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Emerging contaminants pose a potential risk to aquatic ecosystems in the Pearl River Basin, China, owing to the high population density and active industry. This study investigated samples from eight sewage treatment plants, and five surface water bodies of related watersheds. To screen the risk of emerging contaminants (ECs), and clarify their sources, this study calculated the risk quotient of detected chemical and performed source identification/apportionment using the positive matrix factorization method. In total, 149 organic pollutants were identified. Pharmaceuticals showed significant concentrations in sewage treatment plant samples (120.87 ng/L), compared with surface water samples (1.13 ng/L). The ecological risk assessment identified three chemicals with a heightened risk to aquatic organisms: fipronil sulfide, caffeine, and roxithromycin. Four principal sources of contaminants were identified: pharmaceutical wastewater, domestic sewage, medical effluent, and agricultural runoff. Pharmaceutical wastewater was the primary contributor (60.4 %), to the cumulative EC concentration and to ECs in sewage treatment plant effluent. Agricultural drainage was the main source of ECs in surface water. This study provides a strategy to obtain comprehensive information on the aquatic risks and potential sources of EC species in areas affected by artificial activities, which is of substantial importance to pollutant management and control.
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Monitoreo del Ambiente , Ríos , Aguas del Alcantarillado , Contaminantes Químicos del Agua , Contaminantes Químicos del Agua/análisis , Ríos/química , China , Aguas del Alcantarillado/análisis , Medición de Riesgo , Preparaciones Farmacéuticas/análisis , Aguas Residuales/análisis , Aguas Residuales/química , Eliminación de Residuos LíquidosRESUMEN
There is usually a trade-off between high mechanical strength and dynamic self-healing because the mechanisms of these properties are mutually exclusive. Herein, we design and fabricate a fluorinated phenolic polyurethane (FPPU) elastomer based on octafluoro-4,4'-biphenol to overcome this challenge. This fluorine-based motif not only tunes interchain interactions through π-π stacking between aromatic rings and free-volume among polymer chains but also improves the reversibility of phenol-carbamate bonds via electron-withdrawing effect of fluorine atoms. The developed FPPU elastomer shows the highest recorded puncture energy (648.0 mJ), high tensile strength (27.0 MPa), as well as excellent self-healing efficiency (92.3%), along with low surface energy (50.9 MJ m-2), notch-insensitivity, and reprocessability compared with non-fluorinated counterpart biphenolic polyurethane (BPPU) elastomer. Taking advantage of the above-mentioned merits of FPPU elastomer, we prepare an anti-fouling triboelectric nanogenerator (TENG) with a self-healable, and reprocessable elastic substrate. Benefiting from stronger electron affinity of fluorine atoms than hydrogen atoms, this electronic device exhibits ultrahigh peak open-circuit voltage of 302.3 V compared to the TENG fabricated from BPPU elastomer. Furthermore, a healable and stretchable conductive composite is prepared. This research provides a distinct and general pathway toward constructing high-performance elastomers and will enable a series of new applications.
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Tartary buckwheat (Fagopyrum tataricum) is frequently employed as a resource to develop health foods, owing to its abundant flavonoids such as rutin. However, the consumption of Tartary buckwheat (TB) is limited in food products due to the strong bitterness induced by the hydrolysis of rutin into quercetin. This transformation is facilitated by the degrading enzyme (RDE). While multiple RDE isoenzymes exist in TB, the superior coding gene of FtRDEs has not been fully explored, which hinders the breeding of TB varieties with minimal bitterness. Here, we found that FtRDE2 is the most abundant enzyme in RDE crude extracts, and its corresponding gene is specifically expressed in TB seeds. Results showed that FtRDE2 has strong rutin hydrolysis activity. Overexpression of FtRDE2 not only significantly promoted rutin hydrolysis and quercetin accumulation but also dramatically upregulated genes involved in the early phase of flavonoid synthesis (FtPAL1ãFtC4H1ãFt4CL1, FtCHI1) and anthocyanin metabolism (FtDFR1). These findings elucidate the role of FtRDE2, emphasizing it as an endogenous factor contributing to the bitterness in TB and its involvement in the metabolic regulatory network. Moreover, correlation analysis revealed a positive relationship between the catalytic activity of RDE extracts and the expression level of FtRDE2 during seed germination. In summary, our results suggest that FtRDE2 can serve as a promising candidate for the molecular breeding of a TB variety with minimal bitterness.
