Comprehensive analysis identifies long non-coding RNA RNASEH1-AS1 as a potential prognostic biomarker and oncogenic target in hepatocellular carcinoma.

RNASEH1-AS1, a long non-coding RNA (lncRNA) divergently transcribed from the antisense strand of its neighboring protein-coding gene ribonuclease H1 (RNASEH1), has recently been demonstrated to be involved in tumor progression. However, the association between RNASEH1-AS1 and hepatocellular carcinoma (HCC) remains unclear. In the present study, first, the expression of RNASEH1-AS1 in HCC and its correlation with clinicopathological features, prognosis, diagnosis, immune cell infiltration of HCC patients was inspected using relevant R packages based on The Cancer Genome Atlas (TCGA) data. RNASEH1-AS1 was found to be up-regulated in most cancer types, including HCC, and its overexpression was significantly associated with histologic grade and AFP level as well as poor prognosis, and was an independent risk factor affecting overall survival with good diagnostic and prognostic values for HCC. RNASEH1-AS1 was inversely associated with the infiltration of most immune cell types, including plasmacytoid dendritic cells (pDC), B cells and neutrophils. Second, a total of 1109 positively co-expressed genes (PCEGs) of RNASEH1-AS1 were screened out in HCC by correlation analysis in batches (|Spearman's r| >0.4 and adjusted P value <0.01). GO and KEGG enrichment analysis indicated that PCEGs of RNASEH1-AS1 were mainly related to RNA processing, ribosome biogenesis, transcription and histone acetylation. The top 10 hub genes (EIF4A3, WDR43, WDR12, DKC1, NAT10, UTP18, DDX18, BYSL, DDX10, PDCD11) were identified by constructing the protein-protein interaction (PPI) network, and they were all highly expressed in HCC and positively correlated with histological grade. Third, a risk model was constructed based on four RNASEH1-AS1-related hub genes (EIF4A3, WDR12, DKC1, and NAT10) with good prognostic predictive potential via univariate Cox and the least absolute selection operator (LASSO) regression analysis. Fourth, experimental validation revealed that RNASEH1-AS1 was significantly elevated in HCC tissues and several cell lines, and its knockdown could suppress the proliferation, migration, and invasion of HCC cells. Finally, mechanistic studies demonstrated that the stability of RNASEH1-AS1 could be regulated by DKC1 via their direct interaction. Taken together, RNASEH1-AS1 may serve as a potential prognostic and diagnostic biomarker and oncogenic lncRNA for HCC.

The Pro-197-Thr mutation in the ALS gene confers novel resistance patterns to ALS-inhibiting herbicides in Bromus japonicus in China.

Introduction: Bromus japonicus is one of the most notorious agricultural weeds in China. The long-term use of ALS-inhibiting herbicides has led to rapid evolution of herbicide resistance in B. japonicus. B. japonicus population (BJ-R) surviving mesosulfuron-methyl treatment was collected from wheatland. Here, we aimed to confirm the resistance mechanisms in this putative resistant population. Methods: The dose-reponse tests were used to test the resistance level of the B. japonicus to ALS-inhibiting herbicides. Pretreatment with P450 and GST inhibitors and GST activity assays were used to determine whether P450 or GST was involved in the resistance of the BJ-R population. Sanger sequencing was used to analyse the ALS mutation of the BJ-R population. RT-qPCR was used to confirm the the expression levels of the ALS gene in mesosulfuron-methyl -resistant (BJ-R) and-susceptible (BJ-S) B. japonicus. An in vitro ALS activity assay was used to determine the ALS activity of the BJ-R and BJ-S populations. Homology modelling and docking were used to determine the binding energy of the BJ-R and BJ-S populations with ALS-inhibiting herbicides. Results: B. japonicus population (BJ-R) was confirmed to be 454- and 2.7-fold resistant to the SU herbicides mesosulfuron-methyl and nicosulfuron, and 7.3-, 2.3-, 1.1- and 10.8-fold resistant to the IMI herbicide imazamox, the TP herbicide penoxsulam, the PTB herbicide pyribenzoxim and the SCT herbicide flucarbazone-sodium, respectively, compared with its susceptible counterpart (BJ-S). Neither a P450 inhibitor nor a GST inhibitor could reverse the level of resistance to mesosulfuron-methyl in BJ-R. In addition, no significant differences in GST activity were found between the BJ-R and BJ-S. ALS gene sequencing revealed a Pro-197-Thr mutation in BJ-R, and the gene expression had no significant differences between the BJ-R and BJ-S. The ALS activity of BJ-R was 106-fold more tolerant to mesosulfuron-methyl than that of BJ-S. Molecular docking showed that the binding energy of the ALS active site and mesosulfuron-methyl was changed from -6.67 to -4.57 kcal mol-1 due to the mutation at position 197. Discussion: These results suggested that the Pro-197-Thr mutation was the main reason for the high resistance level of BJ-R to mesosulfuron-methyl. Unlike previous reports of the cross-resistance pattern conferred by this mutation, we firstly documented that the Pro-197-Thr mutation confers broad cross-resistance spectrums to ALS-inhibiting herbicides in B. japonicus.

