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PURPOSE: To investigate the safety and effectiveness of radiotherapy for advanced upper tract urothelial carcinoma (UTUC) patients intolerant to chemotherapy. METHODS: Data for 21 patients with advanced UTUC intolerant to chemotherapy were retrospectively collected. All patients were treated with conventionally fractionated radiotherapy (50-70 Gy/20-33 f) or partial-SABR boost to the lesions (50-60 Gy/20-25 f with tumor center boosted with 6-8 Gy/f, 3-5 f) for bulky tumors. RESULTS: The median age was 75 years (range, 58-87 years). Primary tumor resection was performed for all patients and none underwent metastatic resection. Seventeen (81%) patients had oligometastasis (1-5 metastases) at diagnosis. Eighteen (85.7%) received irradiation to all tumor lesions. Lymph node metastasis was predominant in the whole group (17/21). Other lesions were distributed as local recurrence (7/21), bone metastases (2/21) and abdominal wall/muscle (2/21). The median follow-up time was 38.5 months (interquartile range, 15.2-48.7 months). Rate of local control (LC), progression-free survival (PFS) and overall survival (OS) of the whole group at 1 year were 90%, 46.6%, and 80.4%, respectively. At 3 years, LC, PFS and OS were 65.6%, 26.6%, and 40.9%, respectively. Fourteen patients developed acute mild gastrointestinal toxicity, generally of grade 1-2; 8 patients developed acute grade 1-2 hematological toxicity, consisting mainly of anemia and leukopenia. No grade 3 or higher acute or late toxicities were observed. CONCLUSION: For patients with advanced UTUC who are not able to tolerate chemotherapy, radiotherapy is a safe treatment and can achieve good local tumor control.
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Whether the dynamic development of peripheral inflammation aggravates brain injury and leads to poor outcome in stroke patients receiving intravenous thrombolysis (IVT), remains unclear and warrants further study. In this study, total of 1034 patients with acute ischemic stroke who underwent IVT were enrolled. Serum leukocyte variation (whether increase from baseline to 24 h after IVT), National Institutes of Health Stroke Scale (NIHSS), infarct volume, early neurologic deterioration (END), the unfavorable outcome at 3-month (modified Rankin Scale [mRS] score ≥3) and mortality were recorded. Serum brain injury biomarkers, including Glial fibrillary acidic protein (GFAP), ubiquitin c-terminal hydrolase L1 (UCH-L1), S100ß, neuron-specific enolase (NSE), were measured to reflect the extent of brain injury. We found that patients with increased serum leukocytes had elevated brain injury biomarkers (GFAP, UCH-L1, and S100ß), larger infarct volume, higher 24 h NIHSS, higher proportion of END, unfavorable outcome and mortality. Furthermore, an increase in serum leukocytes was independently associated with infarct volume, 24 h NIHSS, END, and unfavorable outcome at 3 months, and serum UCH-L1, S100ß, and NSE levels. These results suggest that an increase in serum leukocytes indicates severe brain injury and may be used to predict the outcome of patients with ischemic stroke who undergo IVT.
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Acute pancreatitis (AP) is an inflammatory disease of the pancreas. Despite of a steadily increasing in morbidity and mortality, there is still no effective therapy. Gut microbial dysbiosis and its derived-metabolites disorder have been shown to play an important role in the development of AP, however, little is known regarding the crosstalk between gut microbiota and metabolites. In this study, we assessed the alterations in gut microbiota and metabolites by constructing three AP mouse models by means of metagenomic and metabolomic sequencing, and further clarified their relationship by correlation analysis. The results revealed that each model exhibited unique flora and metabolite profiles. KEGG analysis showed that the differential flora and metabolite-enriched pathway functions were correlated with lipid metabolism and amino acid metabolism. Moreover, two core differential bacterial species on Burkholderiales bacterium YL45 and Bifidobacterium pseudolongum along with eleven differential metabolites appeared to exert certain effects during the course of AP. In conclusion, further exploration of the crosstalk between microbiota and derived metabolites may provide novel insights and strategies into the diagnosis and treatment of AP.
