EGR1 Promotes Erastin-induced Ferroptosis Through Activating Nrf2-HMOX1 Signaling Pathway in Breast Cancer Cells.

Purpose: Early growth response 1 (EGR1) is a crucial transcription factor composed of zinc finger structures, inhibitory and activating regulatory regions. We identified the biological effect and molecular mechanisms of EGR1 in breast cancer (BC). Methods: We used qRT-PCR, western blot and immunohistochemistry to examine the expression of EGR1 in BC samples. CCK-8 and colony assay were performed to reveal the effect of EGR1 on the proliferation of BC cells. LDH release assay, MCB assay, MDA assay, C-AM assay and TMRE assay were performed to measure the levels of LDH release, GSH, MDA, LIP and mitochondrial membrane potential. The regulation of EGR1 on the expression of Nrf2 and HMOX1 was investigated through Western blot. Xenograft models were conducted to determine the impact of EGR1 overexpression on BC in vivo. Results: The expression of EGR1 was downregulated in BC tissues compared with the normal tissues, and lower expression of EGR1 associated with poorer clinical outcome in BC patients. Through in vitro experiments, we found that EGR1 downregulation facilitated the proliferation of BC cells, and overexpression of EGR1 inhibited the proliferation of BC cells. In addition, EGR1 knockdown alleviated erastin-induced ferroptosis and overexpression of EGR1 facilitated erastin-induced ferroptosis in BC cells. Moreover, overexpression of EGR1 facilitated the anti-tumor effect caused by erastin in vivo. Mechanistically, the phosphorylation levels of Nrf2 and the expression of HMOX1 were reduced due to the downregulation of EGR1, and increased due to the upregulation of EGR1. Additionally, the finding that EGR1 facilitated erastin-induced ferroptosis was alleviated by the inhibition of Nrf2-HMOX1. Conclusion: The expression of EGR1 is downregulated in BC, which is correlated with poor prognosis of BC patients. EGR1 suppresses the proliferation of BC cells and facilitates erastin-induced ferroptosis by activating Nrf2-HMOX1 signaling pathway in BC cells.

Prognostic Impact of Left Atrial Appendage Patency After Device Closure.

BACKGROUND: The prognostic impact of left atrial appendage (LAA) patency, including those with and without visible peri-device leak (PDL), post-LAA closure in patients with atrial fibrillation, remains elusive. METHODS: Patients with atrial fibrillation implanted with the WATCHMAN 2.5 device were prospectively enrolled. The device surveillance by cardiac computed tomography angiography was performed at 3 months post-procedure. Adverse events, including stroke/transient ischemic attack (TIA), major bleeding, cardiovascular death, all-cause death, and the combined major adverse events (MAEs), were compared between patients with complete closure and LAA patency. RESULTS: Among 519 patients with cardiac computed tomography angiography surveillance at 3 months post-LAA closure, 271 (52.2%) showed complete closure, and LAA patency was detected in 248 (47.8%) patients, including 196 (37.8%) with visible PDL and 52 (10.0%) without visible PDL. During a median of 1193 (787-1543) days follow-up, the presence of LAA patency was associated with increased risks of stroke/TIA (adjusted hazard ratio for baseline differences, 3.22 [95% CI, 1.17-8.83]; P=0.023) and MAEs (adjusted hazard ratio, 1.12 [95% CI, 1.06-1.17]; P=0.003). Specifically, LAA patency with visible PDL was associated with increased risks of stroke/TIA (hazard ratio, 3.66 [95% CI, 1.29-10.42]; P=0.015) and MAEs (hazard ratio, 3.71 [95% CI, 1.71-8.07]; P=0.001), although LAA patency without visible PDL showed higher risks of MAEs (hazard ratio, 3.59 [95% CI, 1.28-10.09]; P=0.015). Incidences of stroke/TIA (2.8% versus 3.0% versus 6.7% versus 22.2%; P=0.010), cardiovascular death (0.9% versus 0% versus 1.7% versus 11.1%; P=0.005), and MAEs (4.6% versus 9.0% versus 11.7% versus 22.2%; P=0.017) increased with larger PDL (0, >0 to ≤3, >3 to ≤5, or >5 mm). Older age and discontinuing antiplatelet therapy at 6 months were independent predictors of stroke/TIA and MAEs in patients with LAA patency. CONCLUSIONS: LAA patency detected by cardiac computed tomography angiography at 3 months post-LAA closure is associated with unfavorable prognosis in patients with atrial fibrillation implanted with WATCHMAN 2.5 device. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03788941.

