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INTRODUCTION: Balloon pulmonary angioplasty (BPA) is an effective intervention for patients with chronic thromboembolic pulmonary disease (CTEPD). We aimed to identify the patient group with a low success rate or high complication rate of BPA, which is still unclear. METHODS: Both CTEPD patients with or without pulmonary hypertension (CTEPH and NoPH-CTEPD) were included. CTEPH patients were divided into groups with or without pulmonary endarterectomy (PEA-CTEPH and NoPEA-CTEPH). The efficacy and safety of BPA were compared among the groups. RESULTS: There were 450, 66, and 41 sessions in the NoPEA-CTEPH, PEA-CTEPH, and NoPH-CTEPD groups, respectively. The success rate (≥1 degree improvement in flow grade) in the PEA-CTEPH group was 94.5%, significantly lower than that in the NoPEA-CTEPH (97.1%) and NoPH-CTEPD (98.4%) groups (p = 0.014). The percentage of complete flow recovery in treated vessels was also lower in PEA-CTEPH group. BPA-related complication rate in NoPEA-CTEPH, PEA-CTEPH, and NoPH-CTEPD patients was 6.1%, 6.0%, and 0.0%, respectively (p = 0.309). One BPA-related death occurred (solely in NoPEA-CTEPH). Mean pulmonary artery pressure ≥41.5 mm Hg was a predictor of BPA-related complications. NoPEA-CTEPH patients had more improvement in 6-min walk distance (6MWD, 87 ± 93 m NoPEA-CTEPH vs. 40 ± 43 m PEA-CTEPH vs. 18 ± 20 m NoPH-CTEPD, p = 0.012). CONCLUSIONS: BPA was safe and effective for all CTEPD groups with less improvement for the PEA-CTEPH and NoPH-CTEPD groups. The success rate of BPA was lower in the PEA-CTEPH group and the complication rate was lower in the NoPH-CTEPD group. Pre-BPA treatment to lower pulmonary artery pressure should not be overlooked in CTEPD patients.

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The Internet of Vehicles (IoV) counts for much in advancing intelligent transportation by connecting people, vehicles, infrastructures, and cloud servers (CS). However, the open-access wireless channels within the IoV are susceptible to malicious attacks. Therefore, an authentication key agreement protocol becomes essential to ensure secure vehicular communications and protect vehicle privacy. Nevertheless, although the vehicles in the group are compromised, they can still update the group key and obtain the communication content in the existing group key agreement protocols. Therefore, it is still challenging to guarantee post-compromise forward security (PCFS). Dynamic key rotation is a common approach to realizing PCFS, which brings a heavy computation and communication burden. To address these issues, an efficient and robust continuous group key agreement (ER-CGKA) scheme with PCFS is designed for IoV. The propose-and-commit flow is employed to support asynchronous group key updates. Besides, the computation cost and communication overhead are significantly reduced based on the TreeKEM architecture. Furthermore, we adopt the threshold mechanism to resist the collusion attacks of malicious vehicles, which enhances the ER-CGKA scheme's robustness. Security analysis indicates that the proposed scheme satisfies all the fundamental security requirements of the IoV and achieves PCFS. The performance evaluation results show that our ER-CGKA scheme demonstrates a reduction in the computation cost of 18.82% (Client) and 33.18% (CS) approximately, and an increase in communication overhead of around 55.57% since pseudonyms are utilized to achieve conditional privacy-preserving. Therefore, our ER-CGKA scheme is secure and practical.

Asunto(s)

Seguridad Computacional , Algoritmos , Internet , Tecnología Inalámbrica , Humanos , Nube Computacional