Barriers and Implications of 5G Technology Adoption for Hospitals in Western China: Integrated Interpretive Structural Modeling and Decision-Making Trial and Evaluation Laboratory Analysis.

BACKGROUND: 5G technology is gaining traction in Chinese hospitals for its potential to enhance patient care and internal management. However, various barriers hinder its implementation in clinical settings, and studies on their relevance and importance are scarce. OBJECTIVE: This study aimed to identify critical barriers hampering the effective implementation of 5G in hospitals in Western China, to identify interaction relationships and priorities of the above-identified barriers, and to assess the intensity of the relationships and cause-and-effect relations between the adoption barriers. METHODS: This paper uses the Delphi expert consultation method to determine key barriers to 5G adoption in Western China hospitals, the interpretive structural modeling to uncover interaction relationships and priorities, and the decision-making trial and evaluation laboratory method to reveal cause-and-effect relationships and their intensity levels. RESULTS: In total, 14 barriers were determined by literature review and the Delphi method. Among these, "lack of policies on ethics, rights, and responsibilities in core health care scenarios" emerged as the fundamental influencing factor in the entire system, as it was the only factor at the bottom level of the interpretive structural model. Overall, 8 barriers were classified as the "cause group," and 6 as the "effect group" by the decision-making trial and evaluation laboratory method. "High expense" and "organizational barriers within hospitals" were determined as the most significant driving barrier (the highest R-C value of 1.361) and the most critical barrier (the highest R+C value of 4.317), respectively. CONCLUSIONS: Promoting the integration of 5G in hospitals in Western China faces multiple complex and interrelated barriers. The study provides valuable quantitative evidence and a comprehensive approach for regulatory authorities, hospitals, and telecom operators, helping them develop strategic pathways for promoting widespread 5G adoption in health care. It is suggested that the stakeholders cooperate to explore and solve the problems in the 5G medical care era, aiming to achieve the coverage of 5G medical care across the country. To our best knowledge, this study is the first academic exploration systematically analyzing factors resisting 5G integration in Chinese hospitals, and it may give subsequent researchers a solid foundation for further studying the application and development of 5G in health care.

Fibrillarin promotes homologous recombination repair by facilitating the recruitment of recombinase RAD51 to DNA damage sites. / çº¤ç»´è›‹ç™½é€šè¿‡ä¿ƒè¿›é‡ç»„é ¶RAD51在DNA损伤位点的招募参与同源重组修复.

Eukaryotic organisms constantly face a wide range of internal and external factors that cause damage to their DNA. Failure to accurately and efficiently repair these DNA lesions can result in genomic instability and the development of tumors (Canela et al., 2017). Among the various forms of DNA damage, DNA double-strand breaks (DSBs) are particularly harmful. Two major pathways, non-homologous end joining (NHEJ) and homologous recombination (HR), are primarily responsible for repairing DSBs (Katsuki et al., 2020; Li and Yuan, 2021; Zhang and Gong, 2021; Xiang et al., 2023). NHEJ is an error-prone repair mechanism that simply joins the broken ends together (Blunt et al., 1995; Hartley et al., 1995). In contrast, HR is a precise repair process. It involves multiple proteins in eukaryotic cells, with the RAD51 recombinase being the key player, which is analogous to bacterial recombinase A (RecA) (Shinohara et al., 1992). The central event in HR is the formation of RAD51-single-stranded DNA (ssDNA) nucleoprotein filaments that facilitate homology search and DNA strand invasion, ultimately leading to the initiation of repair synthesis (Miné et al., 2007; Hilario et al., 2009; Ma et al., 2017).