Distinct ER and PR expression patterns significantly affect the clinical outcomes of early HER2-positive breast cancer: A real-world analysis of 871 patients treated with neoadjuvant therapy.

INTRODUCTION: The impact of distinct estrogen receptor (ER) and progesterone receptor (PR) expression patterns on tumor behavior and treatment outcomes within HER2-positive breast cancer is not fully explored. This study aimed to comprehensively examine the clinical differences among patients with HER2-positive breast cancer harboring distinct ER and PR expression patterns in the neoadjuvant setting. METHODS: This retrospective analysis included 871 HER2-positive breast patients treated with neoadjuvant therapy at our hospital between 2011 and 2022. Comparisons were performed across the three hormone receptor (HR)-specific subtypes, namely the ER-negative/PR-negative/HER2-positive (ER-/PR-/HER2+), the single HR-positive (HR+)/HER2+, and the triple-positive breast cancer (TPBC) subtypes. RESULTS: Of 871 patients, 21.0% had ER-/PR-/HER2+ tumors, 33.6% had single HR+/HER2+ disease, and 45.4% had TPBC. Individuals with single HR+/HER2+ tumors and TPBC cases demonstrated significantly lower pathological complete response (pCR) rates compared to those with ER-/PR-/HER2+ tumors (36.9% vs. 24.3% vs. 49.2%, p < 0.001). Multivariate analysis confirmed TPBC as significantly associated with decreased pCR likelihood (OR = 0.42, 95%CI 0.28-0.63, p < 0.001). Survival outcomes, including disease-free survival (DFS) and overall survival (OS), showed no significant differences across HR-specific subtypes in the overall patient population. However, within patients without anti-HER2 therapy, TPBC was linked to improved DFS and a trend towards better OS. CONCLUSIONS: HER2-positive breast cancer exhibited three distinct HR-specific subtypes with varying clinical manifestations and treatment responses. These findings suggest personalized treatment strategies considering ER and PR expression patterns, emphasizing the need for further investigations to unravel molecular traits underlying HER2-positive breast cancer with distinct HR expression patterns.

Sequential neoadjuvant chemotherapy using pegylated liposomal doxorubicin and cyclophosphamide followed by taxanes with complete trastuzumab and pertuzumab treatment for HER2-positive breast cancer: A phase II single-arm study.

Objective: Despite cardiotoxicity overlap, the trastuzumab/pertuzumab and anthracycline combination remains crucial due to significant benefits. Pegylated liposomal doxorubicin (PLD), a less cardiotoxic anthracycline, was evaluated for efficacy and cardiac safety when combined with cyclophosphamide and followed by taxanes with trastuzumab/pertuzumab in human epidermal growth factor receptor-2 (HER2)-positive early breast cancer (BC). Methods: In this multicenter, phase II study, patients with confirmed HER2-positive early BC received four cycles of PLD (30-35 mg/m2) and cyclophosphamide (600 mg/m2), followed by four cycles of taxanes (docetaxel, 90-100 mg/m2 or nab-paclitaxel, 260 mg/m2), concomitant with eight cycles of trastuzumab (8 mg/kg loading dose, then 6 mg/kg) and pertuzumab (840 mg loading dose, then 420 mg) every 3 weeks. The primary endpoint was total pathological complete response (tpCR, ypT0/is ypN0). Secondary endpoints included breast pCR (bpCR), objective response rate (ORR), disease control rate, rate of breast-conserving surgery (BCS), and safety (with a focus on cardiotoxicity). Results: Between May 27, 2020 and May 11, 2022, 78 patients were treated with surgery, 42 (53.8%) of whom had BCS. After neoadjuvant therapy, 47 [60.3%, 95% confidence interval (95% CI), 48.5%-71.2%] patients achieved tpCR, and 49 (62.8%) achieved bpCR. ORRs were 76.9% (95% CI, 66.0%-85.7%) and 93.6% (95% CI, 85.7%-97.9%) after 4-cycle and 8-cycle neoadjuvant therapy, respectively. Nine (11.5%) patients experienced asymptomatic left ventricular ejection fraction (LVEF) reductions of ≥10% from baseline, all with a minimum value of >55%. No treatment-related abnormal cardiac function changes were observed in mean N-terminal pro-BNP (NT-proBNP), troponin I, or high-sensitivity troponin. Conclusions: This dual HER2-blockade with sequential polychemotherapy showed promising activity with rapid tumor regression in HER2-positive BC. Importantly, this regimen showed an acceptable safety profile, especially a low risk of cardiac events, suggesting it as an attractive treatment approach with a favorable risk-benefit balance.