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Microbioma Gastrointestinal , Metabolómica , Metagenómica , Pancreatitis , Pancreatitis/microbiología , Pancreatitis/metabolismo , Animales , Metabolómica/métodos , Metagenómica/métodos , Ratones , Metaboloma , Modelos Animales de Enfermedad , Disbiosis/microbiología , Disbiosis/metabolismo , Ratones Endogámicos C57BL , Masculino , Enfermedad AgudaRESUMEN
The role of circular RNAs (circRNAs) in cancers is gaining more and more attention, yet related reporters are limited. In triple-negative breast cancer (TNBC), circRNA circ_0084653 originated from COP9 signalosome subunit 5 (COPS5), and COPS5 has been validated to be upregulated in breast cancer before. In our research, COPS5 was also upregulated in TNBC cells, and knockdown of it repressed cell proliferation, invasion, EMT, stemness and PDL-1 protein expression but increased T-cell percentage. Further, circ_0084653 was an aberrantly upregulated circRNA in TNBC cells, and similarly, circ_0084653 silence inhibited TNBC development. Besides, circ_0084653 expression was distributed in both cytoplasm and nucleus. COPS5 overexpression partially rescued the suppressing effects of circ_0084653 depletion in TNBC. Subsequently, circ_0084653 triggered deubiquitination of MYC, the upstream transcription factor of COPS5, via recruiting ubiquitin specific peptidase 36 (USP36). Moreover, circ_0084653 served as the sponge of miR-1323 to release the expression the target gene SRY-box transcription factor 5 (SOX5). SOX5 upregulation completely remedied the inhibiting influence of circ_0084653 downregulation in TNBC. Meanwhile, transcription factor SOX5 activated transcriptionally circ_0084653. To sum up, SOX5-induced circ_0084653 promotes TNBC via the deubiquitination of USP36, which may provide some fresh ideas for TNBC-related molecular mechanisms.
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PURPOSE: To assess the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) of gemcitabine and oxaliplatin (GEMOX) plus systemic gemcitabine chemotherapy (GEM-SYS) in combination with lenvatinib and programmed cell death protein-1 (PD-1) inhibitor for patients with large unresectable intrahepatic cholangiocarcinoma (uICC). METHODS: From November 2019 to December 2022, 21 large uICC patients who underwent GEMOX-HAIC (Day 1) and GEM-SYS (Day 8) (3w/cycle) combined with lenvatinib and PD-1 inhibitor were retrospectively enrolled. Local tumor response, progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were analyzed. Tumor response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. AEs were evaluated by the common terminology criteria for adverse events (CTCAE) version 5.0. RESULTS: After a median follow-up duration of 16.0 months (range 5-43.5 months), 17 patients had died. The median OS was 19.5 months (range 9-43.5 months), and the median PFS was 6.0 months (range 2.5-38.5 months). The 1-, 2-, and 3-year OS rates were 71.4 %, 42.9 %, and 19.0 %, respectively. The 1-, 2-, and 3-year PFS rates were 33.3 %, 19.0 %, and 9.5 %, respectively. Complete response, partial response, stable disease, and progressive disease were observed in 0 (0 %), 11 (52.3 %), 5 (23.8 %), and 5 (23.8 %) patients, respectively. The disease control rate and objective response rate were 76.1 % and 52.3 %, respectively. None of the enrolled patients experienced grade 5 AEs. CONCLUSIONS: GEMOX-HAIC plus GEM-SYS in combination with lenvatinib and PD-1 inhibitor was effective and well tolerated for patients with large uICC.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de los Conductos Biliares , Colangiocarcinoma , Desoxicitidina , Gemcitabina , Compuestos de Fenilurea , Quinolinas , Humanos , Masculino , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/mortalidad , Femenino , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Desoxicitidina/administración & dosificación , Persona de Mediana Edad , Anciano , Quinolinas/uso terapéutico , Quinolinas/administración & dosificación , Quinolinas/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Compuestos de Fenilurea/administración & dosificación , Compuestos de Fenilurea/uso terapéutico , Compuestos de Fenilurea/efectos adversos , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/mortalidad , Estudios Retrospectivos , Infusiones Intraarteriales , Oxaliplatino/uso terapéutico , Oxaliplatino/administración & dosificación , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Adulto , Arteria Hepática , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Compuestos OrganoplatinosRESUMEN
