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BACKGROUND: Lung adenocarcinoma (LUAD) is a highly aggressive and rapidly fatal malignancy worldwide. Collagen XVII (COL17A1) has been implicated in various protumorigenic processes. However, the functions and mechanisms of COL17A1 in LUAD progression still remain elusive. METHODS: COL17A1 and ubiquitin-specific protease 22 (USP22) mRNA analysis was performed by quantitative PCR, and their protein levels were detected by immunoblotting and immunohistochemistry. The functional influence was evaluated by determining cell viability, proliferation, apoptosis, invasion, migration, and ferroptosis in vitro, as well as xenograft growth in vivo. Co-immunoprecipitation (Co-IP) and IP experiments were used to examine the USP22/COL17A1 interaction and COL17A1 deubiquitination. Cycloheximide treatment was used to analyze COL17A1 protein stability. RESULTS: COL17A1 and USP22 were upregulated in human LUAD tissues and cell lines. Functionally, COL17A1 knockdown acted for the suppression of LUAD cell growth, invasion, and migration as well as promotion of cell apoptosis and ferroptosis in vitro. COL17A1 knockdown could diminish the tumorigenicity of LUAD cells in vivo. Mechanistically, USP22 stabilized and upregulated COL17A1 by enhancing the deubiquitination of COL17A1. Additionally, reexpression of COL17A1 could reverse USP22 silencing-induced phenotype changes of LUAD cells in vitro. CONCLUSION: Our findings demonstrate that USP22-stabilized COL17A1 possesses oncogenic activity in LUAD. We propose that USP22 and COL17A1 would be potential targets for the establishment of therapeutic approaches against LUAD.
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Adenocarcinoma del Pulmón , Proliferación Celular , Progresión de la Enfermedad , Neoplasias Pulmonares , Ubiquitina Tiolesterasa , Humanos , Ubiquitina Tiolesterasa/metabolismo , Ubiquitina Tiolesterasa/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Ratones , Proliferación Celular/genética , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/metabolismo , Animales , Línea Celular Tumoral , Apoptosis/genética , Masculino , Femenino , Regulación Neoplásica de la Expresión Génica , Movimiento Celular/genética , UbiquitinaciónRESUMEN
Introduction: The gut microbiota and the microbiota-gut-brain axis have gained considerable attention in recent years, emerging as key players in the mechanisms that mediate the occurrence and progression of many central nervous system-related diseases, including epilepsy. In clinical practice, one of the side effects of quinolone antibiotics is a lower seizure threshold or aggravation. However, the underlying mechanism remains unclear. Methods: We aimed to unravel the intrinsic mechanisms through 16S rRNA sequencing and serum untargeted metabolomic analysis to shed light on the effects of gut microbiota in ciprofloxacin-induced seizure susceptibility and lithium pilocarpine-induced epilepsy rat models. Results: We observed that ciprofloxacin treatment increased seizure susceptibility and caused gut dysbiosis. We also found similar changes in the gut microbiota of rats with lithium pilocarpine-induced epilepsy. Notably, the levels of Akkermansia and Bacteroides significantly increased in both the ciprofloxacin-induced seizure susceptibility and lithium pilocarpine-induced epilepsy rat models. However, Marvinbryantia, Oscillibacter, and Ruminococcaceae_NK4A214_group showed a coincidental reduction. Additionally, the serum untargeted metabolomic analysis revealed decreased levels of indole-3-propionic acid, a product of tryptophan-indole metabolism, after ciprofloxacin treatment, similar to those in the plasma of lithium pilocarpine-induced epilepsy in rats. Importantly, alterations in the gut microbiota, seizure susceptibility, and indole-3-propionic acid levels can be restored by fecal microbiota transplantation. Conclusion: In summary, our findings provide evidence that ciprofloxacin-induced seizure susceptibility is partially mediated by the gut microbiota and tryptophan-indole metabolism. These associations may play a role in epileptogenesis, and impacting the development progression and treatment outcomes of epilepsy.
