Structure-based design of non-hypertrophic apelin receptor modulator.

Apelin is a key hormone in cardiovascular homeostasis that activates the apelin receptor (APLNR), which is regarded as a promising therapeutic target for cardiovascular disease. However, adverse effects through the ß-arrestin pathway limit its pharmacological use. Here, we report cryoelectron microscopy (cryo-EM) structures of APLNR-Gi1 complexes bound to three agonists with divergent signaling profiles. Combined with functional assays, we have identified "twin hotspots" in APLNR as key determinants for signaling bias, guiding the rational design of two exclusive G-protein-biased agonists WN353 and WN561. Cryo-EM structures of WN353- and WN561-stimulated APLNR-G protein complexes further confirm that the designed ligands adopt the desired poses. Pathophysiological experiments have provided evidence that WN561 demonstrates superior therapeutic effects against cardiac hypertrophy and reduced adverse effects compared with the established APLNR agonists. In summary, our designed APLNR modulator may facilitate the development of next-generation cardiovascular medications.

Heavy Metal Exposure and Cardiovascular Disease.

Heavy metals are harmful environmental pollutants that have attracted widespread attention due to their health hazards to human cardiovascular disease. Heavy metals, including lead, cadmium, mercury, arsenic, and chromium, are found in various sources such as air, water, soil, food, and industrial products. Recent research strongly suggests a connection between cardiovascular disease and exposure to toxic heavy metals. Epidemiological, basic, and clinical studies have revealed that heavy metals can promote the production of reactive oxygen species, which can then exacerbate reactive oxygen species generation and induce inflammation, resulting in endothelial dysfunction, lipid metabolism distribution, disruption of ion homeostasis, and epigenetic changes. Over time, heavy metal exposure eventually results in an increased risk of hypertension, arrhythmia, and atherosclerosis. Strengthening public health prevention and the application of chelation or antioxidants, such as vitamins and beta-carotene, along with minerals, such as selenium and zinc, can diminish the burden of cardiovascular disease attributable to metal exposure.

Endothelial FIS1 DeSUMOylation Protects Against Hypoxic Pulmonary Hypertension.

BACKGROUND: Hypoxia is a major cause and promoter of pulmonary hypertension (PH), a representative vascular remodeling disease with poor prognosis and high mortality. However, the mechanism underlying how pulmonary arterial system responds to hypoxic stress during PH remains unclear. Endothelial mitochondria are considered signaling organelles on oxygen tension. Results from previous clinical research and our studies suggested a potential role of posttranslational SUMOylation (small ubiquitin-like modifier modification) in endothelial mitochondria in hypoxia-related vasculopathy. METHODS: Chronic hypoxia mouse model and Sugen/hypoxia rat model were employed as PH animal models. Mitochondrial morphology and subcellular structure were determined by transmission electron and immunofluorescent microscopies. Mitochondrial metabolism was determined by mitochondrial oxygen consumption rate and extracellular acidification rate. SUMOylation and protein interaction were determined by immunoprecipitation. RESULTS: The involvement of SENP1 (sentrin-specific protease 1)-mediated SUMOylation in mitochondrial remodeling in the pulmonary endothelium was identified in clinical specimens of hypoxia-related PH and was verified in human pulmonary artery endothelial cells under hypoxia. Further analyses in clinical specimens, hypoxic rat and mouse PH models, and human pulmonary artery endothelial cells and human embryonic stem cell-derived endothelial cells revealed that short-term hypoxia-induced SENP1 translocation to endothelial mitochondria to regulate deSUMOylation (the reversible process of SUMOylation) of mitochondrial fission protein FIS1 (mitochondrial fission 1), which facilitated FIS1 assembling with fusion protein MFN2 (mitofusin 2) and mitochondrial gatekeeper VDAC1 (voltage-dependent anion channel 1), and the membrane tethering activity of MFN2 by enhancing its oligomerization. Consequently, FIS1 deSUMOylation maintained the mitochondrial integrity and endoplasmic reticulum-mitochondria calcium communication across mitochondrial-associated membranes, subsequently preserving pulmonary endothelial function and vascular homeostasis. In contrast, prolonged hypoxia disabled the FIS1 deSUMOylation by diminishing the availability of SENP1 in mitochondria via inducing miR (micro RNA)-138 and consequently resulted in mitochondrial dysfunction and metabolic reprogramming in pulmonary endothelium. Functionally, introduction of viral-packaged deSUMOylated FIS1 within pulmonary endothelium in mice improved pulmonary endothelial dysfunction and hypoxic PH development, while knock-in of SUMO (small ubiquitin-like modifier)-conjugated FIS1 in mice exaggerated the diseased cellular and tissue phenotypes. CONCLUSIONS: By maintaining endothelial mitochondrial homeostasis, deSUMOylation of FIS1 adaptively preserves pulmonary endothelial function against hypoxic stress and consequently protects against PH. The FIS1 deSUMOylation-SUMOylation transition in pulmonary endothelium is an intrinsic pathogenesis of hypoxic PH.

