Cardiomyocyte ßII spectrin plays a critical role in maintaining cardiac function by regulating mitochondrial respiratory function.

AIMS: ßII spectrin is a cytoskeletal protein known to be tightly linked to heart development and cardiovascular electrophysiology. However, the roles of ßII spectrin in cardiac contractile function and pathological post-myocardial infarction remodeling remain unclear. Here, we investigated whether and how ßII spectrin, the most common isoform of non-erythrocytic spectrin in cardiomyocytes, is involved in cardiac contractile function and ischemia/reperfusion (I/R) injury. METHODS AND RESULTS: We observed that the levels of serum ßII spectrin breakdown products (ßII SBDPs) were significantly increased in patients with acute myocardial infarction (AMI). Concordantly, ßII spectrin was degraded into ßII SBDPs by calpain in mouse hearts after I/R injury. Using tamoxifen-inducible cardiac-specific ßII spectrin knockout mice, we found that deletion of ßII spectrin in the adult heart resulted in spontaneous development of cardiac contractile dysfunction, cardiac hypertrophy and fibrosis at 5 weeks after tamoxifen treatment. Moreover, at 1 week after tamoxifen treatment, although spontaneous cardiac dysfunction in cardiac-specific ßII spectrin knockout mice had not developed, deletion of ßII spectrin in the heart exacerbated I/R-induced cardiomyocyte death and heart failure. Furthermore, restoration of ßII spectrin expression via adenoviral small activating RNA (saRNA) delivery into the heart reduced I/R injury. Immunoprecipitation coupled with mass spectrometry (IP-LC-MS/MS) analyses and functional studies revealed that ßII spectrin is indispensable for mitochondrial complex I activity and respiratory function. Mechanistically, ßII spectrin promotes translocation of NADH:ubiquinone oxidoreductase 75 kDa Fe-S protein 1 (NDUFS1) from the cytosol to mitochondria by crosslinking with actin filaments (F-actin) to maintain F-actin stability. CONCLUSION: ßII spectrin is an essential cytoskeletal element for preserving mitochondrial homeostasis and cardiac function. Defects in ßII spectrin exacerbate cardiac I/R injury.

Characterization of acute-on-chronic liver diseases: A multicenter prospective cohort study.

BACKGROUND: Acute-on-chronic liver disease (AoCLD) accounts for the majority of patients hospitalized in the Department of Hepatology or Infectious Diseases. AIM: To explore the characterization of AoCLD to provide theoretical guidance for the accurate diagnosis and prognosis of AoCLD. METHODS: Patients with AoCLD from the Chinese Acute-on-Chronic Liver Failure (ACLF) study cohort were included in this study. The clinical characteristics and outcomes, and the 90-d survival rate associated with each clinical type of AoCLD were analyzed, using the Kaplan-Meier method and the log-rank test. RESULTS: A total of 3375 patients with AoCLD were enrolled, including 1679 (49.7%) patients with liver cirrhosis acute decompensation (LC-AD), 850 (25.2%) patients with ACLF, 577 (17.1%) patients with chronic hepatitis acute exacerbation (CHAE), and 269 (8.0%) patients with liver cirrhosis active phase (LC-A). The most common cause of chronic liver disease (CLD) was HBV infection (71.4%). The most common precipitants of AoCLD was bacterial infection (22.8%). The 90-d mortality rates of each clinical subtype of AoCLD were 43.4% (232/535) for type-C ACLF, 36.0% (36/100) for type-B ACLF, 27.0% (58/215) for type-A ACLF, 9.0% (151/1679) for LC-AD, 3.0% (8/269) for LC-A, and 1.2% (7/577) for CHAE. CONCLUSION: HBV infection is the main cause of CLD, and bacterial infection is the main precipitant of AoCLD. The most common clinical type of AoCLD is LC-AD. Early diagnosis and timely intervention are needed to reduce the mortality of patients with LC-AD or ACLF.

Interfacial Engineering Boosting the Activity and Stability of MIL-53(Fe) toward Electrocatalytic Nitrogen Reduction.