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OBJECTIVE: The aim is to assess and contrast the effectiveness and safety of employing robotic surgery versus traditional open surgery in managing cases of hilar cholangiocarcinoma. METHODS: Computer searches were conducted in PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), and Wanfang Database to identify case-control studies comparing robotic surgery with traditional open surgery in the treatment of hilar cholangiocarcinoma from inception until July 2023. References from retrieved articles were reviewed to broaden the search. This review was prospectively registered in the PROSPERO database (PROSPERO ID: CRD42024527511) and reported in line with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and AMSTAR (Assessing the methodological quality of systematic reviews) Guidelines.The primary outcome measures included operation time, intraoperative blood transfusion rate, R0 resection rate, lymph node metastasis rate, incidence of postoperative complications, and postoperative hospital stay. Data analysis was performed using RevMan 5.4 software, calculating combined odds ratios (OR), mean differences (MD), and 95% confidence intervals (95% CI). RESULTS: A total of 4 studies encompassing 267 patients diagnosed with hilar cholangiocarcinoma (177 males and 90 females, mean age of (58.8±5.7) years) were included in this analysis. Among these, 165 patients underwent open surgery, while 102 patients underwent robotic surgery. The results of the meta-analysis demonstrated comparable outcomes between the two groups. Specifically, the operation time between the robotic surgery and open surgery cohorts did not significantly differ (MD=-103.96, 95% CI: -216.90 to 8.98, P=0.070). Additionally, the intraoperative blood transfusion rate (OR=1.32, 95% CI: 0.43 to 4.07, P=0.630), R0 resection rate (OR=1.41, 95% CI: 0.71 to 2.81, P=0.330), and lymph node metastasis rate (OR=1.62, 95% CI: 0.46 to 5.63, P=0.450) showed no significant differences between the groups. Similarly, there were no statistically significant disparities observed in the incidence of postoperative complications (OR=0.60, 95% CI: 0.28 to 1.31, P=0.200) and postoperative hospital stay (MD=2.17, 95% CI: -11.56 to 15.90, P=0.760). CONCLUSION: In the treatment of hilar cholangiocarcinoma, robotic surgery demonstrates comparable safety and feasibility to traditional open surgery. However, due to the limited quantity and quality of the included studies, these conclusions warrant validation through additional high-quality investigations.

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BACKGROUND: The caudate lobe (S1) of the liver, due to its deep central position, presents a formidable challenge for laparoscopic resection. Historical skepticism about laparoscopic approaches has been overshadowed by advancements in technology and technique, with recent studies showing comparable outcomes to open surgery. METHODS: This paper introduces the "Easy First" technique and the Sextet strategies for laparoscopic hepatic caudate lobectomy. The strategies include meticulous preoperative planning, optimal trocar placement, and team positioning, tailored to the anatomical complexities of the caudate lobe. RESULTS: With a 0% conversion and mortality rate, our series demonstrates the safety of the "Easy First" technique. The Sextet strategies have been instrumental in navigating the technical challenges, emphasizing the importance of patient selection and surgeon expertise. CONCLUSION: The "Easy First" technique, with its structured approach and the Sextet strategies, offers a replicable method for laparoscopic caudate lobectomy. It underscores the need for stringent patient selection, advanced technical skill, and high-volume center expertise to ensure procedural success and patient safety.

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Hepatectomía , Laparoscopía , Humanos , Laparoscopía/métodos , Hepatectomía/métodos , Neoplasias Hepáticas/cirugía , Femenino , Selección de Paciente , Masculino , Persona de Mediana Edad , Anciano

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Hepatitis B virus (HBV) infection, as a serious global public health issue, is closely related to the immune dysfunction. Herein, thirty-seven 1-(indolin-1-yl)-2-(thiazol-4-yl)ethan-1-one derivatives were prepared as potential immunomodulatory anti-HBV agents. Anti-HBV activity evaluation confirmed compound 11a could significantly suppress the HBV DNA replication in both wild and resistant HBV stains, with IC50 values of 0.13 µM and 0.36 µM, respectively. Preliminary action mechanism studies showed that 11a had an inhibitory effect on cellular HBsAg secretion and could effectively activate TLR7, thereby inducing the secretion of TLR7-regulated cytokines IL-12, TNF-α and IFN-α in human PBMC cells. SPR analysis confirmed that 11a could bind to TLR7 protein with an affinity of 7.06 µM. MD simulation predicted that 11a could form tight interactions with residues in the binding pocket of TLR7. Physicochemical parameters perdition and pharmacokinetic analysis indicated that 11a displayed relatively favorable drug-like properties. Considering all the results, compound 11a might be a promising lead for developing novel immunomodulatory anti-HBV agents.