Association between Homologous Recombination Repair Defect Status and Long-Term Prognosis of Early HER2-Low Breast Cancer: A Retrospective Cohort Study.

BACKGROUND: As a newly identified subtype of HER2-negative tumors associated with a less favorable prognosis, it remains crucial to evaluate potential prognostic and predictive factors, particularly non-invasive biomarkers, for individuals with human epidermal growth factor 2 (HER2) low early-stage breast cancer (EBC). Multiple investigations have highlighted that HER2-negative patients with EBC exhibiting high homologous recombination deficiency (HRD) scores display lower rates of pathological complete response (PCR) to neoadjuvant chemotherapy (NAC). Nevertheless, no study to date has explored the correlation between HRD and the long-term prognosis in HER2-low patients with EBC. PATIENTS AND METHODS: This retrospective observational study focuses on primary EBC sourced from The Cancer Genome Atlas dataset (TCGA). It reveals the gene mutation landscape in EBC with low HER2 expression and elucidates the tumor immune landscape across different HRD states. Utilizing bioinformatics analysis and Cox proportional models, along with the Kaplan-Meier method, the study assesses the correlation between HRD status and disease-specific survival (DSS), disease-free interval (DFI), and progression-free interval (PFI). Subgroup analyses were conducted to identify potential variations in the association between HRD and prognosis. RESULTS: In the patients with HER2-low breast cancer, patients with homologous recombination related genes (HRRGs) defects had an HRD score about twice that of those without related genes mutations, and were at higher risk of acquiring ARID1A, ATM, and BRCA2 mutations. We also found that most immune cell abundances were significantly higher in EBC tumors with high HRD than in EBC tumors with low HRD or HRD-medium, particularly plasma B-cell abundance, CD8 T-cell abundance, and M1 macrophages. In addition, these tumors with HRD-high also appear to have significantly higher tumor immune scores and lower interstitial scores. Then, we analyzed the relationship between different HRD status and prognosis. There was statistical significance (P = .036 and P = .046, respectively) in DSS and PFI between the HRD-low and HRD-high groups, and patients with HRD-high EBC showed relatively poor survival outcomes. A medium HRD score (hazard ratio, HR = 2.15, 95% CI: 1.04-4.41, P = .038) was a significant risk factor for PFI. Hormone receptor positivity is an important factor in obtaining medium-high HRD score and poor prognosis. CONCLUSION: Higher HRD scores were associated with poorer PFI outcomes, particularly in people with HR+/HER2-low. Varied HRD states exhibited distinctions in HRRGs and the tumor immune landscape. These insights have the potential to assist clinicians in promptly identifying high-risk groups and tailoring personalized treatments for patients with HER2-low EBC, aiming to enhance long-term outcomes.

Differential diagnosis of breast mucinous carcinoma with an oval shape from fibroadenoma based on ultrasonographic features.

