cut-off value, with specificity = 0.94 and sensitivity = 0.50. Conclusion: US was useful in evaluating MGD. Combining US and clinical features in a nomogram showed good diagnostic performance for predicting MGD.

OGG1 aggravates renal ischemia-reperfusion injury by repressing PINK1-mediated mitophagy.

Renal ischemia-reperfusion injury (IRI) is mainly responsible for acute kidney injury for which there is no effective therapy. Accumulating evidence has indicated the important role of mitophagy in mitochondrial homeostasis under stress. OGG1 (8-oxoguanine DNA glycosylase) is known for functions in excision repair of nuclear and mitochondrial DNA. However, the role of OGG1 in renal IRI remains unclear. Herein, we identified OGG1, induced during IRI, as a key factor mediating hypoxia-reoxygenation-induced apoptosis in vitro and renal tissue damage in a renal IRI model. We demonstrated that OGG1 expression during IRI negatively regulates mitophagy by suppressing the PINK1/Parkin pathway, thereby aggravating renal ischemic injury. OGG1 knockout and pharmacological inhibition attenuated renal IRI, in part by activating mitophagy. Our results elucidated the damaging role of OGG1 activation in renal IRI, which is associated with the regulatory role of the PINK1/Parkin pathway in mitophagy.

MiR-20a-5p alleviates kidney ischemia/reperfusion injury by targeting ACSL4-dependent ferroptosis.

Ischemia/reperfusion injury (IRI) is prone to occur after kidney transplantation, leading to delayed graft function (DGF). MicroRNAs play a crucial role in the pathogenesis of ischemia/reperfusion-induced acute kidney injury, and miR-20a-5p was found to be the most significantly upregulated gene in a DGF patient cohort. However, the roles of microRNAs in transplanted kidneys remain largely unknown. In this study, we found that miR-20a-5p was upregulated in the kidneys of acute kidney injury mice and in patients with DGF. We identified early growth response-1 as a critical upstream target and verified the binding of early growth response-1 to a predicted sequence in the promoter region of the miR-20a-5p gene. Functionally, the miR-20a-5p mimic attenuated IRI and postischemic renal fibrosis, whereas the miR-20a-5p inhibitor delivery aggravated IRI and fibrosis. Importantly, delivery of the miR-20a-5p mimic or inhibitor in the donor kidneys attenuated or aggravated renal loss and structural damage in cold storage transplantation injury. Furthermore, our study identified miR-20a-5p as a negative regulator of acyl-CoA synthetase long-chain family member 4 (ACSL4) by targeting the 3' untranslated region of ACSL4 mRNA, thereby inhibiting ACSL4-dependent ferroptosis. Our results suggest a potential therapeutic application of miR-20a-5p in kidney transplantation through the inhibition of ACSL4-dependent ferroptosis.

PIM1 attenuates renal ischemia-reperfusion injury by inhibiting ASK1-JNK/P38.

Renal ischemia-reperfusion injury (IRI) is the main cause of acute kidney injury (AKI), yet therapeutic approaches to alleviate IRI remain limited. PIM1 (provirus integration site for Moloney murine leukemia virus 1) is a constitutive serine threonine kinase that phosphorylates various substrates to regulate cell death and survival. However, the role of PIM1 in renal IRI remains unclear. This study aims to investigate the effect of PIM1 on renal IRI and explore its downstream regulatory mechanism. In this study, we inhibited or overexpressed PIM1 in mice and cultured proximal tubular cells, and then induced renal IRI model in vivo and hypoxia reoxygenation (HR) model in vitro. Renal function, renal structure injuries and cellular death were assessed to reflect the extent of IRI. The expression of PIM1 and the levels of ASK1, MAPK and their phosphorylated forms were detected by immunoblot. RNA sequencing of kidney cortex was performed to analyze downstream pathway of PIM1 in renal IRI. The results showed that PIM1 expression was significantly upregulated in renal IRI mouse model and in renal tubular cell HR model. AZD1208 (a PIM1 inhibitor) aggravated renal IRI, while PIM1 overexpression ameliorated renal IRI. This was involved in the regulation of the ASK1-MAPK pathway. Moreover, results demonstrated that ASK1 was a downstream target of PIM1 by administering Selonsertib (an inhibitor of ASK1 activity), and inhibiting ASK1 alleviated cell death after HR in PIM1 knockdown cells by reducing JNK/P38 activation. In conclusion, this study elucidated the protective effect of PIM1 on renal IRI, and the underlying mechanism may be related to ASK1-JNK/P38 signaling pathway. Taken together, PIM1 may be a potential therapeutic target for renal IRI.

Deep learning-based system for automatic prediction of triple-negative breast cancer from ultrasound images.