Asunto(s)

Antivirales , Virus de la Hepatitis B , Receptor Toll-Like 7 , Humanos , Antivirales/farmacología , Antivirales/química , Antivirales/síntesis química , Virus de la Hepatitis B/efectos de los fármacos , Receptor Toll-Like 7/metabolismo , Receptor Toll-Like 7/agonistas , Relación Estructura-Actividad , Estructura Molecular , Relación Dosis-Respuesta a Droga , Indoles/química , Indoles/farmacología , Indoles/síntesis química , Tiazoles/química , Tiazoles/farmacología , Tiazoles/síntesis química , Replicación Viral/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Animales , Células Hep G2

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BACKGROUND: Gushukang (GSK), a traditional Chinese medical prescription, has made a great and extensive contribution to the treatment of different forms of osteoporosis, but polypharmacology studies of its mechanism of action are lacking. This study investigates the pharmacological mechanism of osteoporosis using network pharmacology and molecular docking. Experimental verification was carried out to confirm the efficacy of GSK on RANKLinduced osteoclast differentiation in RAW264.7 cells to verify the network pharmacology studies. METHODS: The effective chemical components and corresponding targets of osteoporosis with oral bioavailability of more than 30% and drug-like properties greater than 0.18 were searched in the TCMSP and TCM-ID databases. DrugBank, GeneCards, OMIM, TTD, and other databases were examined for targets related to osteoporosis. Using Cytoscape software, a network of possible TCM-active ingredient-osteoporosis targets was created. STRING software was used to create the networks of protein-protein interactions. The DAVID program was carried out to conduct GO and KEGG pathway enrichment analyses of the targets. Molecular docking and pattern of action analysis were carried out using software like AutoDock Vina and Discovery Studio Visualizer. The growth media for RAW264.7 cells contained varying doses of GSK serum and 50 ng/mL RANKL. The activity of TRAP was altered. Additionally, genes related to osteoclasts were examined using an RT-PCR assay. RESULTS: Network pharmacological analysis revealed that the primary efficacy targets of osteoporosis were PTGS2, PTGS1, HSP90AA1, NCOA2, ADRB2, ESR1, NCOA1, and AR. The pharmacological targets of osteoporosis may be mediated by substances including quercetin, kaempferol, luteolin, naringenin, icariin, anthocyanin, tanshinone IIA, and cryptotanshinone. GSK markedly inhibited RANKL-induced TRAP activity. qRT-PCR results revealed decreased expression of the PTGS2 and ADRB2 genes upon GSK treatment. CONCLUSION: The findings of network pharmacology, molecular docking, as well as experimental verification provide a new further study for elucidating the pharmacodynamic substance basis and polypharmacology mechanism of GSK in treating osteoporosis.

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BACKGROUND: Inflammation and dysregulated immunity play vital roles in idiopathic pulmonary arterial hypertension (IPAH), while the mechanisms that initiate and promote these processes are unclear. METHODS: Transcriptomic data of lung tissues from IPAH patients and controls were obtained from the Gene Expression Omnibus database. Weighted gene co-expression network analysis (WGCNA), differential expression analysis, protein-protein interaction (PPI) and functional enrichment analysis were combined with a hemodynamically-related histopathological score to identify inflammation-associated hub genes in IPAH. The monocrotaline-induced rat model of pulmonary hypertension was utilized to confirm the expression pattern of these hub genes. Single-cell RNA-sequencing (scRNA-seq) data were used to identify the hub gene-expressing cell types and their intercellular interactions. RESULTS: Through an extensive bioinformatics analysis, CXCL9, CCL5, GZMA and GZMK were identified as hub genes that distinguished IPAH patients from controls. Among these genes, pulmonary expression levels of Cxcl9, Ccl5 and Gzma were elevated in monocrotaline-exposed rats. Further investigation revealed that only CCL5 and GZMA were highly expressed in T and NK cells, where CCL5 mediated T and NK cell interaction with endothelial cells, smooth muscle cells, and fibroblasts through multiple receptors. CONCLUSIONS: Our study identified a new inflammatory pathway in IPAH, where T and NK cells drove heightened inflammation predominantly via the upregulation of CCL5, providing groundwork for the development of targeted therapeutics.