Spleen-Derived CCL9 Recruits MDSC to Facilitate Tumor Growth in Orthotopic Hepatoma Mice.

Objectives Spleen is involved in multiple diseases, the role of the spleen and spleen-derived factors in hepatocellular carcinoma (HCC) is still not clarified. Methods In the current study, a murine H22 orthotopic hepatoma model was established. Three groups were divided: normal mice, tumor-bearing mice with spleen-preserving, and tumor-bearing mice with splenectomy. Spleen and tumor weights were recorded by weeks 1 and 2. The proportion of myeloid-derived suppressor cell (MDSC) in peripheral blood and tumor tissue was detected using flow cytometry. Protein chip assay was used to compare the differential cytokines between normal liver supernatant and tumor supernatant. The common upregulated cytokines both in spleen and tumor were focused and analyzed using gene expression profiling interactive analysis (GEPIA) database. Enzyme-linked immunosorbent assay was performed to verify the chip result, and to examine CCL9 expression before and after splenectomy. Spleen MDSC was sorted using flow cytometry, and chemotaxis assay was performed to demonstrate whether CCL9 attracted spleen MDSC. Results The spleen enlarged during tumor progression, and compared with splenectomy group, there were faster tumor growth, shorter survival time, and higher proportions of MDSC in spleen-preserving group. Protein chip assay and GEPIA database revealed CCL9 was the most promising chemokine involved in HCC upregulated both in spleen and tumor tissue. CCL9 attracted MDSC in vitro, the level of CCL9 in tumor tissue was downregulated, and the percentage of MDSC was decreased after splenectomy. Conclusion The results demonstrate that CCL9 may be derived from spleen; it facilitated HCC growth via the chemotaxis of MDSC, targeting CCL9 may be a promising strategy in HCC treatment.

DHX37 Is a Promising Prognostic Biomarker and a Therapeutic Target for Immunotherapy and Chemotherapy in HCC.

DHX37, a member of the DEAD/H-box RNA helicase family, has been implicated in various diseases, including tumors. However, the biological characteristics and prognostic significance of DHX37 in HCC remain unclear. In this study, we use R software 3.6.3 and multiple bioinformatics analysis tools, such as GDSC, HPA, STRING, TISCH, and TIMER2, to analyze the characterization and function of DHX37 in HCC. In addition, Western blot (WB) and immunohistochemistry (IHC) based on clinical samples validated some of the findings. DHX37 was more highly expressed in HCC samples compared to adjacent non-tumor tissues. Higher DHX37 expression is correlated with various clinicopathological characteristics in HCC, including AFP, adjacent hepatic tissue inflammation, histologic grade, T stage, and pathologic stage. Survival analysis revealed that the high DHX37 group had significantly shorter overall survival (OS), progress-free interval (PFI), and disease-specific survival (DSS) compared to the low DHX37 group. By analyzing the correlation between DHX37 and the IC50 of chemotherapeutic drugs, the results showed that DHX37 expression level was negatively correlated with the IC50 of 11 chemotherapeutic drugs. Further analysis indicated that DHX37 and its co-expressed genes may play important roles in activating the cell cycle, DNA repair, chemokine signaling pathways, and regulating the immune response, which leads to a poor prognosis in HCC. High expression of DHX37 is an independent risk factor for poor prognosis in HCC, and DHX37 is expected to be a potential target to inhibit tumor progression. Targeting DHX37 may enhance chemotherapeutic drug sensitivity and immunotherapeutic efficacy in HCC.

PRMT1 methylation of WTAP promotes multiple myeloma tumorigenesis by activating oxidative phosphorylation via m6A modification of NDUFS6.

Epigenetic modifications play important roles during the pathogenesis of multiple myeloma (MM). Herein, we found that protein arginine methyltransferase 1 (PRMT1) was highly expressed in MM patients, which was positively correlated with MM stages. High PRMT1 expression was correlated with adverse prognosis in MM patients. We further showed that silencing PRMT1 inhibited MM proliferation and tumorigenesis in vitro and in vivo. Mechanistically, we revealed that the knockdown of PRMT1 reduced the oxidative phosphorylation (OXPHOS) of MM cells through NDUFS6 downregulation. Meanwhile, we identified that WTAP, a key component of the m6A methyltransferase complex, was methylated by PRMT1, and NDUFS6 was identified as a bona fide m6A target of WTAP. Finally, we found that the combination of PRMT1 inhibitor and bortezomib synergistically inhibited MM progression. Collectively, our results demonstrate that PRMT1 plays a crucial role during MM tumorigenesis and suggeste that PRMT1 could be a potential therapeutic target in MM.