FANCD2 deficiency sensitizes SHH medulloblastoma to radiotherapy via ferroptosis.

Radiotherapy is one of the standard therapeutic regimens for medulloblastoma (MB). Tumor cells utilize DNA damage repair (DDR) mechanisms to survive and develop resistance during radiotherapy. It has been found that targeting DDR sensitizes tumor cells to radiotherapy in several types of cancer, but whether and how DDR pathways are involved in the MB radiotherapy response remain to be determined. Single-cell RNA sequencing was carried out on 38 MB tissues, followed by expression enrichment assays. Fanconi anemia group D2 gene (FANCD2) expression was evaluated in MB samples and public MB databases. The function of FANCD2 in MB cells was examined using cell counting assays (CCK-8), clone formation, lactate dehydrogenase activity, and in mouse orthotopic models. The FANCD2-related signaling pathway was investigated using assays of peroxidation, a malondialdehyde assay, a reduced glutathione assay, and using FerroOrange to assess intracellular iron ions (Fe2+ ). Here, we report that FANCD2 was highly expressed in the malignant sonic hedgehog (SHH) MB subtype (SHH-MB). FANCD2 played an oncogenic role and predicted worse prognosis in SHH-MB patients. Moreover, FANCD2 knockdown markedly suppressed viability, mobility, and growth of SHH-MB cells and sensitized SHH-MB cells to irradiation. Mechanistically, FANCD2 deficiency led to an accumulation of Fe2+ due to increased divalent metal transporter 1 expression and impaired glutathione peroxidase 4 activity, which further activated ferroptosis and reduced proliferation of SHH-MB cells. Using an orthotopic mouse model, we observed that radiotherapy combined with silencing FANCD2 significantly inhibited the growth of SHH-MB cell-derived tumors in vivo. Our study revealed FANCD2 as a potential therapeutic target in SHH-MB and silencing FANCD2 could sensitize SHH-MB cells to radiotherapy via inducing ferroptosis. © 2024 The Pathological Society of Great Britain and Ireland.

Reduced Mitochondrial Protein Translation Promotes Cardiomyocyte Proliferation and Heart Regeneration.

BACKGROUND: The importance of mitochondria in normal heart function are well recognized and recent studies have implicated changes in mitochondrial metabolism with some forms of heart disease. Previous studies demonstrated that knockdown of the mitochondrial ribosomal protein S5 (MRPS5) by small interfering RNA (siRNA) inhibits mitochondrial translation and thereby causes a mitonuclear protein imbalance. Therefore, we decided to examine the effects of MRPS5 loss and the role of these processes on cardiomyocyte proliferation. METHODS: We deleted a single allele of MRPS5 in mice and used left anterior descending coronary artery ligation surgery to induce myocardial damage in these animals. We examined cardiomyocyte proliferation and cardiac regeneration both in vivo and in vitro. Doxycycline treatment was used to inhibit protein translation. Heart function in mice was assessed by echocardiography. Quantitative real-time polymerase chain reaction and RNA sequencing were used to assess changes in transcription and chromatin immunoprecipitation (ChIP) and BioChIP were used to assess chromatin effects. Protein levels were assessed by Western blotting and cell proliferation or death by histology and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assays. Adeno-associated virus was used to overexpress genes. The luciferase reporter assay was used to assess promoter activity. Mitochondrial oxygen consumption rate, ATP levels, and reactive oxygen species were also analyzed. RESULTS: We determined that deletion of a single allele of MRPS5 in mice results in elevated cardiomyocyte proliferation and cardiac regeneration; this observation correlates with improved cardiac function after induction of myocardial infarction. We identified ATF4 (activating transcription factor 4) as a key regulator of the mitochondrial stress response in cardiomyocytes from Mrps5+/- mice; furthermore, ATF4 regulates Knl1 (kinetochore scaffold 1) leading to an increase in cytokinesis during cardiomyocyte proliferation. The increased cardiomyocyte proliferation observed in Mrps5+/- mice was attenuated when one allele of Atf4 was deleted genetically (Mrps5+/-/Atf4+/-), resulting in the loss in the capacity for cardiac regeneration. Either MRPS5 inhibition (or as we also demonstrate, doxycycline treatment) activate a conserved regulatory mechanism that increases the proliferation of human induced pluripotent stem cell-derived cardiomyocytes. CONCLUSIONS: These data highlight a critical role for MRPS5/ATF4 in cardiomyocytes and an exciting new avenue of study for therapies to treat myocardial injury.