The lymph node is the most common site of distant metastasis of cervical squamous cell carcinoma (CSCC), which elicits dismal prognosis and limited efficiency for treatment. Elucidation of the mechanisms underlying CSCC lymphatic metastasis would provide potential therapeutic strategies for nodal metastatic of CSCC. Here, based on in vivo lymphatic metastasis screening model, a circular RNA is identified that is termed as lymph node metastasis associated circRNA (LNMAC), is markedly upregulated in lymphatic metastatic CSCC and correlated with lymph node metastasis. Overexpression of LNMAC dramatically augments the metastatic capability of CSCC cells to the lymph node via inducing lymphangiogenesis. Mechanistically, LNMAC epigenetically upregulates fibroblast growth factor 2 (FGF2) expression by directly associating with histone acacetylase 1 (HDAC1), preventing Importin α6/8-mediated nuclear translocation of HDAC1 and eliciting histone H3K27ac-induced FGF2 transcriptional activation. Treatment with 3F12E7, an anti-FGF2 monoclonal antibody, effectively inhibits LNMAC-induced CSCC lymphatic metastasis. Taken together, these findings indicate that LNMAC plays a crucial role in FGF2-mediated lymphangiogenesis and lymphatic metastasis, highlighting that LNMAC might be a therapeutic target for lymph node metastasis in CSCC patients.
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OBJECTIVE: This study aimed to evaluate the effects of tranexamic acid (TXA) in preventing postpartum haemorrhage (PPH) among women with identified risk factors for PPH undergoing vaginal delivery in China. METHODS: This prospective, randomized, open-label, blinded endpoint (PROBE) trial enrolled 2258 women with one or more risk factors for PPH who underwent vaginal delivery. Participants were randomly assigned in a 1:1 ratio to receive an intravascular infusion of 1 g TXA or a placebo immediately after the delivery of the infant. The primary outcome assessed was the incidence of PPH, defined as blood loss ≥500 mL within 24 h after delivery, while severe PPH was considered as a secondary outcome and defined by total blood loss ≥1000 mL within 24 h. RESULTS: 2245 individuals (99.4%) could be followed up to their primary outcome. PPH occurred in 186 of 1128 women in the TXA group and in 215 of 1117 women in the placebo group (16.5% vs. 19.2%; RR, 0.86; 95% CI, 0.72 to 1.02; p = 0.088). Regarding secondary outcomes related to efficacy, women in the TXA group had a significant lower rate of severe PPH than those in the placebo group (2.7% vs. 5.6%; RR, 0.49; 95% CI, 0.32 to 0.74; p = 0.001; adjusted p = 0.002). Similarly, there was a significant reduction in the use of additional uterotonic agents (7.8% vs. 15.6%; RR, 0.50; 95% CI, 0.39 to 0.63; p < 0.001; adjusted p = 0.001). No occurrence of thromboembolic events and maternal deaths were reported in both groups within 30 days after delivery. CONCLUSIONS: In total population with risk factors for PPH, the administration of TXA following vaginal delivery did not result in a statistically significant reduction in the incidence of PPH compared to placebo; however, it was associated with a significantly lower incidence of severe PPH.
Prophylactic administration of TXA did not yield a statistically significant reduction in the incidence of PPH among women with risk factors in vaginal deliveries.Prophylactic use of TXA may help to reduce the incidence of severe PPH.