A Positive Feedback Loop of lncRNA HOXD-AS2 and SMYD3 Facilitates Hepatocellular Carcinoma Progression via the MEK/ERK Pathway.

Purpose: HOX cluster-embedded long noncoding RNAs (HOX-lncRNAs) have been shown to be tightly related to hepatocellular carcinoma (HCC). However, the potential biological roles and underlying molecular mechanism of HOX-lncRNAs in HCC largely remains to be elucidated. Methods: The expression signature of eighteen HOX-lncRNAs in HCC cell lines were measured by qRT-PCR. HOXD-AS2 expression and its clinical significance in HCC was investigated by bioinformatics analysis utilizing the TCGA data. Subcellular localization of HOXD-AS2 in HCC cells was observed by RNA-FISH. Loss­of­function experiments in vitro and in vivo were conducted to probe the roles of HOXD-AS2 in HCC. Potential HOXD-AS2-controlled genes and signaling pathways were revealed by RNA-seq. Rescue experiments were performed to validate that SMYD3 mediates HOXD-AS2 promoting HCC progression. The positive feedback loop of HOXD-AS2 and SMYD3 was identified by luciferase reporter assay and ChIP-qPCR. Results: HOXD-AS2 was dramatically elevated in HCC, and its up-regulation exhibited a positive association with aggressive clinical features (T stage, pathologic stage, histologic grade, AFP level, and vascular invasion) and unfavorable prognosis of HCC patients. HOXD-AS2 was distributed both in the nucleus and the cytoplasm of HCC cells. Knockdown of HOXD-AS2 restrained the proliferation, migration, invasion of HCC cells in vitro, as well as tumor growth in subcutaneous mouse model. Transcriptome analysis demonstrated that SMYD3 expression and activity of MEK/ERK pathway were impaired by silencing HOXD-AS2 in HCC cells. Rescue experiments revealed that SMYD3 as downstream target mediated oncogenic functions of HOXD-AS2 in HCC cells through altering the expression of cyclin B1, cyclin E1, MMP2 as well as the activity of MEK/ERK pathway. Additionally, HOXD-AS2 was uncovered to be positively regulated at transcriptional level by its downstream gene of SMYD3. Conclusion: HOXD-AS2, a novel oncogenic HOX-lncRNA, facilitates HCC progression by forming a positive feedback loop with SMYD3 and activating the MEK/ERK pathway.

Liquiritigenin Confers Liver Protection by Enhancing NRF2 Signaling through Both Canonical and Non-canonical Signaling Pathways.

Oxidative stress plays a critical role in drug-induced liver injury. In recent years, liquiritigenin (LQ), a natural flavonoid distributed in Glycyrrhizae Radix et Rhizoma (Gan Cao), shows protective effects against oxidative hepatotoxicity. However, the underlying mechanism remains unclear. In this study, we mainly investigated the role of NRF2, a core transcription factor in oxidative stress, in LQ-induced hepatoprotection. Our results indicated that the function of LQ to eliminate reactive oxygen species in liver cells was dependent on NRF2 activation. Both a canonical signaling pathway and a non-canonical signaling pathway are involved in LQ-induced NRF2 activation. LQ induced NRF2 activation in a KEAP1-C151-dependent manner partially. Meanwhile, LQ led to the blockage of autophagic flux and upregulation of p62, which competitively bound with KEAP1 and conferred NRF2 activation in a KEAP1-C151-independent manner. Totally, our study reveals a novel molecular mechanism underlying the hepatoprotection of LQ, providing a new insight into the pathogenesis and therapeutic strategy of oxidative liver injury.

Detoxification mechanism of herbicide in Polypogon fugax and its influence on rhizosphere enzyme activities.