BACKGROUND: Approximately 50% of breast mucinous carcinomas (MCs) are oval and have the possibility of being misdiagnosed as fibroadenomas (FAs). We aimed to identify the key features that can help differentiate breast MC with an oval shape from FA on ultrasonography (US). METHODS: Seventy-six MCs from 71 consecutive patients and 50 FAs with an oval shape from 50 consecutive patients were included in our study. All lesions pathologically diagnosed. According to the Breast Imaging Reporting and Data System (BI-RADS), first, the ultrasonographic features of the MCs and FAs were recorded and a final category was assessed. Then, the differences in ultrasonographic characteristics between category 4 A (low-risk group) and category 4B-5 (medium-high- risk group) MCs were identified. Finally, other ultrasonographic features of MC and FA both with an oval shape were compared to determine the key factors for differential diagnosis. The Mann-Whitney test, χ2 test or Fisher's exact test was used to compare data between groups. RESULTS: MCs with an oval shape (81.2%) and a circumscribed margin (25%) on US were more commonly assessed in the low-risk group (BI-RADS 4 A) than in the medium-high-risk group (BI-RADS 4B-5) (20%, p < 0.001 and 0%, p = 0.001, respectively). Compared with those with FA, patients with MC were older, and tended to have masses with non-hypoechoic patterns, not circumscribed margins, and a posterior echo enhancement on US (p < 0.001, p < 0.001, and p = 0.003, respectively). CONCLUSION: The oval shape was the main reason for the underestimation of MCs. On US, an oval mass found in the breast of women of older age with non-hypoechoic patterns, not circumscribed margins, and a posterior echo enhancement was associated with an increased risk of being an MC, and should be subjected to active biopsy.

Deep learning combining mammography and ultrasound images to predict the malignancy of BI-RADS US 4A lesions in women with dense breasts: a diagnostic study.

OBJECTIVES: The authors aimed to assess the performance of a deep learning (DL) model, based on a combination of ultrasound (US) and mammography (MG) images, for predicting malignancy in breast lesions categorized as Breast Imaging Reporting and Data System (BI-RADS) US 4A in diagnostic patients with dense breasts. METHODS: A total of 992 patients were randomly allocated into the training cohort and the test cohort at a proportion of 4:1. Another, 218 patients were enrolled to form a prospective validation cohort. The DL model was developed by incorporating both US and MG images. The predictive performance of the combined DL model for malignancy was evaluated by sensitivity, specificity, and area under the receiver operating characteristic curve (AUC). The combined DL model was then compared to a clinical nomogram model and to the DL model trained using US image only and to that trained MG image only. RESULTS: The combined DL model showed satisfactory diagnostic performance for predicting malignancy in breast lesions, with an AUC of 0.940 (95% CI: 0.874-1.000) in the test cohort, and an AUC of 0.906 (95% CI: 0.817-0.995) in the validation cohort, which was significantly higher than the clinical nomogram model, and the DL model for US or MG alone ( P <0.05). CONCLUSIONS: The study developed an objective DL model combining both US and MG imaging features, which was proven to be more accurate for predicting malignancy in the BI-RADS US 4A breast lesions of patients with dense breasts. This model may then be used to more accurately guide clinicians' choices about whether performing biopsies in breast cancer diagnosis.

Association of FTH1-Expressing Circulating Tumor Cells With Efficacy of Neoadjuvant Chemotherapy for Patients With Breast Cancer: A Prospective Cohort Study.

BACKGROUND: The association between different phenotypes and genotypes of circulating tumor cells (CTCs) and efficacy of neoadjuvant chemotherapy (NAC) remains uncertain. This study was conducted to evaluate the relationship of FTH1 gene-associated CTCs (F-CTC) with/without epithelial-mesenchymal transition (EMT) markers, or their dynamic changes with the efficacy of NAC in patients with non-metastatic breast cancer. PATIENTS AND METHODS: This study enrolled 120 patients with non-metastatic breast cancer who planned to undergo NAC. The FTH1 gene and EMT markers in CTCs were detected before NAC (T0), after 2 cycles of chemotherapy (T1), and before surgery (T2). The associations of these different types of CTCs with rates of pathological complete response (pCR) and breast-conserving surgery (BCS) were evaluated using the binary logistic regression analysis. RESULTS: F-CTC in peripheral blood ≥1 at T0 was an independent factor for pCR rate in patients with HER2-positive (odds ratio [OR]=0.08, 95% confidence interval [CI], 0.01-0.98, P = .048). The reduction in the number of F-CTC at T2 was an independent factor for BCS rate (OR = 4.54, 95% CI, 1.14-18.08, P = .03). CONCLUSIONS: The number of F-CTC prior to NAC was related to poor response to NAC. Monitoring of F-CTC may help clinicians formulate personalized NAC regimens and implement BCS for patients with non-metastatic breast cancer.

