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RAS oncogenes (collectively NRAS, HRAS and especially KRAS) are among the most frequently mutated genes in cancer, with common driver mutations occurring at codons 12, 13 and 611. Small molecule inhibitors of the KRAS(G12C) oncoprotein have demonstrated clinical efficacy in patients with multiple cancer types and have led to regulatory approvals for the treatment of non-small cell lung cancer2,3. Nevertheless, KRASG12C mutations account for only around 15% of KRAS-mutated cancers4,5, and there are no approved KRAS inhibitors for the majority of patients with tumours containing other common KRAS mutations. Here we describe RMC-7977, a reversible, tri-complex RAS inhibitor with broad-spectrum activity for the active state of both mutant and wild-type KRAS, NRAS and HRAS variants (a RAS(ON) multi-selective inhibitor). Preclinically, RMC-7977 demonstrated potent activity against RAS-addicted tumours carrying various RAS genotypes, particularly against cancer models with KRAS codon 12 mutations (KRASG12X). Treatment with RMC-7977 led to tumour regression and was well tolerated in diverse RAS-addicted preclinical cancer models. Additionally, RMC-7977 inhibited the growth of KRASG12C cancer models that are resistant to KRAS(G12C) inhibitors owing to restoration of RAS pathway signalling. Thus, RAS(ON) multi-selective inhibitors can target multiple oncogenic and wild-type RAS isoforms and have the potential to treat a wide range of RAS-addicted cancers with high unmet clinical need. A related RAS(ON) multi-selective inhibitor, RMC-6236, is currently under clinical evaluation in patients with KRAS-mutant solid tumours (ClinicalTrials.gov identifier: NCT05379985).
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Antineoplásicos , Mutação , Neoplasias , Proteína Oncogênica p21(ras) , Proteínas Proto-Oncogênicas p21(ras) , Animais , Humanos , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Guanosina Trifosfato/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Proteína Oncogênica p21(ras)/antagonistas & inibidores , Proteína Oncogênica p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Nucleus pulposus cell (NPC) senescence is a major cause of intervertebral disc degeneration (IVDD). Oxidative stress and reactive oxygen species (ROS) play critical roles in regulating cell senescence. Selenophosphate synthetase 1 (SEPHS1) was reported to play an important role in mitigating oxidative stress in an osteoarthritis (OA) model by reducing the production of ROS, thereby, delaying the occurrence and development of osteoarthritis. In this study, we explored the, hitherto unknown, role of SEPHS1 in IVDD in vitro and in vivo using an interleukin-1ß (IL-1ß)-induced NPC senescence model and a rat needle puncture IVDD model, respectively. SEPHS1 delayed NPC senescence in vitro by reducing ROS production. Age-related dysfunction was also ameliorated by the overexpression of SEPHS1 and inhibition of the Hippo-Yap/Taz signaling pathway. In vivo experiments revealed that the overexpression of SEPHS1 and inhibition of Hippo-Yap/Taz alleviated IVDD in rats. Moreover, a selenium (Se)-deficient diet and lack of SEPHS1 synergistically aggravated IVDD progression. Taken together, our results demonstrate that SEPHS1 plays a significant role in NPC senescence. Overexpression of SEPHS1 and inhibition of Hippo-Yap/Taz can delay NPC senescence, restore the balance of extracellular matrix metabolism, and attenuate IVDD. SEPHS1 could be a promising therapeutic target for IVDD.NEW & NOTEWORTHY Selenophosphate synthetase 1 (SEPHS1) deficiency leads to an increase in reactive oxygen species levels and in the subsequent activation of the Hippo-Yap/Taz signaling pathway. In the rat model of intervertebral disc degeneration (IVDD), overexpression of SEPHS1 and inhibition of Hippo-YAP/Taz mitigated the progression of disc degeneration indicating the involvement of SEPHS1 in IVDD. SEPHS1 is a promising therapeutic target for IVDD.