Age-Dependent Female Survival Advantage in Hepatocellular Carcinoma: A Multicenter Cohort Study.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) has a higher incidence in males, but the association of sex with survival remains controversial. This study aimed to examine the effect of sex on HCC survival and its association with age. METHODS: Among 33,238 patients with HCC from 12 Chinese tertiary hospitals, 4175 patients who underwent curative-intent hepatectomy or ablation were analyzed. Cancer-specific survival (CSS) was analyzed using Cox regression and Kaplan-Meier methods. Two propensity score methods and multiple mediation analysis were applied to mitigate confounding. To explore the effect of estrogen, a candidate sex-specific factor that changes with age, female participants' history of estrogen use, and survival were analyzed. RESULTS: There were 3321 males and 854 females included. A sex-related disparity of CSS was present and showed a typical age-dependent pattern: a female survival advantage over males appeared at the perimenopausal age of 45 to 54 years (hazard risk [HR], 0.77; 5-year CSS, 85.7% vs 70.6%; P = .018), peaked at the early postmenopausal age of 55 to 59 years (HR, 0.57; 5-year CSS, 89.8% vs 73.5%; P = .015), and was not present in the premenopausal (<45 y) and late postmenopausal groups (≥60 y). Consistent patterns were observed in patients after either ablation or hepatectomy. These results were sustained with propensity score analyses. Confounding or mediation effects accounted for only 19.5% of sex survival disparity. Female estrogen users had significantly longer CSS than nonusers (HR, 0.74; 5-year CSS, 79.6% vs 72.5%; P = .038). CONCLUSIONS: A female survival advantage in HCC depends on age, and this may be associated with age-dependent, sex-specific factors.

Multiparametric US for Identifying Metabolic Dysfunction-associated Steatohepatitis: A Prospective Multicenter Study.

Background Noninvasive evaluation of metabolic dysfunction-associated fatty liver disease (MAFLD) with multiparametric US is essential, but multicenter studies are lacking. Purpose To evaluate the ability of multiparametric US with attenuation imaging (ATI) and two-dimensional (2D) shear-wave elastography (SWE) for predicting metabolic dysfunction-associated steatohepatitis (MASH) in participants with MAFLD, regardless of hepatitis B virus infection status. Materials and Methods This prospective cross-sectional multicenter study of consecutive adults with MAFLD who underwent multiparametric US with ATI and 2D SWE, as well as liver biopsy, from September 2020 to June 2022 was conducted in 12 tertiary hospitals in China. Multivariable logistic regression was performed to assess risk factors associated with MASH. Area under the receiver operating characteristic curve (AUC) analysis was used to evaluate diagnostic performance in predicting MASH in training and validation groups (6:4 ratio of participants), and for a post hoc subgroup analysis of hepatitis B virus infection and diabetes. Results A total of 424 participants (median age, 47 years; IQR, 34-59 years; 244 male) were evaluated, including 332 participants (78%) with MASH and 92 (22%) without. Attenuation coefficient (AC) (odds ratio [OR], 3.32 [95% CI: 1.94, 5.71]; P < .001), alanine aminotransferase (ALT) level (OR, 4.42 [95% CI: 1.78, 10.94]; P = .001), and international normalized ratio (INR) (OR, 0.59 [95% CI: 0.37, 0.95]; P = .03) were independently associated with MASH. A combined model (AC, ALT, and INR) had AUCs of 0.85 (95% CI: 0.79, 0.91) and 0.77 (95% CI: 0.69, 0.85) for predicting MASH in the training and validation groups, respectively. AUC values for the subgroups with and without diabetes were 0.83 (95% CI: 0.72, 0.94) and 0.81 (95% CI: 0.75, 0.87) and for the subgroups with and without hepatitis B were 0.82 (95% CI: 0.74, 0.90) and 0.79 (95% CI: 0.71, 0.87), respectively. Conclusion A model combining AC, ALT level, and INR showed good discrimination ability for predicting MASH in participants with MAFLD. Clinical trial registration no. NCT04551716 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Reuter in this issue.

Dynamic Room Temperature Phosphorescence of Silane-Functionalized Carbon Dots Confining within Silica for Anti-Counterfeiting Applications.