The excessive use of chemical herbicides has resulted in evolution of herbicide-resistant weeds. Cytochrome P450 monooxygenases (P450s) are vital detoxification enzymes for herbicide-resistant weeds. Herein, we confirmed a resistant (R) Polypogon fugax population showing resistance to quizalofop-p-ethyl, acetolactate synthase (ALS)-inhibiting herbicide pyroxsulam, and several other ACCase (acetyl-CoA carboxylase)-inhibiting herbicides. Molecular analysis revealed no target-site gene mutations in the R population. Foliar spraying with malathion clearly reversed the quizalofop-p-ethyl phytotoxicity. Higher level of quizalofop-p-ethyl degradation was confirmed in the R population using HPLC analysis. Subsequently, RNA-Seq transcriptome analysis indicated that the overexpression of CYP89A2 gene appeared to be responsible for reducing quizalofop-p-ethyl phytotoxicity. The molecular docking results supported a metabolic effect of CYP89A2 protein on most herbicides tested. Furthermore, we found that low doses of herbicides stimulated the rhizosphere enzyme activities in P. fugax and the increase of rhizosphere dehydrogenase of R population may be related to its resistance mechanism. In summary, our research has shown that metabolic herbicide resistance mediated by CYP89A2, contributes to quizalofop-p-ethyl resistance in P. fugax.

A Glucose Metabolic Intervention Nanoplatform for Enhanced Chemodynamic Therapy and Sensitized Photothermal Therapy of Hepatocellular Carcinoma.

Traditional treatments for hepatocellular carcinoma (HCC) still lack effectiveness. Recently, the combined mode of chemodynamic therapy (CDT) and photothermal therapy (PTT) has shown great potential against HCC. However, insufficient Fenton reaction rates and hyperthermia-induced heat shock responses greatly impair their efficiency, hindering their further clinical application. Here, we constructed a cascade-amplified PTT/CDT nanoplatform by coating an IR780-embedded red blood cell membrane on glucose oxidase (GOx)-loaded Fe3O4 nanoparticles for effective HCC treatment. On the one hand, the nanoplatform interfered with glucose metabolism through the action of GOx to reduce the synthesis of ATP, which reduced the expression of heat shock proteins, thereby sensitizing the IR780-mediated PTT. On the other hand, hydrogen peroxide generated during GOx catalysis and the thermal effect of PTT accelerated the Fe3O4-mediated Fenton reaction, realizing enhanced CDT. Consequently, the sensitized PTT and enhanced CDT for HCC management could be simultaneously achieved by interfering with glucose metabolism, providing an alternative strategy for the effective treatment of tumors.

MS-Net: Learning to assess the malignant status of a lung nodule by a radiologist and her peers.

BACKGROUND: Automatically assessing the malignant status of lung nodules based on CTscan images can help reduce the workload of radiologists while improving their diagnostic accuracy. PURPOSE: Despite remarkable progress in the automatic diagnosis of pulmonary nodules by deep learning technologies, two significant problems remain outstanding. First, end-to-end deep learning solutions tend to neglect the empirical (semantic) features accumulated by radiologists and only rely on automatic features discovered by neural networks to provide the final diagnostic results, leading to questionable reliability, and interpretability. Second, inconsistent diagnosis between radiologists, a widely acknowledged phenomenon in clinical settings, is rarely examined and quantitatively explored by existing machine learning approaches. This paper solves these problems. METHODS: We propose a novel deep neural network called MS-Net, which comprises two sequential modules: A feature derivation and initial diagnosis module (FDID), followed by a diagnosis refinement module (DR). Specifically, to take advantage of accumulated empirical features and discovered automatic features, the FDID model of MS-Net first derives a range of perceptible features and provides two initial diagnoses for lung nodules; then, these results are fed to the subsequent DR module to refine the diagnoses further. In addition, to fully consider the individual and panel diagnosis opinions, we propose a new loss function called collaborative loss, which can collaboratively optimize the individual and her peers' opinions to provide a more accurate diagnosis. RESULTS: We evaluate the performance of the proposed MS-Net on the Lung Image Database Consortium image collection (LIDC-IDRI). It achieves 92.4% of accuracy, 92.9% of sensitivity, and 92.0% of specificity when panel labels are the ground truth, which is superior to other state-of-the-art diagnosis models. As a byproduct, the MS-Net can automatically derive a range of semantic features of lung nodules, increasing the interpretability of the final diagnoses. CONCLUSIONS: The proposed MS-Net can provide an automatic and accurate diagnosis of lung nodules, meeting the need for a reliable computer-aided diagnosis system in clinical practice.

Collectin-11 promotes cancer cell proliferation and tumor growth.