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Quimiocina CCL5 , Hipertensión Pulmonar Primaria Familiar , Células Asesinas Naturales , RNA-Seq , Análisis de la Célula Individual , Linfocitos T , Animales , Humanos , Quimiocina CCL5/metabolismo , Quimiocina CCL5/genética , Células Asesinas Naturales/metabolismo , Células Asesinas Naturales/inmunología , Hipertensión Pulmonar Primaria Familiar/genética , Hipertensión Pulmonar Primaria Familiar/patología , Hipertensión Pulmonar Primaria Familiar/metabolismo , Linfocitos T/metabolismo , Linfocitos T/inmunología , Masculino , Comunicación Celular/genética , Ratas Sprague-Dawley , Pulmón/patología , Ratas , Redes Reguladoras de Genes , Monocrotalina , Mapas de Interacción de Proteínas/genética , Biología Computacional

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The mechanisms underlying the dynamic remodelling of cellular membrane phospholipids to prevent phospholipid peroxidation-induced membrane damage and evade ferroptosis, a non-apoptotic form of cell death driven by iron-dependent lipid peroxidation, remain poorly understood. Here we show that lysophosphatidylcholine acyltransferase 1 (LPCAT1) plays a critical role in ferroptosis resistance by increasing membrane phospholipid saturation via the Lands cycle, thereby reducing membrane levels of polyunsaturated fatty acids, protecting cells from phospholipid peroxidation-induced membrane damage and inhibiting ferroptosis. Furthermore, the enhanced in vivo tumour-forming capability of tumour cells is closely associated with the upregulation of LPCAT1 and emergence of a ferroptosis-resistant state. Combining LPCAT1 inhibition with a ferroptosis inducer synergistically triggers ferroptosis and suppresses tumour growth. Therefore, our results unveil a plausible role for LPCAT1 in evading ferroptosis and suggest it as a promising target for clinical intervention in human cancer.

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1-Acilglicerofosfocolina O-Aciltransferasa , Ferroptosis , Fosfolípidos , Animales , Humanos , Ratones , 1-Acilglicerofosfocolina O-Aciltransferasa/metabolismo , 1-Acilglicerofosfocolina O-Aciltransferasa/genética , Línea Celular Tumoral , Membrana Celular/metabolismo , Proliferación Celular , Peroxidación de Lípido , Ratones Desnudos , Neoplasias/patología , Neoplasias/metabolismo , Neoplasias/genética , Fosfolípidos/metabolismo

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Agricultural non-point sources, as major sources of organic pollution, continue to flow into the river network area of the Jiangnan Plain, posing a serious threat to the quality of water bodies, the ecological environment, and human health. Therefore, there is an urgent need for a method that can accurately identify various types of agricultural organic pollution to prevent the water ecosystems in the region from significant organic pollution. In this study, a network model called RA-GoogLeNet is proposed for accurately identifying agricultural organic pollution in the river network area of the Jiangnan Plain. RA-GoogLeNet uses fluorescence spectral data of agricultural non-point source water quality in Changzhou Changdang Lake Basin, based on GoogLeNet architecture, and adds an efficient channel attention (ECA) mechanism to its A-Inception module, which enables the model to automatically learn the importance of independent channel features. ResNet are used to connect each A-Reception module. The experimental results show that RA-GoogLeNet performs well in fluorescence spectral classification of water quality, with an accuracy of 96.3%, which is 1.2% higher than the baseline model, and has good recall and F1 score. This study provides powerful technical support for the traceability of agricultural organic pollution.

Asunto(s)

Agricultura , Monitoreo del Ambiente , Redes Neurales de la Computación , Ríos , Ríos/química , Monitoreo del Ambiente/métodos , China , Contaminantes Químicos del Agua/análisis , Contaminación del Agua/análisis

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Bibliometría , Humanos , Publicaciones Periódicas como Asunto/estadística & datos numéricos