Room temperature phosphorescent (RTP) materials with long-lived, excitation-dependent, and time-dependent phosphorescence are highly desirable but very hard to achieve. Herein, this work reports a rational strategy of multiple wavelength excitation and time-dependent dynamic RTP color by confining silane-functionalized carbon dots (CDs) in a silica matrix (Si-CDs@SiO2). The Si-CDs@SiO2 possesses unique green-light-excitation and a change in phosphorescence color from yellow to green. A slow-decaying phosphorescence at 500 nm with a lifetime of 1.28 s and a fast-decaying phosphorescence at 580 nm with a lifetime of 0.90 s are observed under 365 nm of irradiation, which originated from multiple surface triplet states of the Si-CDs@SiO2. Given the unique dynamic RTP properties, the Si-CDs@SiO2 are demonstrated for applications in fingerprint recognition and multidimensional dynamic information encryption. These findings will open an avenue to explore dynamic phosphorescent materials and significantly broaden their applications.

Post-translational protein lactylation modification in health and diseases: a double-edged sword.

As more is learned about lactate, it acts as both a product and a substrate and functions as a shuttle system between different cell populations to provide the energy for sustaining tumor growth and proliferation. Recent discoveries of protein lactylation modification mediated by lactate play an increasingly significant role in human health (e.g., neural and osteogenic differentiation and maturation) and diseases (e.g., tumors, fibrosis and inflammation, etc.). These views are critically significant and first described in detail in this review. Hence, here, we focused on a new target, protein lactylation, which may be a "double-edged sword" of human health and diseases. The main purpose of this review was to describe how protein lactylation acts in multiple physiological and pathological processes and their potential mechanisms through an in-depth summary of preclinical in vitro and in vivo studies. Our work aims to provide new ideas for treating different diseases and accelerate translation from bench to bedside.

R2* mapping and reduced field-of-view diffusion-weighted imaging for preoperative assessment of nonenlarged lymph node metastasis in rectal cancer.

The aim of the current study is to investigate the diagnostic value of R2* mapping versus reduced field-of-view diffusion-weighted imaging (rDWI) of the primary lesion of rectal cancer for preoperative prediction of nonenlarged lymph node metastasis (NLNM). Eighty-one patients with pathologically confirmed rectal cancer underwent preoperative R2* mapping and rDWI sequences before total mesorectal excisions and accompanying regional lymph node dissections. Two radiologists independently performed whole-tumor measurements of R2* and apparent diffusion coefficient (ADC) parameters on primary lesions of rectal cancer. Patients were divided into positive (NLNM+) and negative (NLNM-) groups based on their pathological analysis. The tumor location, maximum diameter of the tumor, and maximum short diameter of the lymph node were assessed. R2* and ADC, pT stage, tumor grade, status of mesorectal fascia, and extramural vascular invasion were also studied for their potential relationships with NLNM using multivariate logistic regression analysis. The NLNM+ group had significantly higher R2* (43.56 ± 8.43 vs. 33.87 ± 9.57, p < 0.001) and lower ADC (1.00 ± 0.13 vs. 1.06 ± 0.22, p = 0.036) than the NLNM- group. R2* and ADC were correlated to lymph node metastasis (r = 0.510, p < 0.001 for R2*; r = -0.235, p = 0.035 for ADC). R2* and ADC showed good and moderate diagnostic abilities in the assessment of NLNM status with corresponding area-under-the-curve values of 0.795 and 0.636. R2* provided a significantly better diagnostic performance compared with ADC for the prediction of NLNM status (z = 1.962, p = 0.0498). The multivariate logistic regression analysis demonstrated that R2* was a compelling factor of lymph node metastasis (odds ratio = 56.485, 95% confidence interval: 5.759-554.013; p = 0.001). R2* mapping had significantly higher diagnostic performance than rDWI from the primary tumor of rectal cancer in the prediction of NLNM status.

Comparing Sonazoid contrast-enhanced ultrasound to contrast-enhanced CT and MRI for differentially diagnosing renal lesions: a prospective multicenter study.

PURPOSE: To evaluate the diagnostic performance of contrast-enhanced (CE) ultrasound using Sonazoid (SNZ-CEUS) by comparing with contrast-enhanced computed tomography (CE-CT) and contrast-enhanced magnetic resonance imaging (CE-MRI) for differentiating benign and malignant renal masses. MATERIALS AND METHODS: 306 consecutive patients (from 7 centers) with renal masses (40 benign tumors, 266 malignant tumors) diagnosed by both SNZ-CEUS, CE-CT or CE-MRI were enrolled between September 2020 and February 2021. The examinations were performed within 7 days, but the sequence was not fixed. Histologic results were available for 301 of 306 (98.37%) lesions and 5 lesions were considered benign after at least 2 year follow-up without change in size and image characteristics. The diagnostic performances were evaluated by sensitivity, specificity, positive predictive value, negative predictive value, and compared by McNemar's test. RESULTS: In the head-to-head comparison, SNZ-CEUS and CE-MRI had comparable sensitivity (95.60 vs. 94.51%, P = 0.997), specificity (65.22 vs. 73.91%, P = 0.752), positive predictive value (91.58 vs. 93.48%) and negative predictive value (78.95 vs. 77.27%); SNZ-CEUS and CE-CT showed similar sensitivity (97.31 vs. 96.24%, P = 0.724); however, SNZ-CEUS had relatively lower than specificity than CE-CT (59.09 vs. 68.18%, P = 0.683). For nodules > 4 cm, CE-MRI demonstrated higher specificity than SNZ-CEUS (90.91 vs. 72.73%, P = 0.617) without compromise the sensitivity. CONCLUSIONS: SNZ-CEUS, CE-CT, and CE-MRI demonstrate desirable and comparable sensitivity for the differentiation of renal mass. However, the specificity of all three imaging modalities is not satisfactory. SNZ-CEUS may be a suitable alternative modality for patients with renal dysfunction and those allergic to gadolinium or iodine-based agents.