The electrochemical nitrogen reduction reaction (eNRR) has emerged as a promising strategy for green ammonia synthesis. However, it suffers unsatisfactory reaction performance owing to the low aqueous solubility of N2 in aqueous solution, the high dissociation energy of N≡N, and the unavoidable competing hydrogen evolution reaction (HER). Herein, a MIL-53(Fe)@TiO2 catalyst is designed and synthesized for highly efficient eNRR. Relative to simple MIL-53(Fe), MIL-53(Fe)@TiO2 achieves a 2-fold enhancement in the Faradaic efficiency (FE) with an improved ammonia yield rate by 76.5% at -0.1 V versus reversible hydrogen electrode (RHE). After four cycles of electrocatalysis, MIL-53(Fe)@TiO2 can maintain a good catalytic activity, while MIL-53(Fe) exhibits a significant decrease in the NH3 yield rate and FE by 79.8 and 82.3%, respectively. Benefiting from the synergetic effect between TiO2 and MIL-53(Fe) in the composites, Fe3+ ions can be greatly stabilized in MIL-53(Fe) during the eNRR process, which greatly hinders the catalyst deactivation caused by the electrochemical reduction of Fe3+ ions. Further, the charge transfer ability in the interface of composites can be improved, and thus, the eNRR activity is significantly boosted. These findings provide a promising insight into the preparation of efficient composite electrocatalysts.

Effectiveness and economic evaluation of rhTPO and rhIL-11 in the treatment of cancer therapy induced thrombocytopenia based on real-world research.

Objective: Based on real-world research, we aimed to evaluate the effectiveness and economy of recombinant human thrombopoietin (rhTPO) and recombinant human interleukin 11 (rhIL-11) in the treatment of cancer therapy induced thrombocytopenia (CTIT). Methods: We retrospectively collected clinical data of patients with CTIT who were treated with rhTPO or rhIL-11 in a single cancer hospital from January 2020 to December 2021. Propensity score matching (PSM) was applied to eliminate confounding factors. The measurements of effectiveness analysis were the platelet compliance rate, days of medication, days of compliance, highest platelet count after medication, platelet count elevation before and after medication, and the lowest platelet count after next-cycle cancer therapy. The economic evaluation was performed according to the results of the effectiveness evaluation. At the same time, patients were stratified according to type of tumor and grade of thrombocytopenia for subgroup analysis. Results: A total of 262 patients were collected and 174 patients were enrolled after PSM, 87 in the rhTPO group and 87 in the rhIL-11 group. In all patients, there were no significant differences in the platelet compliance rate, mean days of medication, median days of compliance, median highest platelet count after medication, and the median platelet count elevation before and after medication between the two groups (p > 0.05), but the median lowest platelet count after next-cycle cancer therapy in the rhTPO group was lower than that in the rhIL-11 group (p = 0.014). The subgroup analysis showed that the rhTPO group had longer mean days of medication than the rhIL-11 group in patients with hematological malignancies (p = 0.042), and a lower median lowest platelet count after next-cycle cancer therapy in patients with grade I/II thrombocytopenia than rhIL-11 group (p = 0.022), with no significant difference in other outcome indicators (p > 0.05). As there was no statistically significant difference in platelet compliance rate between the two groups, the cost-minimization analysis showed that the rhIL-11 group had lower treatment costs than the rhTPO group. Conclusion: RhTPO and rhIL-11 showed similar effectiveness in the treatment of CTIT, but rhIL-11 was more advantageous in economic cost.

MRPS9-Mediated Regulation of the PI3K/Akt/mTOR Pathway Inhibits Neuron Apoptosis and Protects Ischemic Stroke.