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Recognizing the significance of SPECT in nuclear medicine and the pivotal role of fibroblast activation protein (FAP) in cancer diagnosis and therapy, this study focuses on the development of 99mTc-labeled dimeric HF2 with high tumor uptake and image contrast. The dimeric HF2 was synthesized and radiolabeled with 99mTc in one pot using various coligands (tricine, TPPTS, EDDA, and TPPMS) to yield [99mTc]Tc-TPPTS-HF2, [99mTc]Tc-EDDA-HF2, and [99mTc]Tc-TPPMS-HF2 dimers. SPECT imaging results indicated that [99mTc]Tc-TPPTS-HF2 exhibited higher tumor uptake and tumor-to-normal tissue (T/NT) ratio than [99mTc]Tc-EDDA-HF2 and [99mTc]Tc-TPPMS-HF2. Notably, [99mTc]Tc-TPPTS-HF2 exhibited remarkable tumor accumulation and retention in HT-1080-FAP and U87-MG tumor-bearing mice, thereby surpassing the monomeric [99mTc]Tc-TPPTS-HF. Moreover, [99mTc]Tc-TPPTS-HF2 achieved acceptable T/NT ratios in the hepatocellular carcinoma patient-derived xenograft (HCC-PDX) model, which provided identifiable contrast and imaging quality. In conclusion, this study presents proof-of-concept research on 99mTc-labeled FAP inhibitor dimers for the visualization of multiple tumor types. Among these candidate compounds, [99mTc]Tc-TPPTS-HF2 showed excellent clinical potential, thereby enriching the SPECT tracer toolbox.
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Compuestos de Organotecnecio , Tomografía Computarizada de Emisión de Fotón Único , Animales , Humanos , Ratones , Tomografía Computarizada de Emisión de Fotón Único/métodos , Compuestos de Organotecnecio/química , Compuestos de Organotecnecio/farmacocinética , Compuestos de Organotecnecio/síntesis química , Línea Celular Tumoral , Diseño de Fármacos , Radiofármacos/química , Radiofármacos/síntesis química , Radiofármacos/farmacocinética , Tecnecio/química , Distribución Tisular , Dimerización , Ratones Desnudos , Proteínas de la Membrana/antagonistas & inhibidores , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/química , Endopeptidasas/metabolismo , Serina Endopeptidasas/metabolismo , Serina Endopeptidasas/químicaRESUMEN
Due to the complex heterogeneity in different cancer types, the heterodimeric strategy has been intensively practiced to improve the effectiveness of tumor diagnostics. In this study, we developed a series of novel 18F-labeled biotin/FAPI-conjugated heterobivalent radioligands ([18F]AlF-NSFB, [18F]AlF-NSFBP2, and [18F]AlF-NSFBP4), synergistically targeting both fibroblast activation protein (FAP) and biotin receptor (BR), to enhance specific tumor uptake and retention. The in vitro and in vivo biological properties of these dual-targeting tracers were evaluated, with a particular focus on positron emission tomography imaging in A549 and HT1080-FAP tumor-bearing mice. Notably, in comparison to the corresponding FAP-targeted monomer [18F]AlF-NSF, biotin/FAPI-conjugated heterodimers exhibited a high uptake in tumor and prolong retention. In conclusion, as a proof-of-concept study, the findings validated the superiority of biotin/FAPI-conjugated heterodimers and the positive influence of biotin and linker on pharmacokinetics of radioligands. Within them, the bispecific [18F]AlF-NSFBP4 holds significant promise as a candidate for further clinical translational studies.
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Biotina , Radioisótopos de Flúor , Animales , Humanos , Radioisótopos de Flúor/química , Biotina/química , Biotina/farmacocinética , Ratones , Diseño de Fármacos , Radiofármacos/química , Radiofármacos/farmacocinética , Radiofármacos/síntesis química , Radiofármacos/farmacología , Tomografía de Emisión de Positrones , Ratones Desnudos , Distribución Tisular , Dimerización , Línea Celular Tumoral , Ratones Endogámicos BALB CRESUMEN
A new glycoside (1) along with six known analogues (1-7) were isolated from Codonopsis pilosula collected at Shanxi in China. The structure of 1 was established based on comprehensive spectroscopic data and literature comparison. The anti-inflammatory effects of isolated compounds were further investigated in LPS-induced RAW264.7 macrophage.