Feeding artery: a valuable feature for differentiation of regenerative nodule, dysplastic nodules and small hepatocellular carcinoma in CEUS LI-RADS.

OBJECTIVE: To investigate whether the feeding artery (FA) feature can aid in discriminating small hepatocellular carcinoma (HCC) using the contrast-enhanced ultrasound (CEUS) Liver Imaging Reporting and Data System (LI-RADS) from precancerous lesions. METHODS: Between June 2017 and May 2021, a total of 347 patients with 351 precancerous liver lesions or small HCCs who underwent CEUS were enrolled. Two independent radiologists assigned LI-RADS categories to all lesions and assessed the presence of the FA feature, which was used as an ancillary feature to either upgrade or downgrade the LI-RADS category. The diagnostic performance of CEUS LI-RADS, both with and without the FA feature, was evaluated based on accuracy, sensitivity, specificity, positive predictive value, and negative predictive value. RESULTS: The FA feature was found to be more prevalent in HCC (85.54%, p < 0.001) than in regenerative nodules (RNs, 29.73%), low-grade dysplastic nodules (LGDNs, 33.33%), and high-grade dysplastic nodules (HGDNs, 55.26%). Furthermore, the presence of arterial phase hyperenhancement (APHE), washout (WO), and FA in liver nodules was associated with a higher expression of GPC-3 and Ki-67 compared to the group without these features (p < 0.001). After adjusting, the sensitivity and accuracy of LR-5 for HCC improved from 68.67% (95%CI: 62.46%, 74.30%) to 77.51% (95%CI: 71.72%, 82.44%) and from 69.23% (95%CI: 64.11%, 74.02%) to 73.79% (95%CI: 68.86%, 78.31%), respectively. CONCLUSION: The FA feature is a valuable feature for distinguishing small HCC and precancerous lesions and could be added as a possible ancillary feature in CEUS LI-RADS which was backed up by biomarkers. CLINICAL RELEVANCE STATEMENT: The presence of a feeding artery is a valuable imaging feature in the differentiation of HCC and precancerous lesions. Incorporating this characteristic in the CEUS LI-RADS can enhance the diagnostic ability. KEY POINTS: • Feeding artery is more frequent in HCC than in regenerative nodules, low-grade dysplastic nodules, and high-grade dysplastic nodules. • Feeding artery feature is a valuable ancillary feature for CEUS LI-RADS to differentiate regenerative nodules, low-grade dysplastic nodules, high-grade dysplastic nodules, and HCC. • The existence of feeding artery, arterial phase hyperenhancement, and washout is associated with more GPC-3 positive expression and higher Ki-67 expression than the group without these features.

Efficacy of microwave ablation in the treatment of large benign thyroid nodules: a multi-center study.

OBJECTIVE: To evaluate the efficacy, safety, and improvement of symptoms by ultrasound-guided microwave ablation (MWA) for patients with large benign thyroid nodules (BTNs). METHODS: Eighty-seven patients with 87 BTNs (≥ 4 cm) treated with MWA between April 2015 and March 2021 were enrolled in this retrospective multicenter study, with clinical and ultrasound examinations performed at the 1st, 3rd, 6th, and 12th months. A multivariable linear mixed effects model was employed to explore the alterations in volume and volume reduction ratio (VRR), as well as the potential factors associated with VRR. RESULTS: The mean age of the 87 patients was 45.69 ± 14.21 years (range 18-76 years), and the ratio of men to women was 1:4.8. The mean volumes were much decreased at the 12th month after ablation compared to the initial volumes (p < .001). The mean VRR was 76.09% at the 12th month. The technique efficacy (VRR > 50%) was 90.80% at the 12th month. A multivariate analysis revealed that VRR was related to the initial volume (p = .015), annular flow (p = .010), and nodule composition (p = .024). The mean symptomatic score decreased from 4.40 ± 0.28 to 0.26 ± 0.06 at the 12th month (p < .001). At the same time, the mean cosmetic score decreased from 3.22 ± 0.10 to 1.31 ± 0.08 (p < .001). CONCLUSION: MWA could serve as a safe and effective therapy for large BTNs, significantly reducing the volume of BTNs and significantly improving compressive symptoms and appearance problems. CLINICAL RELEVANCE STATEMENT: Microwave ablation could serve as a safe and effective therapy for large benign thyroid nodules, leading to significant volume reduction and satisfied symptom and cosmetic alleviation period. KEY POINTS: • This multicenter study investigated the feasibility and safety of microwave ablation for large benign thyroid nodules. • After ablation, the nodule volume was significantly reduced, and patients' symptoms and appearance problems were significantly improved. • Microwave ablation is feasible for large benign thyroid nodules and has been a supplement treatment.