To develop a deep-learning system for the automatic identification of triple-negative breast cancer (TNBC) solely from ultrasound images. A total of 145 patients and 831 images were retrospectively enrolled at Peking Union College Hospital from April 2018 to March 2019. Ultrasound images and clinical information were collected accordingly. Molecular subtypes were determined from immunohistochemical (IHC) results. A CNN with VGG-based architecture was then used to predict TNBC. The model's performance was evaluated using randomized k-fold stratified cross-validation. A t-SNE analysis and saliency maps were used for model visualization. TNBC was identified in 16 of 145 (11.03%) patients. One hundred fifteen (80%) patients, 15 (10%) patients, and 15 (10%) patients formed the train, validation, and test set respectively. The deep learning system exhibits good efficacy, with an AUC of 0.86 (95% CI: 0.64, 0.95), an accuracy of 85%, a sensitivity of 86%, a specificity of 86%, and an F1-score of 0.74. In addition, the internal representation features learned by the model showed clear differentiation across molecular subtype groups. Such a deep learning system can automatically predict triple-negative breast cancer preoperatively and accurately. It may help to get to more precise and comprehensive management.

Value of high-frequency ultrasound in the treatment of moderate and severe acne vulgaris.

BACKGROUND: Acne treatment may fail or cause undesirable side effects due to inaccurate evaluation. High-frequency ultrasound (HFUS) can monitor systemic treatment in patients with moderate-to-severe acne vulgaris. MATERIALS AND METHODS: In this prospective study, consecutive patients with moderate-to-severe acne vulgaris were recruited. Patients were graded by a comprehensive clinical assessment before and after therapy. Simultaneous HFUS grading was independently evaluated according to the sonographic scoring system for acne (SSSA). Clinical and HFUS grades were compared through kappa analysis. RESULTS: A total of 70 patients were enrolled. At baseline, 36 (51.4%) and 34 (48.6%) patients were graded as moderate and severe, respectively, through clinical assessment. However, 27 patients (38.6%) scored SSSA-Grade II and 43 (61.4%) scored SSSA-Grade III in the HFUS grading. Sixty-one patients (87.1%) were in the consistent category as per clinical assessment and HFUS grades, with Kappa1  = 0.745, whereas higher HFUS grades were observed in nine patients. By the end of the observation, 65 of all patients (92.9%) showed significant improvement and 5 (7.1%) showed no apparent improvement after the treatment. According to the clinical assessment, 14, 52, and 4 patients were graded as mild, moderate, and severe, respectively. On the other hand, 11, 51, and 8 patients had SSSA-Grade I, II, and III, respectively. Of all patients, 63 (90.0%) had consistent evaluation results, with Kappa2  = 0.762, whereas the remaining seven patients had an HFUS grade higher than the clinical. CONCLUSION: HFUS is a useful tool for dermatologists to monitor the treatment of moderate and severe acne vulgaris.

Maximizing Performance of a Hybrid MnO2/Ni Electrochemical Actuator through Tailoring Lattice Tunnels and Cation Vacancies.

Electrochemical actuators play a key role in converting electrical energy to mechanical energy. However, a low actuation stress and an unsatisfied strain response rate strongly limit the extensive applications of the actuators. Here, we report hybrid manganese dioxide (MnO2) fabricated by introducing ramsdellite (R-MnO2) and Mn vacancies into birnessite (δ-MnO2) nanosheets, which in situ grew on the surface of a nickel (Ni) film, forming a hybrid MnO2/Ni actuator. The actuator demonstrated a rapid strain response of 0.88% s-1 (5.3% intrinsic strain in 6 s) and a large actuation stress of 244 MPa owing to the special R-MnO2 with a high density of sodium ion (Na+)-accessible lattice tunnels, Mn vacancies, and also a high Young's modulus of the hybrid MnO2/Ni composite. Besides, the cyclic stability of the actuator was realized after 1.2 × 104 cycles of electric stimulation under a frequency of 0.05 Hz. The finding of the novel hybrid MnO2/Ni actuator may provide a new strategy to maximize the actuating performance evidently through tailoring the lattice tunnel structure and introducing cation vacancies into electrochemical electrode materials.

Multimodal imaging in the differential diagnosis of glioma recurrence from treatment-related effects: A protocol for systematic review and network meta-analysis.