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OBJECTIVE: Proliferative nodular formation represents a characteristic pathological feature of benign prostatic hyperplasia (BPH) and serves as the primary cause for prostate volume enlargement and consequent lower urinary tract symptoms (LUTS). Its specific mechanism is largely unknown, although several cellular processes have been reported to be involved in BPH initiation and development and highlighted the crucial role of epithelial cells in proliferative nodular formation. However, the technological limitations hinder the in vivo investigation of BPH patients. METHODS: The robust cell type decomposition (RCTD) method was employed to integrate spatial transcriptomics and single cell RNA sequencing profiles, enabling the elucidation of epithelial cell alterations during nodular formation. Immunofluorescent and immunohistochemical staining was performed for verification. RESULTS: The alterations of epithelial cells during the formation of nodules in BPH was observed, and a distinct subgroup of basal epithelial (BE) cells, referred to as BE5, was identified to play a crucial role in driving this progression through the hypoxia-induced epithelial-mesenchymal transition (EMT) signaling pathway. BE5 served as both the initiating cell during nodular formation and the transitional cell during the transformation from luminal epithelial (LE) to BE cells. A distinguishing characteristic of the BE5 cell subgroup in patients with BPH was its heightened hypoxia and upregulated expression of FOS. Histological verification results confirmed a significant association between c-Fos expression and key biological processes such as hypoxia and cell proliferation, as well as the close relationship between hypoxia and EMT in BPH tissues. Furthermore, a strong link between c-Fos expression and the progression of BPH was also been validated. Additionally, notable functional differences were observed in glandular and stromal nodules regarding BE5 cells, with BE5 in glandular nodules exhibiting enhanced capacities for EMT and cell proliferation characterized by club-like cell markers. CONCLUSIONS: This study elucidated the comprehensive landscape of epithelial cells during in vivo nodular formation in patients, thereby offering novel insights into the initiation and progression of BPH.
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Células Epiteliales , Transición Epitelial-Mesenquimal , Hiperplasia Prostática , Análisis de Secuencia de ARN , Análisis de la Célula Individual , Transcriptoma , Humanos , Masculino , Hiperplasia Prostática/patología , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/genética , Células Epiteliales/metabolismo , Células Epiteliales/patología , Transición Epitelial-Mesenquimal/genética , Transcriptoma/genética , Perfilación de la Expresión Génica , Anciano , Persona de Mediana Edad , Proliferación Celular , Análisis EspacialRESUMEN
BACKGROUND: The hyperpolarization-activated cyclic nucleotide-gated cation channel (HCN1) is predominantly located in key regions associated with epilepsy, such as the neocortex and hippocampus. Under normal physiological conditions, HCN1 plays a crucial role in the excitatory and inhibitory regulation of neuronal networks. In temporal lobe epilepsy, the expression of HCN1 is decreased in the hippocampi of both animal models and patients. However, whether HCN1 expression changes during epileptogenesis preceding spontaneous seizures remains unclear. OBJECTIVE: The aim of this study was to determine whether the expression of HCN1 is altered during the epileptic prodromal phase, thereby providing evidence for its role in epileptogenesis. METHODS: We utilized a cobalt wire-induced rat epilepsy model to observe changes in HCN1 during epileptogenesis and epilepsy. Additionally, we also compared HCN1 alterations in epileptogenic tissues between cobalt wire- and pilocarpine-induced epilepsy rat models. Long-term video EEG recordings were used to confirm seizures development. Transcriptional changes, translation, and distribution of HCN1 were assessed using high-throughput transcriptome sequencing, total protein extraction, membrane and cytoplasmic protein fractionation, western blotting, immunohistochemistry, and immunofluorescence techniques. RESULTS: In the cobalt wire-induced rat epilepsy model during the epileptogenesis phase, total HCN1 mRNA and protein levels were downregulated. Specifically, the membrane expression of HCN1 was decreased, whereas cytoplasmic HCN1 expression showed no significant change. The distribution of HCN1 in the distal dendrites of neurons decreased. During the epilepsy period, similar HCN1 alterations were observed in the neocortex of rats with cobalt wire-induced epilepsy and hippocampus of rats with lithium pilocarpine-induced epilepsy, including downregulation of mRNA levels, decreased total protein expression, decreased membrane expression, and decreased distal dendrite expression. CONCLUSIONS: Alterations in HCN1 expression and distribution are involved in epileptogenesis beyond their association with seizure occurrence. Similarities in HCN1 alterations observed in epileptogenesis-related tissues from different models suggest a shared pathophysiological pathway in epileptogenesis involving HCN1 dysregulation. Therefore, the upregulation of HCN1 expression in neurons, maintenance of the HCN1 membrane, and distal dendrite distribution in neurons may represent promising disease-modifying strategies in epilepsy.