Ultrasound-guided microwave ablation versus surgery for solitary T1bN0M0 papillary thyroid carcinoma: a prospective multicenter study.

OBJECTIVE: Microwave ablation (MWA) has emerged as a minimally invasive technology for papillary thyroid microcarcinoma (PTMC), but it has not been widely applied to treat T1bN0M0 PTC with high-level evidence. This study was designed to compare the real-world efficacy and safety of MWA or surgery for treating T1bN0M0 PTC. METHODS: From December 2019 to April 2021, 123 continuous unifocal T1bN0M0 PTC patients without lymph node metastasis (LNM) or distant metastasis (DM) were included from 10 hospitals. Patients were allocated into the MWA or surgery group based on their willingness. The main outcomes were local tumour progression (LTP), new thyroid cancer, LNM, and DM. The secondary outcomes included changes in tumour size and volume, complications, and cosmetic results. Subgroup analyses were conducted to identify influencing factors. RESULTS: Fifty-two patients chose MWA, and 71 patients chose surgery. Patients had similar demographic information and tumour characteristics in the two groups. The follow-up durations after MWA and surgery were 10.6 ± 4.2 and 10.4 ± 3.4 months, respectively. The LNM rate was 5.8% in the MWA group and 1.4% in the surgery group (p = 0.177). No LTP, new thyroid cancer, or distant metastasis (DM) occurred in either group. Five (9.6%) of the 52 patients in the MWA group and 8 (11.3%) of the 71 patients in the surgery group had complications (p = 0.27). Better cosmetic results were found in the MWA group (p < 0.01). CONCLUSION: MWA achieved comparable short-term treatment efficacy with surgery. MWA might be an optional choice for surgery for low-risk T1bN0M0 PTC but concerns about LNM need to be studied further. CLINICAL RELEVANCE STATEMENT: MWA achieved comparable short-time treatment efficacy with surgery. MWA might be an optional choice for surgery for low-risk T1bN0M0 PTC. KEY POINTS: • MWA achieved comparable short-term treatment efficacy with surgery. MWA might be an optional choice for surgery for low-risk T1bN0M0 PTC but concerns about LNM need to be studied further. • The complication rate in the surgery group was higher than that in the MWA group without a significant difference. • There was no statistically significant difference in the LNM rate between the MWA and surgery groups.

Image-Guided Thermal Ablation for Hepatic Epithelioid Hemangioendothelioma: A Multicenter Experience.

PURPOSE: To investigate the feasibility, safety, and clinical outcomes of image-guided thermal ablation in patients with hepatic epithelioid hemangioendothelioma (HEHE). MATERIALS AND METHODS: This was a multicenter retrospective investigation of 18 patients (43.9 years [SD ± 14.8]; 6 men) who underwent image-guided thermal ablation for HEHE between January 2013 and February 2023. A total of 31 ablation sessions (24 involving microwave ablation and 7 involving radiofrequency ablation) were evaluated. The rates of technical success, adverse events, and outcomes were assessed. The Kaplan‒Meier method was used to estimate progression-free survival (PFS) and overall survival (OS) rates. The risk factors affecting PFS were investigated using Cox proportional hazard regression analysis. RESULTS: The technical success rate was 93.5% (29/31). No major adverse events occurred. Local tumor progression occurred after 2 sessions (6.5%, 2/31), and intrahepatic distant metastasis occurred after 16 sessions (51.6%, 16/31). During the medium follow-up time of 37.2 months (range, 3-117 months), the OS and PFS rates were 87.6% and 62.2%, respectively, at 1 year; 75.5% and 37.4%, respectively, at 3 years; and 75.5% and 37.4%, respectively, at 5 years. The median OS and PFS were 90.5 months (95% CI: 68.1-112.8) and 23.8 months (95% CI: 15.4-32.2), respectively. According to the multivariate analysis, a larger tumor size (P = .026) was associated with shorter PFS. CONCLUSIONS: Image-guided thermal ablation is a feasible and safe treatment option for patients with HEHE that resulted in local tumor control and a favorable long-term prognosis.