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Degeneração do Disco Intervertebral , Núcleo Pulposo , Osteoartrite , Ratos , Animais , Degeneração do Disco Intervertebral/genética , Núcleo Pulposo/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Senescência Celular , Osteoartrite/metabolismoRESUMO
The poor durability of Ru-based catalysts limits the practical application in proton exchange membrane water electrolysis (PEMWE). Here, we report that the asymmetric active units in Ru1-xMxO2 (M = Sb, In, and Sn) binary solid solution oxides are constructed by introducing acid-resistant p-block metal sites, breaking the activity and stability limitations of RuO2 in acidic oxygen evolution reaction (OER). Constructing highly asymmetric Ru-O-Sb units with a strong electron delocalization effect significantly shortens the spatial distance between Ru and Sb sites, improving the bonding strength of the overall structure. The unique two-electron redox couples at Sb sites in asymmetric active units trigger additional chemical steps at different OER stages, facilitating continuous proton transfer. The optimized Ru0.8Sb0.2O2 solid solution requires a superlow overpotential of 160 mV at 10 mA cm-2 and a record-breaking stability of 1100 h in an acidic electrolyte. Notably, the scale-prepared Ru0.8Sb0.2O2 achieves efficient PEMWE performance under industrial conditions. General mechanism analysis shows that the enhanced proton transport in the asymmetric Ru-O-M unit provides a new working pathway for acidic OER, breaking the scaling relationship without sacrificing stability.
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Springtails (Collembola) stand as one of the most abundant, widespread, and ancient terrestrial arthropods on earth. However, their evolutionary history and deep phylogenetic relationships remain elusive. In this study, we employed phylogenomic approaches to elucidate the basal relationships among Collembola. We sampled whole-genome data representing all major collembolan lineages in proportion to their known diversity. To account for potential phylogenomic biases, we implemented various data extraction, locus sampling, and signal filtering strategies to generate matrices. Subsequently, we applied a diverse array of tree-searching and rate-modelling methods to reconstruct the phylogeny. Our analyses, utilizing different matrices and methods, converged on the same unrooted relationships among collembolan ingroups, supporting the current ordinal classification and challenging the monophyly of Arthropleona and Symphypleona s.l. However, discrepancies across analyses existed in the root of Collembola. Among various root positions, those based on more informative matrices and biologically realistic models, favoring a basal topology of Entomobryomorpha + (Symphypleona s.s. + (Neelipleona + Poduromorpha)), were supported by subsequent methodological assessment, topology tests, and rooting analyses. This optimal topology suggests multiple independent reduction of the pronotum in non-poduromorph orders and aligns with the plesiomorphic status of neuroendocrine organs and epicuticular structure of Entomobryomorpha. Fossil-calibrated dating analyses based on the optimal topology indicated late-Paleozoic to mid-Mesozoic origins of the crown Collembola and four orders. In addition, our results questioned the monophyly of Isotomidae and Neanuridae, underscoring the need for further attention to the systematics of these families. Overall, this study provides novel insights into the phylogenetic backbone of Collembola, which will inform future studies on the systematics, ecology, and evolution of this significant arthropod lineage.
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Diabetic cardiomyopathy (DCM) is a major complication of diabetes. Transient receptor potential melastatin 2 (TRPM2) activity increases in diabetic oxidative stress state, and it is involved in myocardial damage and repair. We explore the protective effect of TRPM2 knockdown on the progression of DCM. A type 2 diabetes animal model was established in C57BL/6N mice by long-term high-fat diet (HFD) feeding combined with a single injection of 100-mg/kg streptozotocin (STZ). Genetic knockdown of TRPM2 in heart was accomplished by the intravenous injection via the tail vein of adeno-associated virus type 9 carrying TRPM2 shRNA. Neonatal rat ventricular myocytes was exposed to 45 mM of high-glucose (HG) stimulation for 72 h in vitro to mimic the in vivo conditions. Western blot, real-time quantitative PCR (RT-qPCR), immunohistochemistry and fluorescence, electron, CCK-8, and flow cytometry were used to evaluate the phenotype of cardiac inflammation, fibrosis, apoptosis, and autophagy. Mice with HFD/STZ-induced diabetes exhibited systolic and diastolic dysfunction, as demonstrated by increased myocardial apoptosis and autophagy inhibition in the heart. Compared to control group, the protein expression of TRPM2, bax, cleaved caspase-3, and P62 was significantly elevated, and the protein expression of bcl-2 and LC3-II was significantly decreased in the myocardial tissues of the HFD/STZ-induced diabetes group. Knockdown of TRPM2 significantly reversed the HFD/STZ-induced myocardial apoptosis and autophagy inhibition. TRPM2 silencing attenuated HG-induced apoptosis and autophagy inhibition in primary cardiomyocytes via regulating the MEK/ERK mTORC1 signaling pathway. TRPM2 knockdown attenuates hyperglycemia-induced myocardial apoptosis and promotes autophagy in HFD/STZ-induced diabetic mice or HG-stimulated cardiomyocytes via regulating the MEK/ERK and mTORC1 signaling pathway.