Neuronal apoptosis is crucial in the pathophysiology of ischemic stroke (IS), albeit its underly24ing mechanism remaining elusive. Investigating the mechanism of neuronal apoptosis in the context of IS holds substantial clinical value for enhancing the prognosis of IS patients. Notably, the MRPS9 gene plays a pivotal role in regulating mitochondrial function and maintaining structural integrity. Utilizing bioinformatic tactics and the extant gene expression data related to IS, we conducted differential analysis and weighted correlation network analysis (WGCNA) to select important modules. Subsequent gene interaction analysis via the STRING website facilitated the identification of the key gene-mitochondrial ribosomal protein S9 (MRPS9)-that affects the progression of IS. Moreover, possible downstream signaling pathways, namely PI3K/Akt/mTOR, were elucidated via Kyoto Encyclopedia of Gene and Genomes (KEGG) and Gene Ontology (GO) pathway analysis. Experimental models were established utilizing oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro and middle cerebral artery occlusion/reperfusion (MCAO/R) in mice. Changes in gene and protein expression, as well as cell proliferation and apoptosis, were monitored through qPCR, WB, CCK8, and flow cytometry. An OGD/R cell model was further employed to investigate the role of MRPS9 in IS post transfusion of MRPS9 overexpression plasmids into cells. Further studies were conducted by transfecting overexpressed cells with PI3K/Akt/mTOR signaling pathway inhibitor LY294002 to unveil the mechanism of MRPS9 in IS. Bioinformatic analysis revealed a significant underexpression of MRPS9 in ischemic stroke patients. Correspondingly, in vitro experiments with HN cells subjected to OGD/R treatment demonstrated a marked reduction in MRPS9 expression, accompanied by a decline in cell viability, and an increase cell apoptosis. Notably, the overexpression of MRPS9 mitigated the OGD/R-induced decrease in cell viability and augmentation of apoptosis. In animal models, MRPS9 expression was significantly lower in the MCAO/R group compared to the sham surgery group. Further, the KEGG pathway analysis associated MRPS9 expression with the PI3K/Akt/mTOR signaling pathway. In cells treated with the specific PI3K/Akt/mTOR inhibitor LY294002, phosphorylation levels of Akt and mTOR were decreased, cell viability decreased, and apoptosis increased compared to the MRPS9 overexpression group. These findings collectively indicate that MRPS9 overexpression inhibits PI3K/Akt/mTOR pathway activation, thereby protecting neurons from apoptosis and impeding IS progression. However, the PI3K/Akt/mTOR inhibitor LY294002 is capable of counteracting the protective effect of MRPS9 overexpression on neuronal apoptosis and IS. Our observations underscore the potential protective role of MRPS9 in modulating neuronal apoptosis and in attenuating the pathophysiological developments associated with IS. This is achieved through the regulation of the PI3K/Akt/mTOR pathway. These insights forge new perspectives and propose novel targets for the strategic diagnosis and treatment of IS.

Boiling Histotripsy Using Dual-Frequency Protocol on Murine Breast Tumor Model and Promotes Immune Activation.

Histotripsy is an ultrasound-guided, noninvasive, nonthermal ablation therapy that can mechanically lyse target tissues. There have been no reports of enhanced histotripsy for large-volume triple-negative breast cancer (TNBC). This study aims to verify the ability of a novel approach of dual-frequency mode combined with two-stage millisecond-length ultrasound pulses (DF-TS) to accelerate the treatment of murine subcutaneous 4T1 tumors and determine immune changes after treatment. A custom-designed 1.1-/2.2-MHz two-element confocal-annular array was used to treat approximately 6-mm tumors under ultrasound guidance and real-time monitoring. Two-stage millisecond-length ultrasound pulses were used to generate approximate cuboid ablation volumes (diagonal 5-6 mm) within each tumor, with a dose of 100 pulses/point. Immune effects were characterized by changes of pro-inflammatory cytokine levels and infiltration levels of immune cells. In all targeted treatment areas, bubble cloud activity was visualized by ultrasound monitoring. The novel protocol resulted in elliptical and controllable sized lesions, reducing the number of scanning points, and was generally well tolerated. After treatment, tumor growth experienced a seven-day stagnation period, the survival period of mice was prolonged, and the levels of pro-inflammatory cytokines and immune cell infiltration increased. This study demonstrates that DF-TS boiling histotripsy (BH) has a noninvasive, efficient, and precise ablation ability for TNBC and potentially enhances immune responses.

Ultrasound image segmentation using Gamma combined with Bayesian model for focused-ultrasound-surgery lesion recognition.

This study aims to investigate the feasibility of combined segmentation for the separation of lesions from non-ablated regions, which allows surgeons to easily distinguish, measure, and evaluate the lesion area, thereby improving the quality of high-intensity focused-ultrasound (HIFU) surgery used for the non-invasive tumor treatment. Given that the flexible shape of the Gamma mixture model (GΓMM) fits the complex statistical distribution of samples, a method combining the GΓMM and Bayes framework is constructed for the classification of samples to obtain the segmentation result. An appropriate normalization range and parameters can be used to rapidly obtain a good performance of GΓMM segmentation. The performance values of the proposed method under four metrics (Dice score: 85%, Jaccard coefficient: 75%, recall: 86%, and accuracy: 96%) are better than those of conventional approaches including Otsu and Region growing. Furthermore, the statistical result of sample intensity indicates that the finding of the GΓMM is similar to that obtained by the manual method. These results indicate the stability and reliability of the GΓMM combined with the Bayes framework for the segmentation of HIFU lesions in ultrasound images. The experimental results show the possibility of combining the GΓMM with the Bayes framework to segment lesion areas and evaluate the effect of therapeutic ultrasound.