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PURPOSE: Microvascular invasion (MVI) is a major unfavorable prognostic factor for intrahepatic metastasis and postoperative recurrence of hepatocellular carcinoma (HCC). However, the intervention and preoperative prediction for MVI remain clinical challenges due to the absent precise mechanism and molecular marker(s). Herein, we aimed to investigate the mechanisms underlying vascular invasion that can be applied to clinical intervention for MVI in HCC. EXPERIMENTAL DESIGN: The histopathologic characteristics of clinical MVI+/HCC specimens were analyzed using multiplex immunofluorescence staining. The liver orthotopic xenograft mouse model and mechanistic experiments on human patient-derived HCC cell lines, including coculture modeling, RNA-sequencing, and proteomic analysis, were used to investigate MVI-related genes and mechanisms. RESULTS: IQGAP3 overexpression was correlated significantly with MVI status and reduced survival in HCC. Upregulation of IQGAP3 promoted MVI+-HCC cells to adopt an infiltrative vessel co-optive growth pattern and accessed blood capillaries by inducing detachment of activated hepatic stellate cells (HSC) from the endothelium. Mechanically, IQGAP3 overexpression contributed to HCC vascular invasion via a dual mechanism, in which IQGAP3 induced HSC activation and disruption of the HSC-endothelial interaction via upregulation of multiple cytokines and enhanced the trans-endothelial migration of MVI+-HCC cells by remodeling the cytoskeleton by sustaining GTPase Rac1 activity. Importantly, systemic delivery of IQGAP3-targeting small-interfering RNA nanoparticles disrupted the infiltrative vessel co-optive growth pattern and reduced the MVI of HCC. CONCLUSIONS: Our results revealed a plausible mechanism underlying IQGAP3-mediated microvascular invasion in HCC, and provided a potential target to develop therapeutic strategies to treat HCC with MVI.

Asunto(s)

Carcinoma Hepatocelular , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas , Invasividad Neoplásica , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Humanos , Animales , Ratones , Línea Celular Tumoral , Proteínas Activadoras de ras GTPasa/genética , Proteínas Activadoras de ras GTPasa/metabolismo , Microvasos/patología , Microvasos/metabolismo , Masculino , Neovascularización Patológica/genética , Neovascularización Patológica/patología , Neovascularización Patológica/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Femenino , Proliferación Celular , Pronóstico , Células Estrelladas Hepáticas/metabolismo , Células Estrelladas Hepáticas/patología , Movimiento Celular/genética

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Aggression is an instinctive behavior that has been reported to be influenced by early-life stress. However, the potential effects of acute stress during the postweaning period, a key stage for brain development, on defensive aggression and the associated mechanism remain poorly understood. In the present study, aggressive behaviors were evaluated in adolescent mice exposed to postweaning stress. Serum corticosterone and testosterone levels, neural dendritic spine density, and gut microbiota composition were determined to identify the underlying mechanism. Behavioral analysis showed that postweaning stress reduced locomotor activity in mice and decreased defensive aggression in male mice. ELISA results showed that postweaning stress reduced serum testosterone levels in female mice. Golgi staining analysis demonstrated that postweaning stress decreased neural dendritic spine density in the medial prefrontal cortex of male mice. 16S rRNA sequencing results indicated that postweaning stress altered the composition of the gut microbiota in male mice. Combined, these results suggested that postweaning stress alters defensive aggression in male mice, which may be due to changes in neuronal structure as well as gut microbiota composition. Our findings highlight the long-lasting and sex-dependent effects of early-life experience on behaviors.

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Microbioma Gastrointestinal , Ratones , Animales , Masculino , Femenino , Microbioma Gastrointestinal/fisiología , ARN Ribosómico 16S/genética , Encéfalo , Conducta Animal , Testosterona

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Mitochondria are dynamic organelles in cellular metabolism and physiology. Mitochondrial DNA (mtDNA) mutations are associated with a broad spectrum of clinical abnormalities. However, mechanisms underlying mtDNA mutations regulate intracellular signaling related to the mitochondrial and cellular integrity are less explored. Here, we demonstrated that mt-tRNAMet 4435A>G mutation-induced nucleotide modification deficiency dysregulated the expression of nuclear genes involved in cytosolic proteins involved in oxidative phosphorylation system (OXPHOS) and impaired the assemble and integrity of OXPHOS complexes. These dysfunctions caused mitochondrial dynamic imbalance, thereby increasing fission and decreasing fusion. Excessive fission impaired the process of autophagy including initiation phase, formation, and maturation of autophagosome. Strikingly, the m.4435A>G mutation upregulated the PARKIN dependent mitophagy pathways but downregulated the ubiquitination-independent mitophagy. These alterations promoted intrinsic apoptotic process for the removal of damaged cells. Our findings provide new insights into mechanism underlying deficient tRNA posttranscription modification regulated intracellular signaling related to the mitochondrial and cellular integrity.