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Modelos Animales de Enfermedad , Epilepsia , Hipocampo , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización , Canales de Potasio , Ratas Sprague-Dawley , Animales , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización/metabolismo , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización/genética , Masculino , Epilepsia/metabolismo , Epilepsia/inducido químicamente , Epilepsia/genética , Epilepsia/fisiopatología , Ratas , Hipocampo/metabolismo , Canales de Potasio/metabolismo , Canales de Potasio/genética , Pilocarpina/toxicidad , Cobalto/farmacología , Electroencefalografía , Neuronas/metabolismo , Neocórtex/metabolismoRESUMEN
The stimulator of interferon genes (STING) is pivotal in mediating STING-dependent type I interferon production, which is crucial for enhancing tumor rejection. Visualizing STING within the tumor microenvironment is valuable for STING-related treatments, yet the availability of suitable STING imaging probes is limited. In this study, we developed [18F]AlF-ABI, a novel 18F-labeled agent featuring an amidobenzimidazole core structure, for positron emission tomography (PET) imaging of STING in B16F10 and CT26 tumors. [18F]AlF-ABI was synthesized with a decay-corrected radiochemical yield of 38.0 ± 7.9% and radiochemical purity exceeding 97%. The probe exhibited a nanomolar STING binding affinity (KD = 35.6 nM). Upon administration, [18F]AlF-ABI rapidly accumulated at tumor sites, demonstrating significantly higher uptake in B16F10 tumors compared to CT26 tumors, consistent with STING immunofluorescence patterns. Specificity was further validated through in vitro cell experiments and in vivo blocking PET imaging. These findings suggest that [18F]AlF-ABI holds promise as an effective agent for visualizing STING in the tumor microenvironment.
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Bencimidazoles , Radioisótopos de Flúor , Tomografía de Emisión de Positrones , Microambiente Tumoral , Línea Celular Tumoral , Tomografía de Emisión de Positrones/métodos , Radiofármacos/química , Bencimidazoles/química , Bencimidazoles/farmacología , Proteínas de la Membrana/química , Proteínas de la Membrana/metabolismo , Neoplasias/diagnóstico por imagen , Neoplasias/metabolismo , HumanosRESUMEN
The NOTCH signaling pathway plays a pivotal role in diverse developmental processes, including cell proliferation and differentiation. In this study, we investigated whether this signaling molecules also contribute to avian adipogenesis. Using previous mRNA-seq datasets, we examined the expression of 11 signaling members during avian adipocyte differentiation. We found most members are down-regulated throughout differentiation (p < 0.05). As a representative, NOTCH1 was decreased in cultured chicken abdominal adipocytes during adipogenesis at mRNA and protein levels (p < 0.05). Moreover, using an overexpression plasmid for NOTCH1's intracellular domain (NICD1), as well as siRNA and DAPT to activate or deplete NOTCH1 in cells, we investigated the role of NOTCH1 in avian adipogenesis. Our findings illuminate that NOTCH1 activates the expression of HES1 and SOCS3 while it decreases NR2F2 and NUMB (p < 0.05), as well as inhibits oleic acid-induced adipocyte differentiation (p < 0.01). We further demonstrate that HES1, a downstream transcription factor activated by NOTCH1, also significantly inhibits adipogenesis by suppressing PPARγ and C/EBPα (p < 0.01). Collectively, these findings establish NOTCH1 as a negative regulator of avian adipocyte differentiation, unveiling NOTCH signaling as a potential target for regulating avian fat deposition.
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Locoregional radiotherapy added to chemotherapy has significantly improved survival in de novo metastatic nasopharyngeal carcinoma (mNPC). However, only 54% of de novo mNPC patients who received sequential chemoradiotherapy have complete or partial response 3 months after radiotherapy. This Simon's optimal two-stage design phase II study (NCT04398056) investigates whether PD-1 inhibitor could improve tumor control in combination with chemoradiation. The primary endpoint is objective response rate (ORR) at 3 months after radiotherapy. Twenty-two patients with primary mNPC are enrolled. The ORR at 3 months after radiotherapy is 81.8% (22.7% complete response, n = 5; 59.1% partial response, n = 13), and the disease control rate is 81.8%. The 3-year progression-free survival (PFS) rate is 44.9% (95% confidence interval 26.4%-76.3%). Fifteen patients (68.2%) experienced grade 3-4 adverse events. Patients with high baseline plasma Epstein-Barr virus DNA copy number (>104 cps/mL) show worse PFS. Addition of toripalimab to sequential chemoradiotherapy suggests promising tumor response in patients with primary mNPC.