BACKGROUND: Glioma is the most common malignant primary brain tumor and it will always recur. To date, various multimodal imaging including magnetic resonance imaging (MRI) and positron emission tomography computed tomography (PET/CT) was used to differentiate the diagnosis of true tumor recurrent (TuR) and treatment-related effects (TrE) in glioma patient but with no overall conclusion. In this study, SROC curve and Bayesian network meta-analysis will be used to conduct a comprehensive analysis of the results of different clinical reports, and assess the efficacy of multimodal imaging in difference TuR and TrE. METHODS: To find more comprehensive information about the application of multimodal imaging in glioma patients, we searched the EMBASE, Pubmed, and Cochrane Central Register of Controlled Trials for relevant clinical trials. We also reviewed their reference lists to avoid omissions. QUADAS-2, RevMan software, Stata, and R software will be used. RESULTS: This study will provide reliable evidence for the efficacy of multimodal imaging in the differential diagnosis of TuR and TrE in glioma patients. CONCLUSION: We will evaluate the effectiveness of different and rank each imaging method in glioma patients to provide a decision-making reference on which method to choose for clinicians. Protocol registration number: CRD42020217861.

In vivo visualization and characterization of inflamed intestinal wall: the exploration of targeted microbubbles in assessing NF-κB expression.

NF-κB, a critical cytokine of inflammatory bowel diseases (IBD), is a viable marker to reflect the inflammatory activity of the intestine. We aimed to develop NF-κB-targeted microbubbles (MBs) and perform molecular contrast-enhanced ultrasound (CEUS) to quantify NF-κB expressions on the intestinal wall in IBD mice in vivo. In this study, NF-κB-targeted MBs were fabricated by connecting biotin-loaded NF-κB antibodies and avidin-loaded MBs. NF-κB-targeted MBs presented as transparent and round bubbles with an average diameter of 1.03/µm±0.01. The specific binding of targeted MBs and inflammatory cells was validated by in vitro experiments, including flow cytometry, Western blot and immunofluorescence, which revealed the specific binding of targeted MBs and inflammatory cells. Subsequently, NF-κB-targeted CEUS imaging was performed on mice with chemical-induced colitis, and the peak intensity (PI) and time-to-peak (TTP) were quantified. Pathological and immunohistochemical (IHC) examinations were further implemented. For the target CEUS group, fast enhancement followed by slow subsiding was observed. The PI of target CEUS of the IBD mice was significantly higher than that of non-target CEUS of the IBD mice, healthy controls and target CEUS of the treated IBD mice (34835%[13379-73492%] VS 437%[236-901%], 130%[79-231%], 528%[274-779%], p<0.0001), in accordance with the IHC results of NF-κB expressions. The TTP of target CEUS of the treated mice was significantly higher than that of untreated mice (35.7s [18.1-49.5s] VS 8.3s [4.2-12.5s], p<0.0001). Therefore, we suggested that NF-κB-targeted CEUS could accurately detect and quantify NF-κB expressions on the intestinal walls of IBD, enabling the evaluation of intestinal inflammation.

MiR-124 Negatively Regulated PARP1 to Alleviate Renal Ischemia-reperfusion Injury by Inhibiting TNFα/RIP1/RIP3 Pathway.

Renal ischemia-reperfusion injury (IRI) is one of the underlying causes of acute kidney injury and also an unavoidable problem in renal transplantation. Lots of miRNAs and targets have been found to participate in some post-transcriptional processes in renal IRI, however, the detailed knowledge of miRNA targets and mechanism is unknown. In this study, miR-124 was found inhibited and PARP1 was overexpressed in renal IRI cells and mouse models. Dual-luciferase reporter assay revealed that miR-124 post-transcriptionally regulated PAPR1 3'UTR activity. Our results also demonstrated miR-124 negatively regulated PARP1 which played a role in necroptosis of renal ischemia-reperfusion injury by activating TNFα. TNFα induced the RIP1/RIP3 necroptosis signaling pathway to aggravate the renal injury. Collectively, these studies identified PARP1 as a direct target of miR-124 and activated RIP1/RIP3 necroptosis signaling pathway through TNFα. It elucidated the protective effect of miR-124 in renal ischemia-reperfusion injury, which demonstrated the regulatory mechanism of miR-124/PARP1 in renal injury and exhibited the potential as a novel therapeutic for the treatment of renal IRI.

Nomogram based on radiomics analysis of primary breast cancer ultrasound images: prediction of axillary lymph node tumor burden in patients.