The outer membrane proteins based seroprevalence strategy for Brucella ovis natural infection in sheep.

Introduction: The diagnosis of brucellosis largely relies on tiger red plate agglutination test (RBPT). However, it is difficult to distinguish between natural infection antibody positive and vaccination antibody positive, nevertheless, the identification of specific Brucella species natural infection. Methods: Here, we analyzed the structure of main outer membrane proteins (OMPs), OMP25 and OMP31 from Brucella ovis (B. ovis) and Brucella melitensis (B. melitensis), which are the main pathogens of sheep brucellosis, and found the OMP25 and OMP31 could be used as the differential antigens for B. ovis and B. melitensis antibody. Then we expressed the OMP25 from B. ovis (OMP25o) and OMP31 from B. melitensis (OMP31m). Results: They have equally efficiency in antibody detection of vaccinated sheep serum, consistent with the RBPT results. However, through epidemiological investigations, we found some RBPT positive samples were negative by the OMP31m based serum antibody detection, but these samples gave positive results by the OMP25o. We verified these OMP31m negative but OMP25o positive samples by B. ovis and B. melitensis specific primers based PCR detection, and all these samples were B. melitensis negative. However, four out of six samples are B. ovis positive. These results showed that we could use the OMP25o and OMP31m to diagnose sheep brucellosis antibody, especially to discriminate the infection of the B. ovis. Discussion: Currently, China has not yet approved a vaccine based on B. ovis and B. ovis positive samples should be naturally infected. There should be some implicit transmission of B. ovis in Jilin province. Further epidemiological investigation should be conducted to monitor the B. ovis natural infection.

Regulation of TREM2 on BV2 inflammation through PI3K/AKT/mTOR pathway.

This work sought to determine how lipopolysaccharide (LPS)-induced pro-inflammatory factor production in BV2 microglia was influenced by myeloid cell 2 (TREM2) expressions. LPS (0.1, 1, and 10 µg/mL) induced inflammation in BV2 cells, MTT and QPCR were used to detect the occurrence of inflammation; TREM2 activation and inhibition vectors were used to activate and inhibit TREM2; Cell Proliferation was detected using CCK-8 and cell cloning experiments. LY294002 was used to inhibit the activity of PI3K/AKT signal pathway; Western blot and ELISA were used to detect cell polarization and signal pathway changes. CCK-8 and cell clone experiments found that the activation of TERM2 can promote the proliferation of BV2 cells; and the activation of TERM2 can promote the expression of IL6, IL1ß, TNFα and the expression of M2 cell phenotype molecules Arg-1 and CD206. The effect of adding LY294002 signaling pathway by TERM2 activation was inhibited, indicating that TERM2 can affect the occurrence of inflammation by regulating the activity of PI3K/AKT signaling pathway. Finally, Western blotting and ELISA showed that activation of TERM2 can promote the expression of Arg-1 and CD206 in BV2 cells, and promote the transformation of BV2 cells to M2 polarization. TERM2 can affect the inflammatory response in microglia through the PI3K/AKT signaling pathway, suggesting that TERM2 may be a target for the treatment of inflammatory response in glial cells. This study provides a treatment plan for alleviating the impact of inflammation on central nervous system.

Experimental and theoretical calculations insight into acetone adsorption by porous carbon at different pressures: Effects of pore structure and oxygen groups.