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Infecciones por Virus de Epstein-Barr , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/tratamiento farmacológico , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Nasofaríngeas/patología , Herpesvirus Humano 4 , Quimioradioterapia/efectos adversosRESUMEN
Agricultural nonpoint source (NPS) pollution loss is closely related to hydrological processes. Understanding the differences in NPS pollution load loss under hydrological processes is useful for the management and prevention of NPS pollution. In this paper, hydrological and water quality data from 2016 to 2018 and monitoring data of physical and chemical indicators in 1347 field soil samples in the Shaying River Basin (SYRB) were used to analyze spatiotemporal variations in NPS pollution using the Soil and Water Assessment Tool and multifactor analysis of variance. The intensities and differences in NPS pollution losses for different soil types and land use patterns were evaluated under different hydrological zones. The annual rainfall in the SYRB decreased gradually from 1136.50 to 404.04 mm, showing a significant zoning. Areas with high loss intensities were mainly distributed in areas with steep slopes and in the 800-1000 mm rainfall zone. Cultivated land had the largest loss of NPS pollution, followed by forest land and rural residential land. Fluvo-aquic soil had the largest loss of NPS pollution, followed by cinnamon soil and lime concretion black soil. A nonlinear regression model was established for rainfall and the NPS pollution loss intensity and had a correlation coefficient of 0.60-0.99 at a 95% confidence level. Slope and rainfall were the main factors influencing the nitrogen and phosphorus losses. In the 800-1000 mm rainfall zone, the soil background nitrogen and phosphorus load was also a major factor influencing the nitrogen and phosphorus loss intensities.
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Contaminación Difusa , Contaminantes Químicos del Agua , Contaminación Difusa/análisis , Contaminantes Químicos del Agua/análisis , Ríos , Monitoreo del Ambiente , Suelo , China , Fósforo/análisis , Nitrógeno/análisisRESUMEN
A simple but efficient strategy to improve the ability of adsorptive denitrogenation (ADN) of MIL-101(M101) was studied by the in situ encapsulation of phosphomolybdic acid (PMA) and the subsequent purification of the as-synthesized product by the NH4F solution. After the NH4F treatment, the vast majority of PMA was removed, loss of organic ligand (BDC) was observed, and the fluorination of the hydroxyl group in the M101 structure occurred. The ADN activities of the Cr-MOF matrix composites before and after fluorination were studied in detail. The rest of PMA interacts strongly with M101 and assists the ADN activity. Coordination unsaturated metal sites (CUS) in M101 are formed after fluorination and also contribute to ADN activity. Further, fluoride anions replace most of the hydroxide groups in M101, which can promote the ADN of quinoline (QUI) and indole (IND) through an acid-base interaction and N-atom coordination with the CUS in M101. P-M101-F 5% exhibits the highest adsorptive capacity and excellent regeneration ability. Special emphasis in this work is placed on structure modulation (including PMA doping, CUS creation, and fluorination) of M101 for enhancing ADN activity, which provides a useful scaffold for future research in the rational design of MOF-based ADN catalysts.
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Glioma is the most common primary malignant brain tumour, and survival is poor. Hirudin has anticancer pharmacological effects through suppression of glioma cell progression, but the molecular target and mechanism are poorly understood. In this study, we observed that hirudin dose- and time-dependently inhibited glioma invasion, migration and proliferation. Mechanistically, hirudin activated LC3-II but not Caspase-3 to induce the autophagic death of glioma cells by decreasing the phosphorylation of mTOR and its downstream substrates ULK1, P70S6K and 4EBP1. Furthermore, hirudin inhibited glioma growth and induced changes in autophagy in cell-derived xenograft (CDX) nude mice, with a decrease in mTOR activity and activation of LC3-II. Collectively, our results highlight a new anticancer mechanism of hirudin in which hirudin-induced inhibition of glioma progression through autophagy activation is likely achieved by inhibition of the mTOR signalling pathway, thus providing a molecular basis for hirudin as a potential and effective clinical drug for glioma therapy.
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Glioma , Hirudinas , Ratones , Animales , Humanos , Hirudinas/farmacología , Ratones Desnudos , Línea Celular Tumoral , Serina-Treonina Quinasas TOR/metabolismo , Glioma/patología , Proliferación Celular , Autofagia , ApoptosisRESUMEN
Background: Treatment options for patients with recurrent/metastatic nasopharyngeal carcinoma (RM-NPC) are not clear after progression on previous treatment with PD-(L)1 inhibitor; critical gaps in evidence remain for such cases. Immunotherapy combined with antiangiogenic therapy has been reported to have synergistic antitumor activity. Therefore, we evaluated the efficacy and safety of camrelizumab plus famitinib in patients with RM-NPC who failed treatment with PD-1 inhibitor-containing regimens. Methods: This multicenter, adaptive Simon minimax two-stage, phase II study enrolled patients with RM-NPC refractory to at least one line of systemic platinum-containing chemotherapy and anti-PD-(L)1 immunotherapy. The patient received camrelizumab 200 mg every 3 weeks and famitinib 20 mg once per day. The primary endpoint was objective response rate (ORR), and the study could be stopped early as criterion for efficacy was met (>5 responses). Key secondary endpoints included time to response (TTR), disease control rate (DCR), progression-free survival (PFS), duration of response (DoR), overall survival (OS), and safety. This trial was registered with ClinicalTrials.gov, NCT04346381. Findings: Between October 12, 2020, and December 6, 2021, a total of 18 patients were enrolled since six responses were observed. The ORR was 33.3% (90% CI, 15.6-55.4) and the DCR was 77.8% (90% CI, 56.1-92.0). The median TTR was 2.1 months, the median DoR was 4.2 months (90% CI, 3.0-not reach), and the median PFS was 7.2 months (90% CI, 4.4-13.3), with a median follow-up duration of 16.7 months. Treatment-related adverse events (TRAEs) of grade ≥3 were reported in eight (44.4%) patients, with the most common being decreased platelet count and/or neutropenia (n = 4, 22.2%). Treatment-related serious AEs occurred in six (33.3%) patients, and no deaths occurred due to TRAEs. Four patients developed grade ≥3 nasopharyngeal necrosis; two of them developed grade 3-4 major epistaxis, and they were cured by nasal packing and vascular embolization. Interpretation: Camrelizumab plus famitinib exhibited encouraging efficacy and tolerable safety profiles in patients with RM-NPC who failed frontline immunotherapy. Further studies are needed to confirm and expand these findings. Funding: Jiangsu Hengrui Pharmaceutical Co., Ltd.