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An effective and stereoselective synthesis of halogenated (E)-4-methylenechromanes with a sulfonyl group was developed via the copper-catalyzed sulfonylative annulation/halogenation of 1,7-enynes, in which sodium sulfinates were used as the sulfonyl reagents and tetrabutylammonium halide provided the halogen sources. The formed alkenyl C-X bonds were valuable and can efficiently undergo the subsequent hydrolysis, alkenylation, alkynylation, arylation, alkylthiolation, and alkoxylation to furnish a series of highly functionalized 4-methylenechromanes.
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OBJECTIVES: To investigate whether the interplay of anti-galectin-3 antibodies (anti-Gal3 Abs) with neutrophils contributes to the development of lupus cutaneous vasculitis. METHODS: Enzyme-linked immunosorbent assay was used to determine the serum level of anti-Gal3 Abs in lupus patients. Flow cytometry, quantitative PCR and western blot were performed to investigate the expression of cell surface receptors, proinflammatory cytokines and signalling molecules in neutrophils stimulated by serum from lupus patients or healthy controls (HCs) or anti-Gal3 Ab, respectively. Immunofluorescence was performed to visualise the formation of neutrophil extracellular traps (NETs). Human umbilical vein endothelial cells were co-cultured with the supernatants from neutrophils stimulated by anti-Gal3 Ab, and cytokine production was measured at mRNA and protein levels. Immunohistochemistry was adopted to reveal the distribution of Gal3, cytokines and myeloperoxidase within lupus skin lesions. REULTS: Serum levels of anti-Gal3 Abs were negatively correlated with peripheral counts of neutrophils. Anti-Gal3 Abs positive sera from SLE patients accelerated neutrophil death, altered cell phenotype and promoted formation of NETs with the involvement of p38 MAPK pathway. Supernatants collected from neutrophils co-cultured with anti-Gal3 Ab provoked endothelial cells to produce cytokines such as IL-1, ICAM-1, SELE and particularly IL-6. Consistently, IL-6 was higher in SLE patients with anti-Gal3 Ab positive sera and enriched in the area of vascular inflammation together with enhanced expression of Gal3 protein and infiltration of neutrophils. CONCLUSIONS: Overall, these findings suggested that neutrophils were crucial mediators in anti-Gal3 Ab induced lupus cutaneous vasculitis.
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In the synthetic laboratory, researchers typically rely on nuclear magnetic resonance (NMR) spectra to elucidate structures of synthesized products and confirm whether they match the desired target compounds. As chemical synthesis technology evolves toward intelligence and continuity, efficient computer-assisted structure elucidation (CASE) techniques are required to replace time-consuming manual analysis and provide the necessary speed. However, current CASE methods typically aim to derive precise chemical structures from spectroscopic data, yet they suffer from drawbacks such as low accuracy, high computational cost, and reliance on chemical libraries. In meticulously designed chemical synthesis reactions, researchers prioritize confirming the attainment of the target product based on NMR spectra, rather than focusing on identifying the specific product obtained. For this purpose, we innovatively developed a binary classification model, termed as MatCS, to directly predict the relationship between NMR spectra image (including 1H NMR and 13C NMR) and the molecular structure of the target compound. After evaluating various feature extraction methods, MatCS employs a combination of the Graph Attention Networks and Graph Convolutional Networks to learn the structural features of molecular graphs and the pretrained ResNet101 network with a Convolutional Block Attention Module to extract features from NMR spectra images. The results show that on a challenging Testsim data set, which poses difficulty in distinguishing spectra of similar molecular structures, MatCS achieves comprehensive evaluation metrics with an F1-score of 0.81 and an AUC value of 0.87. Simultaneously, it exhibited commendable performance on an external SDBS data set containing experimental NMR spectra, showcasing substantial potential for structural verification tasks in real automated chemical synthesis.