Enhancement of tolerance against flonicamid in Solenopsis invicta (Hymenoptera: Formicidae) through overexpression of CYP6A14.

Solenopsis invicta is a main issue in southern China and is causing significant damage to the local ecological environment. The extensive use of insecticides has resulted in the development of tolerance in S. invicta. In our study, ten S. invicta colonies from Sichuan Province exhibited varying degrees of tolerance against flonicamid, with LC50 values from 0.49 mg/L to 8.54 mg/L. The sensitivity of S. invicta to flonicamid significantly increased after treatment with the P450 enzyme inhibitor piperonyl butoxide (PBO). Additionally, the activity of P450 in S. invicta was significantly enhanced after being treated with flonicamid. Flonicamid induced the expression levels of CYP4aa1, CYP9e2, CYP4C1, and CYP6A14. The expression levels of these P450 genes were significantly higher in the tolerant colonies compared to the sensitive colonies, and the relative copy numbers of CYP6A14 in the tolerant colonies were 2.01-2.15 fold. RNAi feeding treatment effectively inhibited the expression of P450 genes, thereby reducing the tolerance of S. invicta against flonicamid. In addition, the overexpression of CYP6A14 in D. melanogaster resulted in reduced sensitivity to flonicamid. Our investigations revealed hydrophobic interactions between flonicamid and seven amino acid residues of CYP6A14, along with the formation of a hydrogen bond between Glu306 and flonicamid. Our findings suggest that flonicamid can effectively control S. invicta and P450 plays a pivotal role in the tolerance of S. invicta against flonicamid. The overexpression of CYP6A14 also increased tolerance to flonicamid.

LncRNA EILA promotes CDK4/6 inhibitor resistance in breast cancer by stabilizing cyclin E1 protein.

CDK4/6 inhibitors (CDK4/6i) plus endocrine therapy are now standard first-line therapy for advanced HR+/HER2- breast cancer, but developing resistance is just a matter of time in these patients. Here, we report that a cyclin E1-interacting lncRNA (EILA) is up-regulated in CDK4/6i-resistant breast cancer cells and contributes to CDK4/6i resistance by stabilizing cyclin E1 protein. EILA overexpression correlates with accelerated cell cycle progression and poor prognosis in breast cancer. Silencing EILA reduces cyclin E1 protein and restores CDK4/6i sensitivity both in vitro and in vivo. Mechanistically, hairpin A of EILA binds to the carboxyl terminus of cyclin E1 protein and hinders its binding to FBXW7, thereby blocking its ubiquitination and degradation. EILA is transcriptionally regulated by CTCF/CDK8/TFII-I complexes and can be inhibited by CDK8 inhibitors. This study unveils the role of EILA in regulating cyclin E1 stability and CDK4/6i resistance, which may serve as a biomarker to predict therapy response and a potential therapeutic target to overcome resistance.

Evidence-based identification of breast cancer and associated ovarian and uterus cancer risk components in source waters from high incidence area in the Pearl River Basin, China.

Breast cancer, ovarian cancer, and uterus cancer are among the most common female cancers. They are suspected to associate with exposures to specific environmental pollutants, which remain unidentified in source waters. In this work, we focused on the Pearl River Basin region in China, which experienced a high incidence of breast, ovarian, and uterus cancers. Combining cancer patient data, mammalian cell cytotoxicity analyses, and exhaustive historical and current chemical assessments, we for the first time identified source water components that promoted proliferation of mammalian cells, and confirmed their association with these female cancers via the estrogen receptor mediated pathway. Therefore, the components that have previously been found to enhance the proliferation of estrogen receptor-containing cells through endocrine disruption could be the crucial factor. Based on this, components that matched with this toxicological characteristic (i.e., estrogen-like effect) were further identified in source waters, including (1) organic components: phthalates, bisphenol A, nonylphenols, and per-/polyfluoroalkyls; (2) inorganic components: Sb, Co, As, and nitrate. Moreover, these identified water components were present at levels comparable to other regions with high female cancer prevalence, suggesting that the potential risk of these components may not be exclusive to the study region. Together, multiple levels of evidence suggested that long-term co-exposures to source water estrogenic components may be important to the development of breast, ovarian, and uterus cancers.