The influence of different pore size and oxygen groups for porous carbons on acetone adsorption at different pressure was studied by using experimental data and theoretical calculation, and the results were applied to prepare carbon-based adsorbents with superior adsorption capacity. First, we successfully prepared five types of porous carbons with different gradient pore structure but similar oxygen contents (4.9 ± 0.25 at.%). We found that the acetone uptake at different pressure depends on the different pore sizes. Besides, we demonstrate how to accurately decompose the acetone adsorption isotherm into multiple sub-isotherms based on different pore sizes. Based on the isotherm decomposition method, the acetone adsorption at 18 kPa is mainly in the form of pore-filling adsorption in the pore size range of 0.6-2.0 nm. When the pore size is greater than 2 nm, the acetone uptake mainly depends on the surface area. Second, porous carbons with different oxygen content, similar surface area and pore structure were prepared to study the influence of oxygen groups on acetone adsorption. The results show that the acetone adsorption capacity is determined by the pore structure at relatively high pressure, and the oxygen groups only slightly increase the adsorption capacity. However, the oxygen groups can provide more active sites, thereby enhancing acetone adsorption at low pressure.

CSF2RB overexpression promotes the protective effects of mesenchymal stromal cells against ischemic heart injury.

Aims: The invasive intramyocardial injection of mesenchymal stromal cells (MSCs) allows for limited repeat injections and shows poor therapeutic efficacy against ischemic heart failure. Intravenous injection is an alternative method because this route allows for repeated, noninvasive, and easy delivery. However, the lack of targeting of MSCs hinders the ability of these cells to accumulate in the ischemic area after intravenous injections. We investigated whether and how the overexpression of colony-stimulating factor 2 receptor beta subunit (CSF2RB) may regulate the cardiac homing of MSCs and their cardioprotective effects against ischemic heart failure. Methods and Results: Adult mice were subjected to myocardial ischemia/reperfusion (MI/R) or sham operations. We observed significantly higher CSF2 protein expression and secretion by the ischemic heart from 1 day to 2 weeks after MI/R. Mouse adipose tissue-derived MSCs (ADSCs) were infected with adenovirus harboring CSF2RB or control adenovirus. Enhanced green fluorescent protein (EGFP)-labeled ADSCs were intravenously injected into MI/R mice every three days for a total of 7 times. Compared with ADSCs infected with control adenovirus, intravenously delivered ADSCs overexpressing CSF2RB exhibited markedly increased cardiac homing. Histological analysis revealed that CSF2RB overexpression significantly enhanced the ADSC-mediated proangiogenic, antiapoptotic, and antifibrotic effects. More importantly, ADSCs overexpressing CSF2RB significantly increased the left ventricular ejection fraction and cardiac contractility/relaxation in MI/R mice. In vitro experiments demonstrated that CSF2RB overexpression increases the migratory capacity and reduces the hypoxia/reoxygenation-induced apoptosis of ADSCs. We identified STAT5 phosphorylation as the key mechanism underlying the effects of CSF2RB on promoting ADSC migration and inhibiting ADSC apoptosis. RNA sequencing followed by cause-effect analysis revealed that CSF2RB overexpression increases the expression of the ubiquitin ligase RNF4. Coimmunoprecipitation and coimmunostaining experiments showed that RNF4 binds to phosphorylated STAT5. RNF4 knockdown reduced STAT5 phosphorylation as well as the antiapoptotic and promigratory actions of ADSCs overexpressing CSF2RB. Conclusions: We demonstrate for the first time that CSF2RB overexpression optimizes the efficacy of intravenously delivered MSCs in the treatment of ischemic heart injury by increasing the response of the MSCs to a CSF2 gradient and CSF2RB-dependent STAT5/RNF4 activation.

Magnetomotive Ultrasound Shear Wave Elastography (MMUS-SWE): A Validation Study From Simulations to Experiments.

Ultrasound elastography is a functional imaging method that enables the measurement of soft tissue elasticity, which is associated with the pathological process of many diseases. However, the measurement area of the conventional elastography method is subjectively selected. Inspired by the targeted imaging technology, we propose a method of magnetomotive ultrasound shear wave elastography (MMUS-SWE). This method utilizes the magnetic force between the magnetic nanoparticles (MNPs) and the external magnetic field to generate shear waves. Then, it can detect the distribution of MNPs and the elasticity of the tissue around the MNPs. As MNPs have been widely used for targeted labeling, the strategy to induce local vibration by MNPs will be more specific than that of the conventional SWE. In this study, the theoretical feasibility was verified by the finite element simulation model. Then, an experimental system was built, and the experimental feasibility of the method was demonstrated through phantom experiments, in vitro tissue experiments, and in vivo experiments. The results show that the distribution of the MNPs and the elastic information of tissues surrounding the MNPs can be detected simultaneously. This technology is expected to realize targeted elasticity measurement based on the MNPs and has potential applications for disease diagnosis.