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Aprendizado Profundo , Espectroscopia de Ressonância Magnética , Espectroscopia de Ressonância Magnética/métodosRESUMO
AIMS: Catheter ablation of ventricular tachycardia (VT) improves VT-free survival in 'classic' arrhythmogenic right ventricular cardiomyopathy (ARVC). This study aims to investigate electrophysiological features and ablation outcomes in patients with ARVC and biventricular (BiV) involvement. METHODS AND RESULTS: We assembled a retrospective cohort of definite ARVC cases with sustained VTs. Patients were divided into the BiV (BiV involvement) group and the right ventricular (RV) (isolated RV involvement) group based on the left ventricular systolic function detected by cardiac magnetic resonance. All patients underwent electrophysiological mapping and VT ablation. Acute complete success was non-inducibility of any sustained VT, and the primary endpoint was VT recurrence. Ninety-eight patients (36 ± 14 years; 87% male) were enrolled, including 50 in the BiV group and 48 in the RV group. Biventricular involvement was associated with faster clinical VTs, a higher VT inducibility, and more extensive arrhythmogenic substrates (all P < 0.05). Left-sided VTs were observed in 20% of the BiV group cases and correlated with significantly reduced left ventricular systolic function. Catheter ablation achieved similar acute efficacy between these two groups, whereas the presence of left-sided VTs increased acute ablation failure (40 vs. 5%, P = 0.012). Over 51 ± 34 months [median, 48 (22-83) months] of follow-up, cumulative VT-free survival was 52% in the BiV group and 58% in the RV group (P = 0.353). A multivariate analysis showed that younger age, lower RV ejection fraction (RVEF), and non-acute complete ablation success were associated with VT recurrence in the BiV group. CONCLUSION: Biventricular involvement implied a worse arrhythmic phenotype and increased the risk of left-sided VTs, while catheter ablation maintained its efficacy for VT control in this population. Younger age, lower RVEF, and non-acute complete success predicted VT recurrence after ablation.
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Displasia Arritmogênica Ventricular Direita , Ablação por Cateter , Taquicardia Ventricular , Humanos , Masculino , Feminino , Displasia Arritmogênica Ventricular Direita/complicações , Displasia Arritmogênica Ventricular Direita/diagnóstico , Displasia Arritmogênica Ventricular Direita/cirurgia , Estudos Retrospectivos , Resultado do Tratamento , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/cirurgia , Ablação por Cateter/métodosRESUMO
BACKGROUND: Management of inferior ramus of the pubis-ischium ramus remains controversial, and related research is sparse. The main intention of this study is to describe the biomechanical and clinical outcomes of pubis-ischium ramus fractures in Tile B pelvic injuries and to identify the feasibility and necessity of fixation of the inferior ramus of the pubis-ischium ramus. METHODS: This study comprised two parts: a biomechanical test and a retrospective clinical study. For the biomechanical tests, Tile B-type pelvic injuries were modeled in six cadaver specimens by performing pubis-ischium osteotomies and disruption of the anterior and interosseous sacroiliac ligaments. The superior and/or inferior rami of the pubis-ischium ramus were repaired with reconstruction plates and separated into three groups (A, B, and C). Specimens were placed in the standing position and were loaded axially with two-leg support for three cycles at 500 N. The displacements of sacroiliac joints at osteotomy were measured with Vernier calipers and compared using statistical software. To investigate the clinical outcomes of this technique, 26 patients were retrospectively analyzed and divided into a superior ramus fixation group (Group D) and a combined superior and inferior ramus of the pubis-ischium ramus fixation group (Group E). The main outcome measures were time of operation, blood loss, postoperative radiographic reduction grading, and functional outcomes. RESULTS: In the vertical loading test, Group E showed better pelvic ring stability than Group D (P < 0.05). However, the shift of the sacroiliac joints was almost identical among the three groups. In our clinical case series, all fractures in Group E achieved bony union. Group E demonstrated earlier weight-bearing functional exercise (2.54 ± 1.45 vs 4.77 ± 2.09; P = 0.004), earlier bony union (13.23 ± 2.89 vs 16.55 ± 3.11; P = 0.013), and better functional outcomes (89.77 ± 7.27 vs 82.38 ± 8.81; P = 0.028) than Group D. The incidence of sexual dysfunction was significantly lower in Group E than that in Group D (2/13 vs 7/13; P = 0.039). Bone nonunion occurred in two patients in Group D, and two patients in Group E had heterotopic ossification. None of the patients exhibited wound complications, infections, implant failures, or bone-implant interface failures. CONCLUSIONS: Fixation of the inferior ramus of a pubis-ischium ramus fracture based on conventional fixation of the anterior pelvic ring is mechanically superior in cadaveric Tile B pelvic injury and shows rapid recovery, good functional outcomes, and low incidence of complications.