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The polyphosphoric acid (PPA) modified asphalt binder is a potential choice as one of the pavement materials for its excellent high-temperature performance and low cost. To further analyze the influences of temperature and load on the service life of pavement from the perspective of deformation behavior, six kinds of asphalt binders with different PPA dosages were prepared for Multiple Stress Creep and Recovery (MSCR) tests at five temperature levels. The deformation behavior is investigated by basic deformation parameters, rheological simulation, and energy parameter changes. The results show that the percent recovery (R) drops sharply while non-recoverable creep compliance (Jnr) goes up slightly with the increase in temperature. Three-element model, composed by E1, η1, and η2, can be used to describe the creep behavior. PPA-modified asphalt binder exhibits nonlinear creep behavior, and the logarithmic model can simulate recovery behavior better than the power-law model. Stored energy and dissipated energy can characterize the change of energy in the creep process under different conditions and show a significant correlation to deformation parameters. It is concluded that the elastic component of asphalt binders is increased by PPA, which is beneficial to the improvement of the deformation resistance and recovery capacity of asphalt binders. The recommended dosage of PPA is 1.5%. This investigation is conducive to a better understanding of the deformation behavior of PPA-modified asphalt binders and provides a reference for its engineering applications.
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PURPOSE: Evans blue as an albumin binder has been widely used to improve pharmacokinetics and enhance tumor uptake of radioligands, including prostate-specific membrane antigen (PSMA) targeting agents. The goal of this study is to develop an optimal Evans blue-modified radiotherapeutic agent that could maximize the absolute tumor uptake and tumor absorbed dose thus the therapeutic efficacy to allow treatment of tumors even with moderate level of PSMA expression. METHODS: [177Lu]Lu-LNC1003 was synthesized based on PSMA-targeting agent and Evans blue. Binding affinity and PSMA targeting specificity were verified through cell uptake and competition binding assay in 22Rv1 tumor model that has moderate level of PSMA expression. SPECT/CT imaging and biodistribution studies in 22Rv1 tumor-bearing mice were performed to evaluate the preclinical pharmacokinetics. Radioligand therapy studies were conducted to systematically assess the therapeutic effect of [177Lu]Lu-LNC1003. RESULTS: LNC1003 showed high binding affinity (IC50 = 10.77 nM) to PSMA in vitro, which was comparable with that of PSMA-617 (IC50 = 27.49 nM) and EB-PSMA-617 (IC50 = 7.91 nM). SPECT imaging of [177Lu]Lu-LNC1003 demonstrated significantly improved tumor uptake and retention as compared with [177Lu]Lu-EB-PSMA and [177Lu]Lu-PSMA-617, making it suitable for prostate cancer therapy. Biodistribution studies further confirmed the remarkably higher tumor uptake of [177Lu]Lu-LNC1003 (138.87 ± 26.53%ID/g) over [177Lu]Lu-EB-PSMA-617 (29.89 ± 8.86%ID/g) and [177Lu]Lu-PSMA-617 (4.28 ± 0.25%ID/g) at 24 h post-injection. Targeted radioligand therapy results showed noteworthy inhibition of 22Rv1 tumor growth after administration of a single dose of 18.5 MBq [177Lu]Lu-LNC1003. There was no obvious antitumor effect after [177Lu]Lu-PSMA-617 treatment under the same condition. CONCLUSION: In this study, [177Lu]Lu-LNC1003 was successfully synthesized with high radiochemical purity and stability. High binding affinity and PSMA targeting specificity were identified in vitro and in vivo. With greatly enhanced tumor uptake and retention, [177Lu]Lu-LNC1003 has the potential to improve therapeutic efficacy using significantly lower dosages and less cycles of 177Lu that promises clinical translation to treat prostate cancer with various levels of PSMA expression.