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Determining novel biomarkers for early identification of chronic thromboembolic pulmonary hypertension (CTEPH) could improve patient outcomes. We used the isobaric tag for relative and absolute quantitation approach to compare the serum protein profiles between CTEPH patients and the controls. Bioinformatics analyses and ELISA were also performed. We identified three proteins including heparanase (HPSE), gelsolin (GSN), and secreted protein acidic and rich in cysteine (SPARC) had significant changes in CTEPH. The receiver operating characteristic curve analysis showed that the areas under the curve of HPSE in CTEPH diagnosis were 0.988. Furthermore, HPSE was correlated with multiple parameters of right ventricular function. HPSE concentrations were significantly higher in patients with a low TAPSE/sPAP ratio (≤0.31 mm/mmHg) (65.4 [60.5,68.0] vs. 59.9 [35.9,63.2] ng/mL, p < 0.05). The CTEPH patients treated by balloon pulmonary angioplasty had significantly lower HPSE levels. The study demonstrates that HPSE may be a promising biomarker for noninvasive detection of CTEPH.

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Balloon pulmonary angioplasty (BPA) has been proven effective for addressing technically inoperable chronic thromboembolic pulmonary hypertension (CTEPH). However, the effectiveness of BPA in technically operable CTEPH patients who, for various reasons, did not undergo the procedure remains an area requiring exploration. This study sought to assess the safety and efficacy of BPA in such cases. We collected and reviewed data from CTEPH patients who underwent BPA in a consecutive manner. Following multidisciplinary team (MDT) decisions, patients were classified into two groups: technically inoperable (group A) and operable (group B). Group B comprised patients deemed technically suitable for pulmonary endarterectomy (PEA) but who did not undergo the procedure for various reasons. All patients underwent a comprehensive diagnostic work-up, including right heart categorization at baseline and the last intervention. This study compared changes in hemodynamic parameters, functional capacity, and quality of life between the two groups. In total, 161 patients underwent 414 procedures at our center, with Group A comprising 112 patients who underwent 282 BPA sessions and group B comprising 49 patients who underwent 132 BPA sessions. Significantly, both groups exhibited improvements in hemodynamics, functional capacity, and quality of life. The occurrence rate of complications, including hemoptysis and lung injury, was similar [12 (63.2%) vs. 7 (36.8%), p = 0.68]. BPA demonstrated favorable outcomes in patients with proximal CTEPH who did not undergo pulmonary endarterectomy. However, the clinical impact of BPA in technically operable CTEPH was found to be less significant than in inoperable cases.

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Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with clinical and pathological heterogeneity. Recent studies have identified cuproptosis as a novel cell death mechanism. However, the role of cuproptosis-related genes in the pathogenesis of IPF is still unclear. Two IPF datasets of the Gene Expression Omnibus database were studied. Mann-Whitney U test, correlation analysis, functional enrichment analyses, single-sample gene set enrichment analysis, CIBERSORT, unsupervised clustering, weighted gene co-expression network analysis, and receiver operating characteristic curve analysis were used to conduct our research. The dysregulated cuproptosis-related genes and immune responses were identified between IPF patients and controls. Two cuproptosis-related molecular clusters were established in IPF, the high immune score group (C1) and the low immune score group (C2). Significant heterogeneity in immunity between clusters was revealed by functional analyses results. The module genes with the strongest correlation to the 2 clusters were identified by weighted gene co-expression network analysis results. Seven hub genes were found using the Cytoscape software. Ultimately, 2 validated diagnostic biomarkers of IPF, CDKN2A and NEDD4, were obtained. Subsequently, the results were validated in GSE47460. Our investigation illustrates that CDKN2A and NEDD4 may be valid biomarkers that were useful for IPF diagnosis and copper-related clustering.

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Genes p16 , Fibrosis Pulmonar Idiopática , Humanos , Muerte Celular , Análisis por Conglomerados , Fibrosis Pulmonar Idiopática/diagnóstico , Fibrosis Pulmonar Idiopática/genética , Biomarcadores