Pleurotus eryngii root waste and soybean meal co-fermented protein improved the growth, immunity, liver and intestinal health of largemouth bass (Micropterus salmoides).

The present study aimed to evaluate the effect of king oyster mushroom (Pleurotus eryngii) root waste and soybean meal co-fermented protein (CFP) on growth performance, feed utilization, immune status, hepatic and intestinal health of largemouth bass (Micropterus salmoides). Largemouth bass (12.33 ± 0.18 g) were divided into five groups, fed with diets containing 0 %, 5 %, 10 %, 15 % and 20 % CFP respectively for 7 weeks. The growth performance and dietary utilization were slightly improved by the supplementation of CFP. In addition, improved immunoglobulin M (IgM) content and lysozyme activity in treatments confirm the enhancement of immunity in fish by the addition of CFP, especially in fish fed 20 % CFP (P < 0.05). Furthermore, CFP significantly improved liver GSH (glutathione) content in groups D10 and D15 (P < 0.05), and slightly improved total antioxidant capacity (T-AOC), superoxide dismutase (SOD) activity while slightly reduced malondialdehyde (MDA) content. Simultaneously, the upregulation of lipolysis-related genes (PPARα, CPT1 and ACO) expression and downregulation of lipid synthesis-related genes (ACC and DGAT1) expression was recorded in the group D20 compared with the control (P < 0.05), which were consistent with the decreased liver lipid contents, suggests that lipid metabolism was improved by CFP. In terms of intestinal structural integrity, ameliorated intestinal morphology in treatments were consistent with the upregulated Occludin, Claudin-1 and ZO-1 genes expression. The intestinal pro-inflammatory cytokines (TNF-α and IL-8) expression were suppressed while the anti-inflammatory cytokines (IL-10 and TGF-ß) were activated in treatments. The expression of antimicrobial peptides (Hepcidin-1, Piscidin-2 and Piscidin-3) and intestinal immune effectors (IgM and LYZ) were slightly up-regulated in treatments. Additionally, the relative abundance of intestinal beneficial bacteria (Firmicutes) increased while the relative abundance of potential pathogenic bacteria (Fusobacterium and Proteobacteria) decreased, which indicated that the intestinal microbial community was well-reorganized by CFP. In conclusion, dietary CFP improves growth, immunity, hepatic and intestinal health of largemouth bass, these data provided a theoretical basis for the application of this novel functional protein ingredient in fish.

Early antiseizure medication withdrawal and risk of seizure recurrence in children after epilepsy surgery: A retrospective study.

OBJECTIVE: The timing of antiseizure medication (ASM) withdrawal in children after epilepsy surgery remains controversial and lacks recognized standards. Given the various negative effects of ASM on development in children, this study aimed to evaluate the safety and feasibility of early ASM withdrawal after epileptic resection surgery. METHODS: We retrospectively assessed the seizure outcomes and ASM profiles of children who had undergone epileptic resection surgery between August 2015 and August 2020 and attempted ASM reduction in the early postoperative phase. Tapering the dose of ASM was attempted when children were seizure-free with no interictal epileptiform discharges (IEDs) on electroencephalogram (EEG) for at least 6 months postoperatively. RESULTS: This study included 145 children with a median follow-up duration of 40 months. Early ASM tapering was attempted postoperatively in 99 (68.3 %) children. Postoperative ASM discontinuation was attempted in 87 (60.0 %) children. Nine (9.1 %) children experienced seizure recurrence during the ASM reduction stage, and 10 (11.5 %) experienced recurrence after ASM discontinuation. Incomplete resection (P = 0.003) and postoperative seizures before ASM tapering (P = 0.003) were independent predictors of seizure recurrence during and after early ASM withdrawal. SIGNIFICANCE: ASM withdrawal is viable and safe to be initiated in children who are seizure-free postoperatively and have no IEDs on the scalp EEG for at least 6 months. Children with incomplete resection and postoperative seizures before ASM withdrawal are at a higher risk of seizure recurrence and may need to continue ASM for a longer period.

Evaluating the performance of the language model ChatGPT in responding to common questions of people with epilepsy.