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Antifibrinolíticos , Parto Obstétrico , Hemorragia Posparto , Ácido Tranexámico , Humanos , Femenino , Ácido Tranexámico/administración & dosificación , Ácido Tranexámico/uso terapéutico , Hemorragia Posparto/prevención & control , Hemorragia Posparto/epidemiología , Hemorragia Posparto/etiología , China/epidemiología , Adulto , Antifibrinolíticos/administración & dosificación , Embarazo , Estudios Prospectivos , Factores de Riesgo , Incidencia , Parto Obstétrico/efectos adversos , Resultado del Tratamiento , Adulto JovenAsunto(s)
Enfermedad de Crohn , Humanos , Enfermedad de Crohn/cirugía , Enfermedad de Crohn/complicaciones , Constricción Patológica/etiología , Constricción Patológica/cirugía , Mucosa Intestinal/cirugía , Mucosa Intestinal/patología , Masculino , Colangiopancreatografia Retrógrada Endoscópica/métodos , Femenino , AdultoRESUMEN
Atrial fibrosis is associated with the occurrence of atrial fibrillation (AF) and regulated by the transforming growth factor-ß1 (TGF-ß1)/Smad2/3 signalling pathway. Unfortunately, the mechanisms of regulation of TGF-ß1/Smad2/3-induced atrial fibrosis and vulnerability to AF remain still unknown. Previous studies have shown that sirtuin3 (SIRT3) sulfhydration has strong anti-fibrotic effects. We hypothesised that SIRT3 sulfhydration inhibits angiotensin II (Ang-II)-induced atrial fibrosis via blocking the TGF-ß1/Smad2/3 signalling pathway. In this study, we found that SIRT3 expression was decreased in the left atrium of patients with AF compared to that in those with sinus rhythm (SR). In vitro, SIRT3 knockdown by small interfering RNA significantly expanded Ang-II-induced atrial fibrosis and TGF-ß1/Smad2/3 signalling pathway activation, whereas supplementation with Sodium Hydrosulfide (NaHS, exogenous hydrogen sulfide donor and sulfhydration agonist) and SIRT3 overexpression using adenovirus ameliorated Ang-II-induced atrial fibrosis. Moreover, we observed suppression of the TGF-ß1/Smad2/3 pathway when Ang-II was combined with NaHS treatment, and the effect of this co-treatment was consistent with that of Ang-II combined with LY3200882 (Smad pathway inhibitor) on reducing atrial fibroblast proliferation and cell migration in vitro. Supplementation with dithiothreitol (DTT, a sulfhydration inhibitor) and adenovirus SIRT3 shRNA blocked the ameliorating effect of NaHS and AngII co-treatment on atrial fibrosis in vitro. Finally, continued treatment with NaHS in rats ameliorated atrial fibrosis and remodelling, and further improved AF vulnerability induced by Ang-II, which was reversed by DTT and adenovirus SIRT3 shRNA, suggesting that SIRT3 sulfhydration might be a potential therapeutic target in atrial fibrosis and AF.
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Angiotensina II , Fibrilación Atrial , Fibrosis , Atrios Cardíacos , Sulfuro de Hidrógeno , Transducción de Señal , Sirtuina 3 , Proteína Smad2 , Proteína smad3 , Factor de Crecimiento Transformador beta1 , Angiotensina II/farmacología , Sirtuina 3/metabolismo , Sirtuina 3/genética , Fibrilación Atrial/metabolismo , Fibrilación Atrial/patología , Fibrilación Atrial/prevención & control , Factor de Crecimiento Transformador beta1/metabolismo , Transducción de Señal/efectos de los fármacos , Proteína smad3/metabolismo , Animales , Proteína Smad2/metabolismo , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/metabolismo , Atrios Cardíacos/patología , Sulfuro de Hidrógeno/farmacología , Sulfuro de Hidrógeno/metabolismo , Masculino , Humanos , Ratas , Ratas Sprague-Dawley , Femenino , Persona de Mediana Edad , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacosRESUMEN
The clinical benefit of anti-programmed cell death protein 1 (PD-1)-based immunotherapy among patients with microsatellite instable (MSI) endometrial cancer (EC) precedes that of microsatellite stable (MSS) EC, the mechanisms of which have not been fully understood. Circular RNAs (circRNAs) were reported to modulate immune evasion in several types of malignancies, while their roles in the immune regulation in EC remain largely unknown. Here, we conducted circRNA array analysis and mRNA-Sequencing of 10 MSI EC samples and 10 MSS EC samples and identified 1083 differentially expressed circRNAs (DE-circRNAs) and 864 differentially expressed mRNAs, based on which we constructed a circRNA-miRNA-mRNA comprehensive network consisting of 35 DE-circRNAs, 56 predicted miRNAs and 24 differentially expressed mRNAs. Finally, we confirmed hsa_circ_0058230 being positively correlated with CD8+ T cells infiltration, suggesting that it might take a part in anti-tumor immunity in EC.