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Placas Ósseas , Ossos Pélvicos , Humanos , Fenômenos Biomecânicos , Masculino , Feminino , Adulto , Ossos Pélvicos/cirurgia , Ossos Pélvicos/lesões , Ossos Pélvicos/diagnóstico por imagem , Pessoa de Meia-Idade , Fenômenos Mecânicos , Cadáver , Fraturas Ósseas/cirurgia , Estudos Retrospectivos , Fixação Interna de Fraturas/instrumentaçãoRESUMO
Constructed wetlands (CWs) have been widely used to ensure effective domestic wastewater treatment. Microorganisms-derived CWs have received extensive attention as they play a crucial role. However, research on the succession patterns of microbial communities and the influencing mechanisms of internal environmental factors throughout entire CW operations remains limited. In this context, three parallel-operated CWs were established in this study to assess the microbial communities and their influencing environmental factors at different substrate depths throughout the operation process using 16S rRNA gene high-throughput sequencing and metagenomic sequencing. The results showed gradual reproduction and accumulation of the microbial communities throughout the CW operation. Although gradual increases in the richness and diversity of the microbial communities were found, there were decreases in the functional expression of the dominant microbial species. The excessive accumulation of microorganisms will decrease the oxidation-reduction potential (ORP) within CWs and attenuate their influence on effluent. Dissolved oxygen (DO) was the major factor influencing the microbial community succession over the CW operation. The main identified functional bacterial genera responsible for the ammonium oxidation, nitrification, and denitrification processes in the CWs were Nitrosospira, Nitrobacter, Nitrospira, Rhodanobacter, and Nakamurella. The narG gene was identified as a key functional gene linking various components of nitrogen cycling, while pH, electrical conductivity (EC), and ORP were the major environmental factors affecting the metabolism characteristics of nitrogen functional microorganisms. This study provides a theoretical basis for the effective regulation of related microbial communities to achieve long-term, efficient, and stable CW operations.
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Collaborative management of environmental pollution and carbon emissions (CMPC) has been a major policy instrument to promote Sustainable Development Goals (SDG) in recent years. However, the relationship between the benefits and drawbacks of this environmental management practice for green growth in and around a local area remains to be clarified. Using 30 provinces in China during 2001-2019 as the object of analysis, we assessed the efficiency of local CMPC practices using the nonradial directional distance function (NDDF) model, predicted local green growth using the frontier green complexity index (GCI), and empirically examined the spatial effects, locational heterogeneity, and threshold characteristics of the relationship using the spatial Durbin model and the panel threshold model. Our study finds that although efficient CMPC does drive local green growth, the promotion effect is nonlinear with decreasing marginal effect. This effect is particularly obvious in economically developed regions with higher CMPCs, which will absorb resources from neighboring regions and create a "siphoning" effect. It was found that local financial support and foreign direct investment (FDI) can radiate green growth to neighboring regions; therefore, CMPC practice needs to pay more attention to the effect of joint governance, supplemented by financial and foreign investment policy tools, to better promote the green transformation of local economy.
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BACKGROUND: In China, enhancing the pooling levels of basic health insurance has consistently been regarded as a pivotal measure to promote the refinement of the healthcare insurance system. From 2020 to 2022, the widespread outbreak of COVID-19 posed new challenges to China's basic health insurance. METHODS: The research utilizes Data Envelopment Analysis (DEA), Malmquist index assessment, and fixed-effects panel Tobit models to analyze panel data from 2020 to 2022, assessing the efficiency of basic health insurance in Gansu Province. RESULTS: From 2020 to 2022, the average overall efficiency of the municipal pooling of Basic Medical Insurance for Urban and Rural Residents was 0.941, demonstrating a stable trend with a modest increase. The efficiency frontier regions have expanded from 5 (35.71%) to 7 (50%). Operational efficiency exhibited a negative correlation with per capita hospitalization expenses and per capita fund balance but a positive correlation with per capita accumulated fund balance and reimbursement rates for hospitalized patients. In 2021, compared to 2020, the county-pooling Basic Medical Insurance for Urban Employees saw a decline of 0.126 in overall efficiency, reducing the efficiency frontier regions from 8 to 3. However, from 2021 to 2022, the municipal-coordinated Basic Medical Insurance for Urban Employees experienced a 0.069 increase in overall efficiency, with the efficiency frontier regions expanding from 3 to 5. Throughout 2020 to 2022, the operational efficiency of the Urban Employee Basic Medical Insurance showed a consistent negative correlation with per capita fund balance. CONCLUSION: From 2020 to 2022, the overall operational performance of basic health insurance in Gansu Province was satisfactory, and enhancing the pooling level is beneficial in addressing the impact of unforeseen events on the health insurance system.