OBJECTIVES: To establish a prediction model for evaluating the axillary lymph node (ALN) status of patients with T1/T2 invasive breast cancer based on radiomics analysis of US images of primary breast lesions. METHODS: Between August 2016 and November 2018, a total of 343 patients with histologically proven malignant breast tumors were included in this study and randomly assigned to the training and validation groups at a ratio of 7:3. ALN tumor burden was defined as low (< 3 metastatic ALNs) or high (≥ 3 metastatic ALNs). Radiomics features were obtained using the PyRadiomics package, and the radiomics score was established by least absolute shrinkage and selection operator regression. A nomogram combining the breast cancer US radiomics score with patient age and lesion size was generated based on the multivariate logistic regression results. RESULTS: In the training and validation cohorts, 29.1% (69/237) and 32.08% (34/106) of patients were pathologically diagnosed with more than 2 metastatic ALNs, respectively. The radiomics score consisted of 16 US features, and patient age and lesion diameter identified by US were included to construct the model. The AUC of the model was 0.846 (95% CI, 0.790-0.902) for the training cohort and 0.733 (95% CI, 0.613-0.852) for the validation cohort. The calibration curves showed good agreement between the predictions and observations. CONCLUSIONS: Our novel nomogram demonstrates high accuracy in predicting ALN tumor burden in breast cancer patients. We also suggest further development of PyRadiomics to improve US radiomics. KEY POINTS: • A nomogram based on US was developed to predict ALN tumor burden (low, < 3 metastatic ALNs; high, ≥ 3 metastatic ALNs). • The nomogram could assist clinicians in evaluating treatment strategies for T1/T2 invasive breast cancer.

Predicting Axillary Lymph Node Status With a Nomogram Based on Breast Lesion Ultrasound Features: Performance in N1 Breast Cancer Patients.

OBJECTIVE: To develop a nomogram for predicting axillary lymph node (ALN) metastases using the breast imaging reporting and data system (BI-RADS) ultrasound lexicon. METHODS: A total of 703 patients from July 2015 to January 2018 were included in this study as a primary cohort for model construction. Moreover, 109 patients including 51 pathologically confirmed N1 patients (TNM staging) and 58 non-metastatic patients were recruited as an external validation cohort from March 2018 to August 2019. Ultrasound images and clinical information of these patients were retrospectively reviewed. The ultrasonic features based on the BI-RADS lexicon were extracted by two radiologists. The features extracted from the primary cohort were used to develop a nomogram using multivariate analysis. Internal and external validations were performed to evaluate the predictive efficacy of the nomogram. RESULTS: The nomogram was based on two features (size, lesion boundary) and showed an area under the curve of 0.75 (95% confidence interval [CI], 0.70-0.79) in the primary cohort and 0.91 (95% CI, 0.84-0.97) in the external validation cohort; it achieved an 88% sensitivity in N1 patients. CONCLUSION: The nomogram based on BI-RADS ultrasonic features can predict breast cancer ALN status with relatively high accuracy. It has potential clinical value in improving the sensitivity and accuracy of the preoperative diagnosis of ALN metastases, especially for N1 patients.

Multimodal VEGF-Targeted Contrast-Enhanced Ultrasound and Photoacoustic Imaging of Rats with Inflammatory Arthritis: Using Dye-VEGF-Antibody-Loaded Microbubbles.

Owing to the heavy health burdens from rheumatoid arthritis, a sensitive and objective imaging method is needed for early diagnosis and accurate evaluation of the disease. We aimed to fabricate vascular epithelial growth factor (VEGF)-targeted microbubbles (MBs) to evaluate the expression levels of VEGF within the inflammatory lesions of rats with adjuvant-induced arthritis (AIA) using a multimodal photoacoustic (PA)/ultrasound (US) imaging system. Fluorescein isothiocyanate-biotin double-labeled vascular endothelial growth factor receptor 2 antibodies and Cy5.5-biotin double-labeled VEGF2 antibodies were added to the avidin-labeled MBs to synthesize VEGF-targeted MBs. The antibodies could specifically bind to the MBs according to the flow cytometry and fluorescence imaging. In vitro experiments on the cellular uptake of the target MBs also validated the interaction of the VEGF antibodies and the MBs. Multimodal contrast-enhanced US (CEUS)/PA imaging was performed in sequence on the inflamed paws of the AIA rats with a single PA/US imaging system after the injection of the targeted MBs. The CEUS and PA signals were then quantified and verified by the pathologic results. A CEUS pattern of fast wash in and slow washout was observed in the AIA rats after injection of targeted MBs. Compared with AIA rats injected with unconnected VEGF antibodies and naked MBs, AIA rats injected with targeted MBs presented a higher peak intensity (p = 0.0079 and 0.0079 respectively) and a longer time to peak (p = 0.0117 and 0.0117, respectively). The PA signals were also significantly enhanced after injection of targeted MBs (p = 0.0112 and 0.0119, respectively), which was in accordance with the pathologic and immunohistochemical results. In conclusion, VEGF-targeted MBs can be used as agents for multimodal CEUS/PA imaging and to detect VEGF expression in the inflammatory lesions of AIA rats in vivo. This strategy may be useful in imaging evaluation of arthritis by identifying inflammation-related molecules in different imaging modes.