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Electrochemically activated persulfate is a potential advanced oxidation process due to its advantages of environmental friendliness, high efficiency, and convenient operation. An Fe-Cu-S granular activated carbon (CuFeS2/GAC, abbreviated as FCSG) particles electrode was developed and applied to degrade carbamazepine (CBZ) combined with electrochemical activation of persulfate (E-PDS-FCSG) in this work. Compared to two-dimensional electrochemical process (E-PDS), the three-dimensional (3D) E-PDS-FCSG process exhibited higher removal efficiency of CBZ and lower energy consumption. The removal efficiency of CBZ and power consumption increased by 96% and reduced by 67%, respectively. Over 98% of CBZ removal rate was reached within 25 min. Apart from the same free radicals in two-dimensional electrochemical process, both Fe2+ and Cu+ on the surface of three-dimensional particle electrodes can directly activate PDS to produce SO4â¢-, and the existence of S2- strengthens the circulation of Fe3+/Fe2+ and Cu2+/Cu+. Furthermore, FCSG particle electrode can not only directly enhance the activation of PDS, but also accelerate the electron transfer, and then effectively promoting reactive species generation. LC-MS analysis showed that the main degradation pathways of CBZ involved decarbonylation, deamination, dealkylation, ring opening and mineralization. Moreover, after five cycle experiments, over 80% of CBZ removal rate could be achieved, demonstrating that the E-PDS-FCSG system had excellent electrocatalytic performance and good stability. These findings indicate that FCSG is a promising material and could be used as a particle electrode for removing organic pollutants from water.
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The pollution resulting from the emergence of the contaminant perchlorate is anticipated to have a substantial effect on the water environment in the foreseeable future. Considerable research efforts have been devoted to investigating treatment technologies for addressing perchlorate contamination, garnering widespread international interest in recent decades. A systematic review was conducted utilizing the Web of Science, Scopus, and Science Direct databases to identify pertinent articles published from 2000 to 2024. A total of 551 articles were chosen for in-depth examination utilizing VOS viewer. Bibliometric analysis indicated that countries such as China, the United States, Chile, India, Japan, and Korea have been prominent contributors to the research on this topic. The order of ClO4- occurrence was as follows: surface water > groundwater > drinking water. Various remediation methods for perchlorate contamination, such as adsorption, ion-exchange, membrane filtration, chemical reduction, and biological reduction, have been suggested. Furthermore, the research critically evaluated the strengths and weaknesses of each approach and offered recommendations for addressing their limitations. Advanced technologies have shown the potential to achieve notably enhanced removal of perchlorate and co-contaminants from water sources. However, the low concentration of perchlorate in natural water sources and the high energy consumption related to these technologies need to be solved in order to effectively remove perchlorate from water.
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Host immunity is central to the virus's spread dynamics, which is significantly influenced by vaccination and prior infection experiences. In this work, we analyzed the co-evolution of SARS-CoV-2 mutation, angiotensin-converting enzyme 2 (ACE2) receptor binding, and neutralizing antibody (NAb) responses across various variants in 822 human and mice vaccinated with different non-Omicron and Omicron vaccines is analyzed. The link between vaccine efficacy and vaccine type, dosing, and post-vaccination duration is revealed. The classification of immune protection against non-Omicron and Omicron variants is co-evolved with genetic mutations and vaccination. Additionally, a model, the Prevalence Score (P-Score) is introduced, which surpasses previous algorithm-based models in predicting the potential prevalence of new variants in vaccinated populations. The hybrid vaccination combining the wild-type (WT) inactivated vaccine with the Omicron BA.4/5 mRNA vaccine may provide broad protection against both non-Omicron variants and Omicron variants, albeit with EG.5.1 still posing a risk. In conclusion, these findings enhance understanding of population immunity variations and provide valuable insights for future vaccine development and public health strategies.