Combined model with acoustic radiation force impulse to rule out high-risk varices in HBV-related cirrhosis with viral suppression.

AIMS: To prospectively evaluate the performance of spleen stiffness measurement (SSM) and liver stiffness measurement (LSM) via acoustic radiation force impulse (ARFI) imaging combined with platelet counts (PLT) in ruling out HRV in HBV-related cirrhotic patients with viral suppression. METHODS: Patients with cirrhosis enrolled between June 2020-March 2022 were divided into a derivation cohort and validation cohort. LSM and SSM ARFI-based, and esophagogastroduodenoscopy (EGD) were performed at enrollment. RESULTS: In the derivation cohort, overall, 236 HBV-related cirrhotic patients with maintained viral suppression were enrolled, and the prevalence of HRV was 19.5% (46/236). With the aim of identifying HRV, the most accurate LSM and SSM cut-offs were chosen of 1.46 m/s and 2.28 m/s, respectively. The combined model (LSM<1.46 m/s and PLT>150 × 109/L strategy combined with SSM ≤ 2.28 m/s) can spare 38.6% of EGDs and 4.3% of HRV cases were misclassified. In the validation cohort, we analysed 323 HBV-related cirrhotic patients with maintained viral suppression and validated the combined model can spare 33.4% (108/323) of EGD, and the HRV missed rate was 3.4%. CONCLUSIONS: A non-invasive prediction model combining LSM<1.46 m/s and PLT>150 × 109/L strategy with SSM ≤ 2.28 m/s exhibited excellent performance in ruling out HRV and avoided a significantly large number (38.6% vs 33.4%) of unnecessary EGDs in HBV-related cirrhotic patients with viral suppression.

Structural characteristics and gel properties of pectin from citrus physiological premature fruit drop.

This study is the first to extract and characterize pectin from citrus physiological premature fruit drop. The extraction yield of pectin reached 4.4 % by acid hydrolysis method. The degree of methoxy-esterification (DM) of citrus physiological premature fruit drop pectin (CPDP) was 15.27 %, indicating it was low-methoxylated pectin (LMP). The monosaccharide composition and molar mass test results showed CPDP was a highly branched macromolecular polysaccharide (ß: 0.02, Mw: 2.006 × 105 g/mol) with rich rhamnogalacturonan I domain (50.40 %) and long arabinose and galactose side chain (32.02 %). Based on the fact that CPDP is LMP, Ca2+ was used to induce CPDP to form gels. Textural and rheological tests showed that the gel strength and storage modulus of CPDP were higher than commercial citrus pectin (CP) used in this paper due to the lower DM and rich neutral sugar side chains of CPDP. Scanning electron microscope (SEM) results showed CPDP had stable gel network structure.

Baveno VII algorithm outperformed other models in ruling out high-risk varices in individuals with HBV-related cirrhosis.

BACKGROUND & AIMS: The Baveno VII consensus recommends that spleen stiffness measurement (SSM) ≤40 kPa is safe for ruling out high-risk varices (HRVs) and avoiding endoscopic screening in patients who do not meet the Baveno VI criteria. This study aimed to validate the performance of the Baveno VII algorithm in individuals with HBV-related cirrhosis. METHODS: Consecutive individuals with HBV-related cirrhosis who underwent liver stiffness measurement (LSM) and SSM - using a 50 Hz shear wave frequency, spleen diameter measurement, and esophagogastroduodenoscopy (EGD) were prospectively enrolled from June 2020. A 100 Hz probe has been adopted for additional SSM assessment since July 2021. RESULTS: From June 2020 to January 2022, 996 patients were screened and 504 were enrolled for analysis. Among the 504 patients in whom SSM was assessed using a 50 Hz probe, the Baveno VII algorithm avoided more EGDs (56.7% vs. 39.1%, p <0.001) than Baveno VI criteria, with a comparable missed HRV rate (3.8% vs. 2.5%). Missed HRV rates were >5% for all other measures: 11.3% for LSM-longitudinal spleen diameter to platelet ratio score, 20.0% for platelet count/longitudinal spleen diameter ratio, and 8.8% for Rete Sicilia Selezione Terapia-hepatitis. SSM@100 Hz was assessed in 232 patients, and the Baveno VII algorithm with SSM@100 Hz spared more EGDs (75.4% vs. 59.5%, p <0.001) than that with SSM@50 Hz, both with a missed HRV rate of 3.0% (1/33). CONCLUSIONS: We validated the Baveno VII algorithm, demonstrating the excellent performance of SSM@50 Hz and SSM@100 Hz in ruling out HRV in individuals with HBV-related cirrhosis. Furthermore, the Baveno VII algorithm with SSM@100 Hz could safely rule out more EGDs than that with SSM@50 Hz. CLINICAL TRIAL NUMBER: NCT04890730. IMPACT AND IMPLICATIONS: The Baveno VII guideline proposed that for patients who do not meet the Baveno VI criteria, SSM ≤40 kPa could avoid further unnecessary endoscopic screening. The current study validated the Baveno VII algorithm using 50 Hz and 100 Hz probes, which both exhibited excellent performance in ruling out HRVs in individuals with HBV-related cirrhosis. Compared with the Baveno VII algorithm with SSM@50 Hz, SSM@100 Hz had a better capability to safely rule out unnecessary EGDs. Baveno VII algorithm will be a practical tool to triage individuals with cirrhosis in future clinical practice.