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The bone is the most common site of distant metastasis of breast cancer, which leads to serious skeletal complications and mortality. Understanding the mechanisms underlying breast cancer bone metastasis would provide potential strategies for the prevention and treatment of breast cancer bone metastasis. In this study, we identified a circular RNA that we named circMMP2(6,7) that was significantly upregulated in bone metastatic breast cancer tissues and correlated with breast cancer-bone metastasis. Upregulation of circMMP2(6,7) dramatically enhanced the metastatic capability of breast cancer cells to the bone via inducing bone metastatic niche formation by disrupting bone homeostasis. Mechanistically, circMMP2(6,7) specifically bound to the promoters of bone-remodeling factors calcium-binding protein S100A4 and carbohydrate-binding protein LGALS3 and formed a complex with ß-catenin and arginine methyltransferase PRMT5, eliciting histone H3R2me1/H3R2me2s-induced transcriptional activation. Treatment with GSK591, a selective PRMT5 inhibitor, effectively inhibited circMMP2(6,7)/ß-catenin/PRMT5 complex-induced breast cancer bone metastasis. These findings reveal a role for circMMP2(6,7) in bone homeostasis disruption and shed light on the mechanisms driving breast cancer bone metastasis. SIGNIFICANCE: Upregulation of bone-remodeling factors S100A4 and LGALS3 mediated by a circMMP2(6,7)/ß-catenin/PRMT5 complex generates a niche that supports breast cancer bone metastasis, identifying PRMT5 as a promising target for treating metastasis.

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Neoplasias Óseas , Neoplasias de la Mama , Proteína-Arginina N-Metiltransferasas , beta Catenina , Femenino , Humanos , beta Catenina/metabolismo , Neoplasias Óseas/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Galectina 3 , Histonas/metabolismo , Homeostasis , Proteína-Arginina N-Metiltransferasas/metabolismo , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/metabolismo

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BACKGROUND: Pyroptosis plays a pivotal role in the tumor immune microenvironment (TME) dynamics, particularly in non-small cell lung cancer (NSCLC). The aim of our study was to explore its effects on tumor progression, TME patterns, and the efficacy of therapeutic interventions in NSCLC. METHODS: Our investigation encompassed a thorough analysis of pyroptosis-related genes (PRGs), integrating immunohistochemistry (IHC) data, TME characteristics, stemness indices, and anticancer drug sensitivities. We aimed to analyze mRNA expression profiles across various cancers, constructing benchmark datasets to assess the clinical significance of PRGs in NSCLC. This included evaluating their association with clinical responses and efficacy. Notably, both our and HPA IHC data demonstrated significantly elevated GSDMD-N protein levels in lung squamous cell carcinoma (LUSC) tissues. RESULTS: The expression of PRGs differed significantly between tumor and normal tissues across various cancers, as validated by IHC data, and was correlated with prognosis (p < 0.05). Moreover, our investigation revealed significant differences (p < 0.05) in the expression of the PRGs among distinct TME subtypes categorized as C1 (wound healing), C3 (inflammatory), C2 (IFN-gamma dominant), C5 (immunological quiet), C4 (lymphocyte deficient), and C6 (TGF-beta dominant). Additionally, our research on anticancer drug sensitivity uncovered compelling connections between specific anticancer medications and the expression of PRGs, including GSDMD, ELANE, IL18, and CHMP4A (p < 0.05). CONCLUSION: Our study provided valuable insights into the critical role of PRGs in TME modulation, tumor stemness, and anticancer drug sensitivity across diverse cancers. Our findings illuminate the intricate relationship between pyroptosis and the TME, offering new perspectives for enhancing NSCLC treatment and prognosis.

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Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Pronóstico , Piroptosis/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Microambiente Tumoral

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Fístula Pancreática , Cirujanos , Humanos , Fístula Pancreática/etiología , Pancreaticoduodenectomía/efectos adversos , Factores de Riesgo , Complicaciones Posoperatorias

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Restoring vegetation in degraded ecosystems is an increasingly common practice for promoting biodiversity and ecological function, but successful implementation is hampered by an incomplete understanding of the processes that limit restoration success. By synthesizing terrestrial and aquatic studies globally (2594 experimental tests from 610 articles), we reveal substantial herbivore control of vegetation under restoration. Herbivores at restoration sites reduced vegetation abundance more strongly (by 89%, on average) than those at relatively undegraded sites and suppressed, rather than fostered, plant diversity. These effects were particularly pronounced in regions with higher temperatures and lower precipitation. Excluding targeted herbivores temporarily or introducing their predators improved restoration by magnitudes similar to or greater than those achieved by managing plant competition or facilitation. Thus, managing herbivory is a promising strategy for enhancing vegetation restoration efforts.

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Biodiversidad , Restauración y Remediación Ambiental , Herbivoria , Plantas