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The novel HLA-C*15:279 allele differs from HLA-C*15:02:01:01 by five nucleotide substitutions in exons 4 and 5.
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Alelos , Pueblo Asiatico , Secuencia de Bases , Exones , Antígenos HLA-C , Prueba de Histocompatibilidad , Análisis de Secuencia de ADN , Humanos , Antígenos HLA-C/genética , Pueblo Asiatico/genética , Análisis de Secuencia de ADN/métodos , Prueba de Histocompatibilidad/métodos , Alineación de Secuencia , Codón , Pueblos del Este de AsiaRESUMEN
Herein, we present an attractive organocatalytic asymmetric addition of P-nucleophiles to five-membered cyclic N-sulfonyl imines facilitated by phosphonium salt catalysis, enabling the highly enantioselective synthesis of tri- and tetra-substituted cyclic phosphorus-containing benzosultams. With this protocol, various cyclic α-aminophosphonates were efficiently synthesized with high yields and exceptional enantioselectivities (up to >99% ee) under mild reaction conditions. The utility and practicality of this method were demonstrated through gram-scale reactions and straightforward elaborations. Notably, the success of this approach relies on the deliberate selection of a synergistic organocatalytic system, which helps circumvent foreseeable side effects while handling secondary phosphine oxides (SPOs). Systematic mechanistic studies, incorporating experiments and DFT calculations, have revealed the critical importance of judiciously selecting bifunctional phosphonium salt catalysts for effectively activating P-nucleophiles while stereoselectively controlling the P-attack process.
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BACKGROUND: Tumor heterogeneity presents a formidable challenge in understanding the mechanisms driving tumor progression and metastasis. The heterogeneity of hepatocellular carcinoma (HCC) in cellular level is not clear. METHODS: Integration analysis of single-cell RNA sequencing data and spatial transcriptomics data was performed. Multiple methods were applied to investigate the subtype of HCC tumor cells. The functional characteristics, translation factors, clinical implications and microenvironment associations of different subtypes of tumor cells were analyzed. The interaction of subtype and fibroblasts were analyzed. RESULTS: We established a heterogeneity landscape of HCC malignant cells by integrated 52 single-cell RNA sequencing data and 5 spatial transcriptomics data. We identified three subtypes in tumor cells, including ARG1+ metabolism subtype (Metab-subtype), TOP2A+ proliferation phenotype (Prol-phenotype), and S100A6+ pro-metastatic subtype (EMT-subtype). Enrichment analysis found that the three subtypes harbored different features, that is metabolism, proliferating, and epithelial-mesenchymal transition. Trajectory analysis revealed that both Metab-subtype and EMT-subtype originated from the Prol-phenotype. Translation factor analysis found that EMT-subtype showed exclusive activation of SMAD3 and TGF-ß signaling pathway. HCC dominated by EMT-subtype cells harbored an unfavorable prognosis and a deserted microenvironment. We uncovered a positive loop between tumor cells and fibroblasts mediated by SPP1-CD44 and CCN2/TGF-ß-TGFBR1 interaction pairs. Inhibiting CCN2 disrupted the loop, mitigated the transformation to EMT-subtype, and suppressed metastasis. CONCLUSION: By establishing a heterogeneity landscape of malignant cells, we identified a three-subtype classification in HCC. Among them, S100A6+ tumor cells play a crucial role in metastasis. Targeting the feedback loop between tumor cells and fibroblasts is a promising anti-metastatic strategy.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Análisis de la Célula Individual , Microambiente Tumoral , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Humanos , Regulación Neoplásica de la Expresión Génica , Transición Epitelial-Mesenquimal/genética , Animales , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Fibroblastos/metabolismo , Fibroblastos/patología , Heterogeneidad Genética , Ratones , Línea Celular Tumoral , Pronóstico , Perfilación de la Expresión Génica , Transcriptoma , Biología Computacional/métodos , Metástasis de la NeoplasiaRESUMEN
Dipines are a type of important antihypertensive drug as L-calcium channel blockers, whose core skeleton is the 1,4-dihydropyridine structure. Since the dihydropyridine ring is a key structural factor for biological activity, the thermodynamics of the aromatization dihydropyridine ring is a significant feature parameter for understanding the mechanism and pathways of dipine metabolism in vivo. Herein, 4-substituted-phenyl-2,6-dimethyl-3,5-diethyl-formate-1,4-dihydropyridines are refined as the structurally closest dipine models to investigate the thermodynamic potential of dipine oxidative metabolism. In this work, the thermodynamic cards of dipine models' aromatization on 21 potential elementary steps in acetonitrile have been established. Based on the thermodynamic cards, the thermodynamic properties of dipine models and related intermediates acting as electrons, hydrides, hydrogen atoms, protons, and two hydrogen ions (atoms) donors are discussed. Moreover, the thermodynamic cards are applied to evaluate the redox properties, and judge or reveal the possible oxidative mechanism of dipine models.