Advances in the study of marketed antibody-drug Conjugates (ADCs) for the treatment of breast cancer.

Breast cancer continues to have a high incidence rate among female malignancies. Despite significant advancements in treatment modalities, the heterogeneous nature of breast cancer and its resistance to various therapeutic approaches pose considerable challenges. Antibody-drug conjugates (ADCs) effectively merge the specificity of antibodies with the cytotoxicity of chemotherapeutic agents, offering a novel strategy for precision treatment of breast cancer. Notably, trastuzumab emtansine (T-DM1) has provided a new therapeutic option for HER2-positive breast cancer patients globally, especially those resistant to conventional treatments. The development of trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG) has further broadened the applicability of ADCs in breast cancer therapy, presenting new hopes for patients with low HER2 expression and triple-negative breast cancer. However, the application of ADCs presents certain challenges. For instance, their treatment may lead to adverse reactions such as interstitial lung disease, thrombocytopenia, and diarrhea. Moreover, prolonged treatment could result in ADCs resistance, complicating the therapeutic process. Economically, the high costs of ADCs might hinder their accessibility in low-income regions. This article reviews the structure, mechanism of action, and clinical trials of commercially available ADCs for breast cancer treatment, with a focus on the clinical trials of the three drugs, aiming to provide insights for clinical applications and future research.

Lipid-mRNA nanoparticles landscape for cancer therapy.

Intracellular delivery of message RNA (mRNA) technique has ushered in a hopeful era with the successive authorization of two mRNA vaccines for the Coronavirus disease-19 (COVID-19) pandemic. A wide range of clinical studies are proceeding and will be initiated in the foreseeable future to treat and prevent cancers. However, efficient and non-toxic delivery of therapeutic mRNAs maintains the key limited step for their widespread applications in human beings. mRNA delivery systems are in urgent demand to resolve this difficulty. Recently lipid nanoparticles (LNPs) vehicles have prospered as powerful mRNA delivery tools, enabling their potential applications in malignant tumors via cancer immunotherapy and CRISPR/Cas9-based gene editing technique. This review discusses formulation components of mRNA-LNPs, summarizes the latest findings of mRNA cancer therapy, highlights challenges, and offers directions for more effective nanotherapeutics for cancer patients.

Identification of an ergosterol derivative with anti-melanoma effect from the sponge-derived fungus Pestalotiopsis sp. XWS03F09.

It is difficult to treat malignant melanoma because of its high malignancy. New and effective therapies for treating malignant melanoma are urgently needed. Ergosterols are known for specific biological activities and have received widespread attention in cancer therapy. Here, LH-1, a kind of ergosterol from the secondary metabolites of the marine fungus Pestalotiopsis sp., was extracted, isolated, purified, and further investigated the biological activities against melanoma. In vitro experiments, the anti-proliferation effect on tumor cells was detected by MTT and colony formation assay, and the anti-metastatic effect on tumor cells was investigated by wound healing assay and transwell assay. Subcutaneous xenograft models, histopathology, and immunohistochemistry have been used to verify the anti-tumor, toxic, and side effect in vivo. Besides, the anti-tumor mechanism of LH-1 was studied by mRNA sequencing. In vitro, LH-1 could inhibit the proliferation and migration of melanoma cells A375 and B16-F10 in a dose-dependent manner and promote tumor cell apoptosis through the mitochondrial apoptosis pathway. In vivo assays confirmed that LH-1 could suppress melanoma growth by inducing cell apoptosis and reducing cell proliferation, and it did not have any notable toxic effects on normal tissues. LH-1 may play an anti-melanoma role by upregulating OBSCN gene expression. These findings suggest that LH-1 may be a potential for the treatment of melanoma.