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COVID-19 , Seguro Saúde , China , Humanos , Seguro Saúde/estatística & dados numéricos , COVID-19/epidemiologia , Eficiência Organizacional , População Rural/estatística & dados numéricosRESUMO
BACKGROUND: Additional resection for invasive cancer at perihilar cholangiocarcinoma (pCCA) resection margins has become a consensus. However, controversy still exists regarding whether additional resection is necessary for residual biliary intraepithelial neoplasia (BilIN). METHOD: Consecutive patients with pCCA from two hospitals were enrolled. The incidence and pattern of resection margin BilIN were summarized. Prognosis between patients with negative margins (R0) and BilIN margins were analyzed. Cox regression with a forest plot was used to identify independent risk factors associated with overall survival (OS) and recurrence-free survival (RFS). Subgroup analysis was performed based on BilIN features and tumor characteristics. RESULTS: 306 pCCA patients receiving curative resection were included. 255 had R0 margins and 51 had BilIN margins. There was no significant difference in OS (P = 0.264) or RFS (P = 0.149) between the two group. Specifically, 19 patients with BilIN at distal bile ducts and 32 at proximal bile ducts. 42 patients showed low-grade BilIN, and 9 showed high-grade. Further analysis revealed no significant difference in long-term survival between different locations (P = 0.354), or between different grades (P = 0.772). Portal vein invasion, poor differentiation and lymph node metastasis were considered independent risk factors for OS and RFS, while BilIN was not. Subgroup analysis showed no significant difference in long-term survival between the lymph node metastasis subgroup, or between the portal vein invasion subgroup. CONCLUSION: For pCCA patients underwent curative resection, residual BilIN at resection margin is acceptable. Additional resection is not necessary for such patients to achieve absolute R0 margin.
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Neoplasias dos Ductos Biliares , Tumor de Klatskin , Margens de Excisão , Humanos , Masculino , Feminino , Neoplasias dos Ductos Biliares/cirurgia , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/mortalidade , Estudos Retrospectivos , Tumor de Klatskin/cirurgia , Tumor de Klatskin/patologia , Tumor de Klatskin/mortalidade , Pessoa de Meia-Idade , Idoso , Prognóstico , Seguimentos , Taxa de Sobrevida , Carcinoma in Situ/cirurgia , Carcinoma in Situ/patologia , Neoplasia Residual/patologia , Neoplasia Residual/cirurgia , Adulto , Transformação Celular Neoplásica/patologia , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Recidiva Local de Neoplasia/epidemiologia , Hepatectomia/métodos , Hepatectomia/mortalidade , Idoso de 80 Anos ou maisRESUMO
This study explores the role of endogenous indole-3-acetic acid (IAA) in modulating plant responses to pollution stress and its effect on pollutant accumulation, with a focus on fluoranthene (Flu) in ryegrass. To elucidate the mechanism, we employed an IAA promoter (α-aminobutyric acid [α-AB]) and an IAA inhibitor (naphthylphthalamic acid [NPA]) to regulate IAA levels and analyze Flu uptake characteristics. The experimental setup included a Flu treatment group (ryegrass with Flu addition) and a control group (ryegrass without Flu). Our findings demonstrate that Flu treatment enhanced IAA content and plant growth in ryegrass compared to the control. The Flu+AB treatment further enhanced these effects, while the Flu+NPA treatment exhibited a contrasting trend. Moreover, Flu+AB treatment led to increased Flu accumulation, in contrast to the inhibitory effect observed with Flu+NPA treatment. Flu treatment also enhanced the activities of key antioxidant enzymes (SOD, POD, CAT) and increased soluble sugar and protein levels, indicative of enzymatic and nonenzymatic defense responses, respectively. The Flu+AB treatment amplified these responses, whereas the Flu+NPA treatment attenuated them. Significantly, Flu treatment raised H+-ATPase activity compared to the control, an effect further elevated by Flu+AB treatment and diminished by Flu+NPA treatment. A random forest analysis suggested that Flu accumulation dependency varied under different treatments: it relied more on H+-ATPase activity under Flu+AB treatment and more on SOD activity under Flu+NPA treatment. Additionally, Flu+AB treatment boosted the transpiration rate in ryegrass, thereby increasing the Flu translocation factor, a trend reversed by Flu+NPA treatment. This research highlights crucial factors influencing Flu accumulation in ryegrass, offering potential new avenues for controlling the gathering of contaminants within plant systems.