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Glutamato Carboxipeptidasa II , Neoplasias de la Próstata , Masculino , Humanos , Animales , Ratones , Distribución Tisular , Azul de Evans/uso terapéutico , Glutamato Carboxipeptidasa II/metabolismo , Antígenos de Superficie/metabolismo , Neoplasias de la Próstata/metabolismo , Radiofármacos/farmacocinética , Tomografía Computarizada por Tomografía Computarizada de Emisión de Fotón Único/métodos , Línea Celular Tumoral , Lutecio/uso terapéutico , Lutecio/farmacocinéticaRESUMEN
It is critical to understand factors associated with nasopharyngeal carcinoma (NPC) metastasis. To track the evolutionary route of metastasis, here we perform an integrative genomic analysis of 163 matched blood and primary, regional lymph node metastasis and distant metastasis tumour samples, combined with single-cell RNA-seq on 11 samples from two patients. The mutation burden, gene mutation frequency, mutation signature, and copy number frequency are similar between metastatic tumours and primary and regional lymph node tumours. There are two distinct evolutionary routes of metastasis, including metastases evolved from regional lymph nodes (lymphatic route, 61.5%, 8/13) and from primary tumours (hematogenous route, 38.5%, 5/13). The hematogenous route is characterised by higher IFN-γ response gene expression and a higher fraction of exhausted CD8+ T cells. Based on a radiomics model, we find that the hematogenous group has significantly better progression-free survival and PD-1 immunotherapy response, while the lymphatic group has a better response to locoregional radiotherapy.
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Carcinoma , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patología , Neoplasias Nasofaríngeas/patología , Relevancia Clínica , Linfocitos T CD8-positivos/patología , Metástasis Linfática/patología , Carcinoma/genética , Carcinoma/patología , Ganglios Linfáticos/patologíaRESUMEN
BACKGROUND: Reirradiation in standard fractionation for locally advanced recurrent nasopharyngeal carcinoma after a previous course of high-dose radiotherapy is often associated with substantial late toxicity, negating its overall benefit. We therefore aimed to investigate the efficacy and safety of hyperfractionation compared with standard fractionation in intensity-modulated radiotherapy. METHODS: This multicentre, randomised, open-label, phase 3 trial was done in three centres in Guangzhou, China. Eligible patients were aged 18-65 years with histopathologically confirmed undifferentiated or differentiated, non-keratinising, advanced locally recurrent nasopharyngeal carcinoma. Participants were randomly assigned (1:1) to either receive hyperfractionation (65 Gy in 54 fractions, given twice daily with an interfractional time interval of at least 6 h) or standard fractionation (60 Gy in 27 fractions, given once a day). Intensity-modulated radiotherapy was used in both groups. A computer program generated the assignment sequence and randomisation was stratified by treatment centre, recurrent tumour stage (T2-T3 vs T4), and recurrent nodal stage (N0 vs N1-N2), determined at the time of randomisation. The two primary endpoints were the incidence of severe late complications defined as the incidence of grade 3 or worse late radiation-induced complications occurring 3 months after the completion of radiotherapy until the latest follow-up in the safety population, and overall survival defined as the time interval from randomisation to death due to any cause in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02456506. FINDINGS: Between July 10, 2015, and Dec 23, 2019, 178 patients were screened for eligibility, 144 of whom were enrolled and randomly assigned to hyperfractionation or standard fractionation (n=72 in each group). 35 (24%) participants were women and 109 (76%) were men. After a median follow-up of 45·0 months (IQR 37·3-53·3), there was a significantly lower incidence of grade 3 or worse late radiation-induced toxicity in the hyperfractionation group (23 [34%] of 68 patients) versus the standard fractionation group (39 [57%] of 68 patients; between-group difference -23% [95% CI -39 to -7]; p=0·023). Patients in the hyperfractionation group had better 3-year overall survival than those in the standard fractionation group (74·6% [95% CI 64·4 to 84·8] vs 55·0% [43·4 to 66·6]; hazard ratio for death 0·54 [95% CI 0·33 to 0·88]; p=0·014). There were fewer grade 5 late complications in the hyperfractionation group (five [7%] nasal haemorrhage) than in the standard fractionation group (16 [24%], including two [3%] nasopharyngeal necrosis, 11 [16%] nasal haemorrhage, and three [4%] temporal lobe necrosis). INTERPRETATION: Hyperfractionated intensity-modulated radiotherapy could significantly decrease the rate of severe late complications and improve overall survival among patients with locally advanced recurrent nasopharyngeal carcinoma. Our findings suggest that hyperfractionated intensity-modulated radiotherapy could be used as the standard of care for these patients. FUNDING: Key-Area Research and Development of Guangdong Province, the National Natural Science Foundation of China, the Special Support Program for High-level Talents in Sun Yat-sen University Cancer Center, the Guangzhou Science and Technology Plan Project, and the National Ten Thousand Talents Program Science and Technology Innovation Leading Talents, Sun Yat-Sen University Clinical Research 5010 Program.