Kamaonensine A-G: Lycaconitine-type C19-diterpenoid alkaloids with anti-inflammatory activities from Delphinium kamaonense Huth.

Delphinium kamaonense Huth is a sort of folkloric plant resource which is cultivated and planted with great ornamental and medicinal values. In this work, seven undescribed lycaconitine-type C19-diterpenoid alkaloids, especially a rare skeleton with -CH=N and N-oxide moieties, along with ten known compounds, were isolated from D. kamaonense, of which the structures were determined by various spectroscopic data, combined with calculated electronic circular dichroism (ECD) and single-crystal X-ray diffraction analysis. In vitro nitric oxide inhibitory activities assay of these compounds indicated that lycaconitine-type C19-diterpenoid alkaloids had significant anti-inflammatory inhibitory activities, with kamaonensine E being the most potent (0.9 ± 0.2 µM) stronger than positive (9.0 ± 1.3 µM). In the network pharmacology studies, binding three key targets mitogen-activated protein kinase 8 (MAPK8), mitogen-activated protein kinase 14 (MAPK14), and heat shock protein HSP 90-alpha (HSP90α), the anti-inflammatory mechanism might be related to MAPK signaling pathways. Furthermore, the molecular docking results revealed that the uncommon amides and methylenedioxy groups might be the most two promising pharmacophores for lycaconitine-type C19-diterpenoid alkaloids.

Research on User Behavior Based on Higher-Order Dependency Network.

In the era of the popularization of the Internet of Things (IOT), analyzing people's daily life behavior through the data collected by devices is an important method to mine potential daily requirements. The network method is an important means to analyze the relationship between people's daily behaviors, while the mainstream first-order network (FON) method ignores the high-order dependencies between daily behaviors. A higher-order dependency network (HON) can more accurately mine the requirements by considering higher-order dependencies. Firstly, our work adopts indoor daily behavior sequences obtained by video behavior detection, extracts higher-order dependency rules from behavior sequences, and rewires an HON. Secondly, an HON is used for the RandomWalk algorithm. On this basis, research on vital node identification and community detection is carried out. Finally, results on behavioral datasets show that, compared with FONs, HONs can significantly improve the accuracy of random walk, improve the identification of vital nodes, and we find that a node can belong to multiple communities. Our work improves the performance of user behavior analysis and thus benefits the mining of user requirements, which can be used to personalized recommendations and product improvements, and eventually achieve higher commercial profits.

Quantifying Intratumoral Heterogeneity and Immunoarchitecture Generated In-Silico by a Spatial Quantitative Systems Pharmacology Model.

Spatial heterogeneity is a hallmark of cancer. Tumor heterogeneity can vary with time and location. The tumor microenvironment (TME) encompasses various cell types and their interactions that impart response to therapies. Therefore, a quantitative evaluation of tumor heterogeneity is crucial for the development of effective treatments. Different approaches, such as multiregional sequencing, spatial transcriptomics, analysis of autopsy samples, and longitudinal analysis of biopsy samples, can be used to analyze the intratumoral heterogeneity (ITH) and temporal evolution and to reveal the mechanisms of therapeutic response. However, because of the limitations of these data and the uncertainty associated with the time points of sample collection, having a complete understanding of intratumoral heterogeneity role is challenging. Here, we used a hybrid model that integrates a whole-patient compartmental quantitative-systems-pharmacology (QSP) model with a spatial agent-based model (ABM) describing the TME; we applied four spatial metrics to quantify model-simulated intratumoral heterogeneity and classified the TME immunoarchitecture for representative cases of effective and ineffective anti-PD-1 therapy. The four metrics, adopted from computational digital pathology, included mixing score, average neighbor frequency, Shannon's entropy and area under the curve (AUC) of the G-cross function. A fifth non-spatial metric was used to supplement the analysis, which was the ratio of the number of cancer cells to immune cells. These metrics were utilized to classify the TME as "cold", "compartmentalized" and "mixed", which were related to treatment efficacy. The trends in these metrics for effective and ineffective treatments are in qualitative agreement with the clinical literature, indicating that compartmentalized immunoarchitecture is likely to result in more efficacious treatment outcomes.