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Fluorenos , Ácidos Indolacéticos , Lolium , Superóxido Dismutase , Fluorenos/toxicidade , Lolium/efeitos dos fármacos , Lolium/crescimento & desenvolvimento , Ácidos Indolacéticos/metabolismo , Superóxido Dismutase/metabolismo , Poluentes do Solo/toxicidade , Reguladores de Crescimento de Plantas , Antioxidantes/metabolismoRESUMO
Continuous discharge of wastewater, emissions, and solid wastes from steelworks poses environmental risks to ecosystems. However, the role of keystone taxa in maintaining multifunctional stability during environmental disturbances remains poorly understood. To address this, we investigated the community diversity, assembly mechanisms, and soil multifunctionality of soils collected from within the steelworks (I), within 2.5 km radius from the steelworks (E), and from an undisturbed area (CK) in Jiangsu Province, China, via 16 S rRNA sequencing. Significant differences were found in the Chao1 and the richness indexes of the total taxa (p < 0.05), while the diversity of keystone taxa was not significant at each site (p > 0.05). The deterministic processes for total taxa were 42.9%, 61.9% and 47.7% in CK, E, and I, respectively. Steelworks stress increased the deterministicity of keystone taxa from 52.3% in CK to 61.9% in E and I soils. The average multifunctionality indices were 0.518, 0.506 and 0.513 for CK, E and I, respectively. Although the soil multifunctionality was positive correlated with α diversity of both the total and keystone taxa, the average degree of keystone taxa in functional network increased significantly (79.96 and 65.58, respectively), while the average degree of total taxa decreased (44.59 and 51.25, respectively) in the E and I. This suggests keystone taxa contribute to promoting the stability of ecosystems. With increasing disturbance, keystone taxa shift their function from basic metabolism (ribosome biogenesis) to detoxification (xenobiotics biodegradation, metabolism, and benzoate degradation). Here we show that keystone taxa are the most important factor in maintaining stable microbial communities and functions, providing new insights for mitigating pollution stress and soil health protection.
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Microbiota , Solo , Microbiologia do Solo , Bactérias/genética , Poluição AmbientalRESUMO
In this study, a hybrid model, the convolutional neural network-support vector regression model, was adopted to achieve prediction of the NO2 profile in Nanjing from January 2019 to March 2021. Given the sudden decline in NO2 in February 2020, the contribution of the Coronavirus Disease-19 (COVID-19) lockdown, Chinese New Year (CNY), and meteorological conditions to the reduction of NO2 was evaluated. NO2 vertical column densities (VCDs) from January to March 2020 decreased by 59.05% and 32.81%, relative to the same period in 2019 and 2021, respectively. During the period of 2020 COVID-19, the average NO2 VCDs were 50.50% and 29.96% lower than those during the pre-lockdown and post-lockdown periods, respectively. The NO2 volume mixing ratios (VMRs) during the 2020 COVID-19 lockdown significantly decreased below 400 m. The NO2 VMRs under the different wind fields were significantly lower during the lockdown period than during the pre-lockdown period. This phenomenon could be attributed to the 2020 COVID-19 lockdown. The NO2 VMRs before and after the CNY were significantly lower in 2020 than in 2019 and 2021 in the same period, which further proves that the decrease in NO2 in February 2020 was attributed to the COVID-19 lockdown. Pollution source analysis of an NO2 pollution episode during the lockdown period showed that the polluted air mass in the Beijing-Tianjin-Hebei was transported southwards under the action of the north wind, and the subsequent unfavorable meteorological conditions (local wind speed of < 2.0 m/sec) resulted in the accumulation of pollutants.
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Poluentes Atmosféricos , Poluição do Ar , COVID-19 , Humanos , COVID-19/epidemiologia , Poluentes Atmosféricos/análise , Dióxido de Nitrogênio/análise , Monitoramento Ambiental , Controle de Doenças Transmissíveis , Poluição do Ar/análise , China/epidemiologia , Material Particulado/análiseRESUMO
Due to the stability issue, It is difficult to prepare a silver nanocluster bearing functional sites, especially at a large scale. We report the synthesis and structure of a stable silver nanocluster bearing multiple surface aldehyde groups [Ag21(Ph2PO2)10(p-CHOPhC≡C)6]SbF6, which allows for postsynthesis modification such as surface functionalization through aldimine condensation to give homochiral clusters. Remarkably, the preparation of this cluster can be done in ~90% high yield at gram scale, which facilitates further studies and potential applications. Through DFT calculations and geometric structure analysis, the high stability of this cluster is attributed to the geometric closure and electronic structure. This is the first time that an effective one-pot method has been developed to synthesize functional silver nanoclusters in high yield. The title cluster will be useful in the development of a variety of cluster-based materials.