Ultrasound-guidedin vivohistotripsy in rabbit kidneys using millisecond-length two-stage ultrasound pulses combined with fundamental and second harmonic superposition.

Objective.Histotripsy is a non-invasive focused ultrasound ablation method that can mechanically disintegrate tissues. This study aims to verify that ultrasound-guided histotripsy using millisecond-length two-stage ultrasound pulses combined with fundamental and second harmonic superposition can enhance treatment in rabbit kidneysin vivo. Approach.Rabbit kidneys (n = 10) were treated using a custom-designed 1.1/2.2 MHz two-element confocal-annular array, with lateral and axial full width at half-maximum pressure dimensions of approximately 1.0 and 6.0 mm. Two-stage ultrasound pulses were applied: stage 1 used 60-80 pulses with a pulse duration of 6 ms and a pulse repetition frequency of 10 Hz. Meanwhile, stage 2 consists of 2-4 periods, each period consists of a concentrated pulse train of localized high DC of 6% and an off-time of 3-5 s, with an average DC of 1%-1.5%. B-mode ultrasound imaging was used to guide and monitor the boiling and cavitation bubbles.Main results.Ultrasound-guided treatment was successful in all rabbits, and the ablation rate is about seven times that of single-frequency combined two-stage pulses, achieving enhanced histotripsy. The regular elliptical lesions with dimensions of 10.6 ± 0.8 mm × 3.9 ± 0.6 mm (axial × lateral) were generated, and a large-volume lesion was generated by multi-point treatment. The size of most lysates was about 2.5µm. Histologically, lesions were completely homogenized and well demarcated between treated-untreated areas. There was no apparent damage to critical structures surrounding lesions. Nonlinear simulations revealed that it may be the interaction between shock front and the cavitation and boiling bubbles generated by the dual-frequency effect enhanced the treatment efficiency.Significance.The novel histotripsy could improve treatment efficiency and generate regular elliptical lesions with controllable shape and axial dimensions, which may be a useful tool in treating renal cell carcinoma.

MELD score < 18 rule out 28-day ACLF development among inpatients with hepatitis B-related previous compensated liver disease.

The acute-on-chronic liver failure (ACLF) development is highly dynamic. Currently, no satisfactory algorithm identifies patients with HBV at risk of this complication. The aim of the study was to characterize ACLF development in hospitalized HBV-related patients without previous decompensation and to test the performance of traditional prognostic models in ruling out ACLF development within 28 days on admission we conducted a cohort study. Two multi-center cohorts with hospitalized HBV-related previous compensated patients were analyzed. Performances of MELD, MELD-Na, CLIF-C AD, and CLIF-C ACLF-D in ruling out ACLF development within 28 days were compared and further validated by ROC analyses. In the derivation cohort (n = 892), there were 102 patients developed ACLF within 28 days, with profound systemic inflammatory levels and higher 28-day mortality rate (31.4% vs. 1.0%) than those without ACLF development. The MELD score (cut-off = 18) achieved acceptable missing rate (missed/total ACLF development) at 2.9%. In the validation cohort (n = 1656), the MELD score (<18) was able to rule out ACLF development within 28 days with missing rate at 3.0%. ACLF development within 28 days were both lower than 1% (0.6%, derivation cohort; 0.5%, validation cohort) in patients with MELD < 18. While in patients with MELD ≥ 18, 26.6% (99/372, derivation cohort) and 17.8% (130/732, validation cohort) developed into ACLF within 28 days, respectively. While MELD-Na score cut-off at 20 and CLIF-AD score cut-off at 42 did not have consistent performance in our two cohorts. MELD < 18 was able to safely rule out patients with ACLF development within 28 days in HBV-related patients without previous decompensation, which had a high 28-day mortality.