Resistance monitoring and mechanism in the fall armyworm Spodoptera frugiperda (Lepidoptera: Noctuidae) for chlorantraniliprole from Sichuan Province, China.

The fall armyworm, Spodoptera frugiperda (Noctuidae: Lepidoptera), is a wide-reaching notorious insect pest of important cereal crops, which has developed resistance to multiple classes of insecticides. It invaded the Sichuan Province of China in 2019. In this study, we performed resistance monitoring of insecticides for 11 field-collected populations from Sichuan, and all the populations were susceptible to emamectin benzoate and chlorpyrifos. The variations in resistance level to indoxacarb (resistance ratio (RR), 9.23-45.53-fold), spinetoram (RR, 4.32-18.05-fold), and chlorantraniliprole (RR, 2.02-10.39-fold) were observed among these populations. To investigate the resistance mechanism of chlorantraniliprole, synergism tests were performed and showed that piperonyl butoxide had a slight synergistic effect on chlorantraniliprole for the QJ-20 population (1.43-fold) in moderate resistance (RR, 10.39-fold) compared with the treatment group without synergist. Furthermore, the expression scanning for resistance-related genes showed that five P450 genes (CYP6AE43, CYP321A8, CYP305A1, CYP49A1, and CYP306A1) and the ryanodine receptor gene (Ryr, chlorantraniliprole target) were overexpressed in the QJ-20 population. These results indicated that the fall armyworm in Sichuan has exhibited diverse susceptibilities to several classes of insecticides, and the overexpression of Ryr and several P450 genes may contribute to the development of resistance in S. frugiperda to chlorantraniliprole.

Diagnostic value of real-time four-dimensional transesophageal echocardiography on the implant-related thrombus.

Objectives: This study aims to evaluate the diagnostic value of real-time four-dimensional transesophageal echocardiography (RT4D-TEE) for implant-related thrombus (IRT). Methods: We collected 1,125 patients with atrial fibrillation from May 2019 to February 2022 in our hospital. All patients accepted transesophageal echocardiography (TEE) examination to exclude any thrombi before the LAAC procedure. Results: There were 760 patients with LAAC, 66 patients with CIED, and 299 patients without any implantations. A total of 40 patients with an established diagnosis of IRT were further analyzed. The accurate detection rate of IRT by RT4D-TEE was 4.8% (40/826), which was higher than 3.8% (31/826) by 2D-TEE (P = 0.004). No IRT was found on TEE in the rest of the 786 patients. These 40 patients were divided into LAAC (n = 23) and CIED (n = 17) groups according to the results of RT4D-TEE. In the LAAC group, IRT distributed on different parts of the LAA occluder surface, 91.3% (21/23) with clumps of thrombi, and 8.7% (2/23) with a thin layer of thrombi covering the surface of the occluder. In the CIED group, thrombi were seen attached to the leads in the right atrium and right ventricle. The thrombi were beaded in 17.6% (3/17), corded in 17.6% (3/17), and clotted in the remaining 64.7% (11/17) of cases. After adjusting the anticoagulant dosage and following up for 6 months, 20% (8/40) of cases were successfully resolved, 67.5% (27/40) became smaller, and 12.5% (5/40) showed no changes. Conclusion: The accurate detection rate of IRT by RT4D-TEE was significantly higher than that by 2D-TEE. 2D-TEE has limitations, but RT4D-TEE can be used as an effective complementary method. Imaging and some clinical features differ significantly between IRT on occluder and IRT on CIED lead.

Novel roles of RNA-binding proteins in drug resistance of breast cancer: from molecular biology to targeting therapeutics.

Therapy resistance remains a huge challenge for current breast cancer treatments. Exploring molecular mechanisms of therapy resistance might provide therapeutic targets for patients with advanced breast cancer and improve their prognosis. RNA-binding proteins (RBPs) play an important role in regulating therapy resistance. Here we summarize the functions of RBPs, highlight their tremendously important roles in regulating therapy sensitivity and resistance and we also reveal current therapeutic approaches reversing abnormal functions of RBPs in breast cancer.