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Oxidación-Reducción , Termodinámica , Dihidropiridinas/química , Dihidropiridinas/metabolismo , Antihipertensivos/química , Antihipertensivos/farmacología , Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/farmacología , Estructura Molecular , Modelos MolecularesRESUMEN
Graphite (Gr)-based lithium-ion batteries with admirable electrochemical performance below -20 °C are desired but are hindered by sluggish interfacial charge transport and desolvation process. Li salt dissociation via Li+-solvent interaction enables mobile Li+ liberation and contributes to bulk ion transport, while is contradictory to fast interfacial desolvation. Designing kinetically-stable solid electrolyte interphase (SEI) without compromising strong Li+-solvent interaction is expected to compatibly improve interfacial charge transport and desolvation kinetics. However, the relationship between physicochemical features and temperature-dependent kinetics properties of SEI remains vague. Herein, we propose four key thermodynamics parameters of SEI potentially influencing low-temperature electrochemistry, including electron work function, Li+ transfer barrier, surface energy, and desolvation energy. Based on the above parameters, we further define a novel descriptor, separation factor of SEI (SSEI), to quantitatively depict charge (Li+/e-) transport and solvent deprivation processes at Gr/electrolyte interface. A Li3PO4-based, inorganics-enriched SEI derived by Li difluorophosphate (LiDFP) additive exhibits the highest SSEI (4.89×103) to enable efficient Li+ conduction, e- blocking and rapid desolvation, and as a result, much suppressed Li-metal precipitation, electrolyte decomposition and Gr sheets exfoliation, thus improving low-temperature battery performances. Overall, our work originally provides visualized guides to improve low-temperature reaction kinetics/thermodynamics by constructing desirable SEI chemistry.
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BACKGROUND: The relationships between 25-hydroxyvitamin D [25(OH)D] and calcium and age-related macular degeneration (AMD) are unclear. OBJECTIVES: This study aimed to investigate the causal role of 25(OH)D concentrations, calcium concentrations, and dietary supplements use of vitamin D and calcium on risk of AMD and its subtypes. METHODS: Independent genetic variants associated with 25(OH)D and calcium concentrations were used as instrumental variables in published genome-wide association studies (GWASs) of European ancestry. The bidirectional 2-sample Mendelian randomization (MR) analyses were performed using summary-level data from the UK Biobank and FinnGen datasets. Sensitivity analyses were conducted to ensure the robustness of the MR results. The meta-analyses were conducted using both fixed-effect and random-effect models to provide comprehensive and reliable estimates. RESULTS: A standard deviation increase in calcium concentrations was linked to a 14%, 17%, and 13% reduction in the likelihood of developing AMD (95% confidence interval [CI]: 0.77, 0.97), wet AMD (95% CI: 0.73, 0.95), and dry AMD (95% CI: 0.75, 1.00), respectively. No significant causal relationships were detected between genetically predicted 25(OH)D concentrations and AMD and its subtypes (all P > 0.05). The combined analyses showed that higher calcium concentrations were associated with a reduced risk of overall AMD, with an odds ratio of 0.89 (95% CI: 0.81, 0.98). CONCLUSIONS: This study provides evidence supporting the causal relationship between calcium concentrations and risk of AMD and its subtypes, which may have important implications for the prevention, monitoring, and treatment of AMD.