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OBJECTIVES: Melanoma is highly malignant and heterogeneous. It is essential to develop a specific prognostic model for improving the patients' survival and treatment strategies. Recent studies have shown that ferroptosis results from the overproduction of lipid peroxidation and is an iron-dependent form of programmed cell death. Despite this, ferroptosis-related genes (FRGs) and their clinical significances remain unknown in malignant melanoma. This study aims to assess the role of FRGs in melanoma, with the goal of developing a novel prognostic model that provides new insights into personalized treatment and improvement of therapeutic outcomes for melanoma. METHODS: We systematically characterized the genetic alterations and mRNA expression of 73 FRGs in The Cancer Genome Atlas (TCGA)-skin cutaneous melanoma (SKCM) dataset in this study. The results were validated with real-time RT-PCR and Western blotting. Subsequently, a multi-gene feature model was constructed using the TCGA-SKCM cohort. Melanoma patients were classified into a high-risk group and a low-risk group based on the feature model. As a final step, correlations between ferroptosis-related signatures and immune features, immunotherapy efficacy, or drug response were analyzed. RESULTS: By analyzing melanoma samples from TCGA-SKCM dataset, FRGs exhibited a high frequency of genetic mutations and copy number variations (CNVs), significantly impacting gene expression. Additionally, compared with normal skin tissue, 30 genes with significantly differential expression were identified in melanoma tissues. A prognostic model related to FRGs, constructed using the LASSO Cox regression method, identified 13 FRGs associated with overall survival prognosis in patients and was validated with external datasets. Finally, functional enrichment and immune response analysis further indicated significant differences in immune cell infiltration, mutation burden, and hypoxia status between the high-risk group and the low-risk group, and the model was effective in predicting responses to immunotherapy and drug sensitivity. CONCLUSIONS: This study develops a strong ferroptosis-related prognostic signature model which could put forward new insights into target therapy and immunotherapy for patients with melanoma.
Assuntos
Ferroptose , Melanoma , Neoplasias Cutâneas , Ferroptose/genética , Humanos , Melanoma/genética , Prognóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Mutação , Melanoma Maligno Cutâneo , Variações do Número de Cópias de DNA , Regulação Neoplásica da Expressão Gênica , MultiômicaRESUMO
Background: The coronavirus disease 2019 (COVID-19) pandemic has severely affected healthcare systems around the world. This study aimed to investigate the perceptions of cardiologists regarding how the COVID-19 pandemic has affected the clinical practice patterns for acute coronary syndrome (ACS). Methods: A multicenter clinician survey was sent to 300 cardiologists working in 22 provinces in China. The survey collected demographic information and inquired about their perceptions of how the COVID-19 pandemic has affected ACS clinical practice patterns. Results: The survey was completed by 211 (70.3%) cardiologists, 82.5% of whom were employed in tertiary hospitals, and 52.1% reported more than 10 years of clinical cardiology practice. Most respondents observed a reduction in ACS inpatients and outpatients in their hospitals during the pandemic. Only 29.9% of the respondents had access to a dedicated catheter room for the treatment of COVID-19-positive ACS patients. Most respondents stated that the COVID-19 pandemic had varying degrees of effect on the treatment of acute ST-segment elevation myocardial infarction (STEMI), acute non-ST-segment elevation myocardial infarction (NSTEMI), and unstable angina. Compared with the assumed non-pandemic period, in the designed clinical questions, the selection of coronary interventional therapy for STEMI, NSTEMI, and unstable angina during the COVID-19 pandemic was significantly decreased (all p < 0.05), and the selection of pharmacotherapy was increased (all p < 0.05). The selection of fibrinolytic therapy for STEMI during the pandemic was higher than in the assumed non-pandemic period (p < 0.05). Conclusions: The COVID-19 pandemic has profoundly affected ACS clinical practice patterns. The use of invasive therapies significantly decreased during the pandemic period, whereas pharmacotherapy was more often prescribed by the cardiologists.