Collectin-11 (CL-11) is a recently described soluble C-type lectin that has distinct roles in embryonic development, host defence, autoimmunity, and fibrosis. Here we report that CL-11 also plays an important role in cancer cell proliferation and tumor growth. Melanoma growth was found to be suppressed in Colec11-/- mice in a s.c. B16 melanoma model. Cellular and molecular analyses revealed that CL-11 is essential for melanoma cell proliferation, angiogenesis, establishment of more immunosuppressive tumor microenvironment, and the reprogramming of macrophages to M2 phenotype within melanomas. In vitro analysis revealed that CL-11 can activate tyrosine kinase receptors (EGFR, HER3) and ERK, JNK, and AKT signaling pathways and has a direct stimulatory effect on murine melanoma cell proliferation. Furthermore, blockade of CL-11 (treatment with L-fucose) inhibited melanoma growth in mice. Analysis of open data sets revealed that COLEC11 gene expression is upregulated in human melanomas and that high COLEC11 expression has a trend toward poor survival. CL-11 also had direct stimulatory effects on human tumor cell proliferation in melanoma and several other types of cancer cells in vitro. Overall, our findings provide the first evidence to our knowledge that CL-11 is a key tumor growth-promoting protein and a promising therapeutic target in tumor growth.

Dynamic Changes in Serum Cytokine Profile in Rats with Severe Acute Pancreatitis.

Background and Objectives: Most published research has only investigated a single timepoint after the onset of severe acute pancreatitis (SAP), meaning that they have been unable to observe the relationship between the dynamic changes in cytokines and SAP progression. In this study, we attempted to reveal the relationship between dynamic changes in cytokine expression levels and SAP disease progression and the relationship between cytokines, using continuous large-scale cytokine detection. Materials and Methods: Seventy rats were randomly assigned to control (Con), sham operation (SO) and SAP groups. The SAP group was randomly allocated to five subgroups at 3, 6, 9, 12 and 15 h after the operation. In the SAP group, 5% sodium taurocholate was injected retrograde into the pancreatic bile duct. Animals in the SO group received a similar incision, a turning over of the pancreas. Control animals did not receive any treatment. We observed the survival, ascites fluid amount, pancreatic histopathological scores and serum amylase activity of SAP rats. We used the cytokine microarray to simultaneously detect 90 cytokines and the dynamic changes in one experiment and to analyze the correlation between cytokine expression and disease progression. Results: The mortality of SAP rats increased with an increase in time. Serum amylase activity, pancreatic histopathological scores and ascites fluid amount were time-dependent. Compared with normal rats, 69 cytokines in SAP rats were significantly changed for at least one timepoint, and 49 cytokines were significantly changed at different timepoints after SAP induction. The changes in inflammatory cytokines were significantly upregulated at 6 and 9 h and 12 h and then significantly decreased. Conclusions: The trend of cytokine expression in SAP rats was not consistent with the disease progression. The cytokine-cytokine receptor interaction and MAPK signal's dominant cytokines were always highly expressed at various time points over the course of SAP.

A novel multi-attention, multi-scale 3D deep network for coronary artery segmentation.

Automatic segmentation of coronary arteries provides vital assistance to enable accurate and efficient diagnosis and evaluation of coronary artery disease (CAD). However, the task of coronary artery segmentation (CAS) remains highly challenging due to the large-scale variations exhibited by coronary arteries, their complicated anatomical structures and morphologies, as well as the low contrast between vessels and their background. To comprehensively tackle these challenges, we propose a novel multi-attention, multi-scale 3D deep network for CAS, which we call CAS-Net. Specifically, we first propose an attention-guided feature fusion (AGFF) module to efficiently fuse adjacent hierarchical features in the encoding and decoding stages to capture more effectively latent semantic information. Then, we propose a scale-aware feature enhancement (SAFE) module, aiming to dynamically adjust the receptive fields to extract more expressive features effectively, thereby enhancing the feature representation capability of the network. Furthermore, we employ the multi-scale feature aggregation (MSFA) module to learn a more distinctive semantic representation for refining the vessel maps. In addition, considering that the limited training data annotated with a quality golden standard are also a significant factor restricting the development of CAS, we construct a new dataset containing 119 cases consisting of coronary computed tomographic angiography (CCTA) volumes and annotated coronary arteries. Extensive experiments on our self-collected dataset and three publicly available datasets demonstrate that the proposed method has good segmentation performance and generalization ability, outperforming multiple state-of-the-art algorithms on various metrics. Compared with U-Net3D, the proposed method significantly improves the Dice similarity coefficient (DSC) by at least 4% on each dataset, due to the synergistic effect among the three core modules, AGFF, SAFE, and MSFA. Our implementation is released at https://github.com/Cassie-CV/CAS-Net.