OBJECTIVE: People with epilepsy desire to acquire accurate information about epilepsy and actively engage in its management throughout the long journey of living with seizures. ChatGPT is a large language model and we aimed to assess the accuracy and consistency of ChatGPT in responding to the common concerns of people with epilepsy and to evaluate its ability to provide emotional support. METHODS: Questions were collected from the International League against Epilepsy and the China Association against Epilepsy. The responses were independently assessed by two board-certified epileptologists from the China Association against Epilepsy, and a third reviewer resolved disagreements. The reviewers assessed its ability to provide emotional support subjectively. RESULTS: A total of 378 questions related to epilepsy and 5 questions related to emotional support were included. ChatGPT provided "correct and comprehensive" answers to 68.4% of the questions. The model provided reproducible answers for 82.3% questions. The model performed poorly in answering prognostic questions, with only 46.8% of the answers rated as comprehensive. When faced with questions requiring emotional support, the model can generate natural and understandable responses. SIGNIFICANCE: ChatGPT provides accurate and reliable answers to patients with epilepsy and is a valuable source of information. It also provides partial emotional support, potentially assisting those experiencing emotional distress. However, ChatGPT may provide incorrect responses, leading users to inadvertently accept incorrect and potentially dangerous advice. Therefore, the direct use of ChatGPT for medical guidance is not recommended and its primary use at present is in patients education.

Percutaneous microwave ablation on management of hereditary renal cell carcinoma in Von Hippel-Lindau disease.

BACKGROUND: The effect of microwave ablation (MWA) for the renal cell carcinoma (RCC) in Von Hippel-Lindau (VHL) disease is unclear. OBJECTIVE: To assess the safety, Technique efficacy, renal function and oncological outcome of MWA for RCC in VHL patients. METHODS: Consecutive patients with RCCs in VHL disease treated by MWA were retrospectively collected from November 2009 to October 2020. The technical efficacy rate and complications were assessed. The outcomes of pre- and post-ablative eGFR were compared. The local recurrent-free survival (LRFS), renal-cancer-free survival (RCFS), cancer-specific survival (CSS), overall survival (OS) and complications were presented. RESULTS: A total of 10 patients (mean age, 39.0 years ± 10.7 [SD]; 3 women) with 28 RCCs (mean tumor size, 3.0 cm ± 0.34; mean tumor volume, 20.7 mL ± 43.3) treated with MWA were included. Th median follow-up time was 52 months(IQR:27-80). The overall technical efficacy rate was 100% with no major complications occurred. No significant statistical difference between pre-ablative and postablative creatinine level (102.0 µmol/L ± 30.4 vs 112.3 µmol/L ± 38.7, p = 0.06), but the pre-ablative eGFR level was significantly higher than the post-ablative eGFR (78.0 mL/(min*1.73m2) ± 28.6 vs 72 mL/(min*1.73m2) ± 31.4, p = 0.04), with the mean decrease of 5.86 ml/(min*1.73m2). The local recurrent-free survival(LRFS) and renal-cancer-free survival (RCFS) were 100% and 60%, respectively. The cancer specifical survival (CSS) and overall survival (OS) were 95.5% and 100%, respectively. CONCLUSION: Microwave ablation is a safe and feasible method for the treatment of RCC in VHL disease, preserving renal function and yielding satisfactory oncological outcomes.

Percutaneous microwave ablation versus sclerotherapy for large hepatic hemangioma: a multi-center cohort study.

OBJECTIVE: The study aimed to compare the effectiveness and safety of ultrasound-guided microwave ablation (MWA) and percutaneous sclerotherapy (PS) for the treatment of large hepatic hemangioma (LHH). METHODS: This retrospective study included 96 patients who underwent MWA (n = 54) and PS (n = 42) as first-line treatment for LHH in three tertiary hospitals from January 2016 to December 2021. Primary outcomes were technique efficacy rate (volume reduction rate [VRR] > 50% at 12 months), symptom relief rate at 12 months and local tumor progression (LTP). Secondary outcomes included procedure time, major complications, treatment sessions, cost and one-, two-, three-year VRR. RESULTS: During a median follow-up of 36 months, the MWA group showed a higher technique efficacy rate (100% vs. 90.4%, p = .018) and symptom relief rate (100% vs. 80%, p = .123) than the PS group. The MWA group had fewer treatment sessions, higher one-, two- and three-year VRR, lower LTP rate (all p < .05), longer procedure time and higher treatment costs than the PS group (both p < .001). MWA shared a comparable major complications rate (1.8% vs. 2.4%, p = .432) with PS. After multivariate analysis, the lesion's heterogeneity and maximum diameter >8.1 cm were independent risk factors for LTP (all p < .05). In the PS group, lesions with a cumulative dose of bleomycin > 0.115 mg/cm3 had a lower risk of LTP (p = .006). CONCLUSIONS: Both MWA and PS treatments for large hepatic hemangioma are safe and effective, with MWA being superior in terms of efficacy.