Asunto(s)
Neoplasias Nasofaríngeas , Radioterapia de Intensidad Modulada , Masculino , Humanos , Femenino , Carcinoma Nasofaríngeo/radioterapia , Radioterapia de Intensidad Modulada/efectos adversos , Recurrencia Local de Neoplasia/radioterapia , Neoplasias Nasofaríngeas/radioterapia , HemorragiaRESUMEN
PURPOSE: To determine the prognostic value of tumour contour irregularity degree (CID) in surgical strategy options for T1bN0M0 renal cell carcinoma (RCC). MATERIALS AND METHODS: We performed a retrospective multi-institutional review of 489 patients with T1bN0M0 RCC treated between January 2009 and June 2019. Cox regression and Kaplan-Meier analyses were performed to analyse the impact of CID on disease-free survival (DFS). RESULTS: The median follow-up time was 55 months (interquartile range, 40-81 months) for 55 (11.2 %) patients with metastasis or recurrence. Logistic analysis indicated that CID was associated with World Health Organization/International Society of Urological Pathology (WHO/ISUP) grades III-IV (odds ratio, 1.015; 95 % confidence interval [CI], 1.008-1.023; p < 0.001). After being classified into high CID (≥50 %) and low CID (<50 %) groups, those with a high CID showed a significantly higher ratio of WHO/IUSP grades III-IV (74/277 [26.7 %] vs 25/212 [11.8 %]) and shorter DFS than the low CID group (p < 0.001). Multivariable Cox regression showed that partial nephrectomy (PN; hazard ratio [HR], 1.889; 95 % CI, 1.020-3.499; p = 0.043), high CID (HR, 6.685; 95 % CI, 2.776-16.100; p < 0.001), and WHO/ISUP grade III-IV (HR, 1.950; 95 % CI, 1.100-3.458; p = 0.022) were independent prognostic factors for DFS. The Kaplan-Meier plot showed that PN had a DFS rate comparable to that of radical nephrectomy (RN; p = 0.994). In the low CID group, patients who underwent PN showed comparable DFS to those who underwent RN (p = 0.903). Furthermore, patients with a high CID tended to have worse DFS in the PN versus RN group (p = 0.044). Multivariable Cox regression showed that PN (HR, 2.049; 95 % CI, 1.065-3.942; p = 0.032) and WHO/ISUP grade III-IV (HR, 2.148; 95 % CI, 1.189-3.881; p = 0.011) were independent prognostic factors of DFS in the high CID group. CONCLUSIONS: CID is a reliable preoperative parameter which is positively correlated with WHO/ISUP grade and can help with surgical decision-making in patients with T1bN0M0 RCC.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/cirugía , Carcinoma de Células Renales/patología , Pronóstico , Neoplasias Renales/cirugía , Neoplasias Renales/patología , Estudios Retrospectivos , Resultado del Tratamiento , Estadificación de Neoplasias , NefrectomíaRESUMEN
Angioimmunoblastic T-cell lymphoma (AITL), a type of malignant lymphoma with unique genomic aberrations, significant clinicopathological features, and poor prognosis, is characterized by immune system dysregulation. Recent sequencing studies have identified recurrent mutations and interactions in tet methylcytosine dioxygenase 2 (TET2), ras homology family member A (RHOA), DNA methyltransferase 3 alpha (DNMT3A), and mitochondrial isocitrate dehydrogenase II (IDH2). Notably, since B-cell lymphomas are frequently observed along with AITL, this review first summarizes its controversial mechanisms based on traditional and recent views. Epigenetic regulation represented by TET2 plays an increasingly important role in understanding the multi-step and multi-lineage tumorigenesis of AITL, providing new research directions and treatment strategies for patients with AITL. Here, we review the latest advances in our understanding of AITL and highlight relevant issues that have yet to be addressed in clinical practice.