Paeonol protects against doxorubicin-induced cardiotoxicity by promoting Mfn2-mediated mitochondrial fusion through activating the PKCε-Stat3 pathway.

INTRODUCTION: The anti-cancer medication doxorubicin (Dox) is largely restricted in clinical usage due to its significant cardiotoxicity. The only medication approved by the FDA for Dox-induced cardiotoxicity is dexrazoxane, while it may reduce the sensitivity of cancer cells to chemotherapy and is restricted for use. There is an urgent need for the development of safe and effective medicines to alleviate Dox-induced cardiotoxicity. OBJECTIVES: The objective of this study was to determine whether Paeonol (Pae) has the ability to protect against Dox-induced cardiotoxicity and if so, what are the underlying mechanisms involved. METHODS: Sprague-Dawley rats and primary cardiomyocytes were used to create Dox-induced cardiotoxicity models. Pae's effects on myocardial damage, mitochondrial function, mitochondrial dynamics and signaling pathways were studied using a range of experimental methods. RESULTS: Pae enhanced Mfn2-mediated mitochondrial fusion, restored mitochondrial function and cardiac performance both in vivo and in vitro under the Dox conditions. The protective properties of Pae were blunted when Mfn2 was knocked down or knocked out in Dox-induced cardiomyocytes and hearts respectively. Mechanistically, Pae promoted Mfn2-mediated mitochondria fusion by activating the transcription factor Stat3, which bound to the Mfn2 promoter in a direct manner and up-regulated its transcriptional expression. Furthermore, molecular docking, surface plasmon resonance and co-immunoprecipitation studies showed that Pae's direct target was PKCε, which interacted with Stat3 and enabled its phosphorylation and activation. Pae-induced Stat3 phosphorylation and Mfn2-mediated mitochondrial fusion were inhibited when PKCε was knocked down. Furthermore, Pae did not interfere with Dox's antitumor efficacy in several tumor cells. CONCLUSION: Pae protects the heart against Dox-induced damage by stimulating mitochondrial fusion via the PKCε-Stat3-Mfn2 pathway, indicating that Pae might be a promising therapeutic therapy for Dox-induced cardiotoxicity while maintaining Dox's anticancer activity.

CD11b + CD43 hi Ly6C lo splenocyte-derived macrophages exacerbate liver fibrosis via spleen-liver axis.

BACKGROUND AND AIMS: Monocyte-derived macrophages (MoMFs), a dominant population of hepatic macrophages under inflammation, play a crucial role in liver fibrosis progression. The spleen serves as an extra monocyte reservoir in inflammatory conditions; however, the precise mechanisms of involvement of the spleen in the pathogenesis of liver fibrosis remain unclear. APPROACH AND RESULTS: By splenectomy and splenocyte transfusion, it was observed that splenic CD11b + cells accumulated intrahepatically as Ly6C lo MoMFs to exacerbate CCl 4 -induced liver fibrosis. The splenocyte migration into the fibrotic liver was further directly visualized by spleen-specific photoconversion with KikGR mice and confirmed by CD45.1 + /CD45.2 + spleen transplantation. Spleen-derived CD11b + cells purified from fibrotic livers were then annotated by single-cell RNA sequencing, and a subtype of CD11b + CD43 hi Ly6C lo splenic monocytes (sM-1s) was identified, which was markedly expanded in both spleens and livers of mice with liver fibrosis. sM-1s exhibited mature feature with high expressions of F4/80, produced much ROS, and manifested preferential migration into livers. Once recruited, sM-1s underwent sequential transformation to sM-2s (highly expressed Mif , Msr1 , Clec4d , and Cstb ) and then to spleen-derived macrophages (sMφs) with macrophage features of higher expressions of CX 3 CR1, F4/80, MHC class II, and CD64 in the fibrotic hepatic milieu. Furthermore, sM-2s and sMφs were demonstrated capable of activating hepatic stellate cells and thus exacerbating liver fibrosis. CONCLUSIONS: CD11b + CD43 hi Ly6C lo splenic monocytes migrate into the liver and shift to macrophages, which account for the exacerbation of liver fibrosis. These findings reveal precise mechanisms of spleen-liver axis in hepatic pathogenesis and shed light on the potential of sM-1 as candidate target for controlling liver diseases.