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Fagopyrum , Quercetina , Quercetina/metabolismo , Fagopyrum/genética , Fagopyrum/metabolismo , Fitomejoramiento , Rutina/metabolismo , Semillas/metabolismoRESUMEN
PURPOSE: To investigate the differences between dominant and nondominant eyes in a predominantly young patient population by analyzing the angle kappa, pupil size, and center position in dominant and nondominant eyes. METHODS: A total of 126 young college students (252 eyes) with myopia who underwent femtosecond laser-combined LASIK were randomly selected. Ocular dominance was determined using the hole-in-card test. The WaveLight Allegro Topolyzer (WaveLight Laser Technologies AG, Erlangen, Germany) was used to measure the pupil size and center position. The offset between the pupil center and the coaxially sighted corneal light reflex (P-Dist) of the patients was recorded by the x- and y-axis eyeball tracking adjustment program of the WaveLight Eagle Vision EX500 excimer laser system (Wavelight GmbH). The patient's vision (uncorrected distance visual acuity [UDVA], best-corrected visual acuity (BCVA), and refractive power (spherical equivalent, SE) were observed preoperatively, 1 week, 4 weeks, and 12 weeks postoperatively, and a quality of vision (QoV) questionnaire was completed. RESULTS: Ocular dominance occurred predominantly in the right eye [right vs. left: (178) 70.63% vs. (74) 29.37%; p < 0.001]. The P-Dist was 0.202 ± 0.095 mm in the dominant eye and 0.215 ± 0.103 mm in the nondominant eye (p = 0.021). The horizontal pupil shift was - 0.07 ± 0.14 mm in dominant eyes and 0.01 ± 0.13 mm in nondominant eyes (p = 0.001) (the temporal displacement of the dominant eye under mesopic conditions). The SE was negatively correlated with the P-Dist (r = - 0.223, p = 0.012 for the dominant eye and r = - 0.199, p = 0.025 for the nondominant eye). At 12 weeks postoperatively, the safety index (postoperative BDVA/preoperative BDVA) of the dominant and nondominant eyes was 1.20 (1.00, 1.22) and 1.20 (1.00, 1.20), respectively, and the efficacy index (postoperative UDVA/preoperative BDVA) was 1.00 (1.00, 1.20) and 1.00 (1.00, 1.20), respectively; the proportion of residual SE within ± 0.50 D was 98 and 100%, respectively. CONCLUSIONS: This study found that ocular dominance occurred predominantly in the right eye. The pupil size change was larger in the dominant eye. The angle kappa of the dominant eye was smaller than that of the nondominant eye and the pupil center of the dominant eye was slightly shifted to the temporal side under mesopic conditions. The correction of myopia in the dominant and nondominant eyes exhibits good safety, efficacy, and predictability in the short term after surgery, and has good subjective visual quality performance after correction. We suggest adjusting the angle kappa percentage in the dominant eye to be lower than that of the nondominant eye in individualized corneal refractive surgery in order to find the ablation center closest to the visual axis.
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A proportion of acute ischemic stroke (AIS) patients suffer from early neurological deterioration (END) within 24 hours following intravenous thrombolysis (IVT), which greatly increases the risk of poor prognosis of these patients. Therefore, we aimed to explore the predictors of early neurological deterioration of ischemic origin (ENDi) in AIS patients after IVT and develop a nomogram prediction model. This study collected 244 AIS patients with post-thrombolysis ENDi as the derivation cohort and 155 patients as the validation cohort. To establish a nomogram prediction model, risk factors were identified by multivariate logistic regression analysis. The results showed that neutrophil to lymphocyte ratio (NLR) (OR 2.616, 95% CI 1.640-4.175, P < 0.001), mean platelet volume (MPV) (OR 3.334, 95% CI 1.351-8.299, P = 0.009), body mass index (BMI) (OR 1.979, 95% CI 1.285-3.048, P = 0.002) and atrial fibrillation (AF) (OR 8.012, 95% CI 1.341-47.873, P = 0.023) were significantly associated with ENDi. The area under the curve of the prediction model constructed from the above four factors was 0.981 (95% CI 0.961-1.000) and the calibration curve was close to the ideal diagonal line. Therefore, this nomogram prediction model exhibited good discrimination and calibration power and might be a reliable and easy-to-use tool to predict post-thrombolysis ENDi in AIS patients.
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Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Accidente Cerebrovascular/terapia , Fibrinolíticos/efectos adversos , Accidente Cerebrovascular Isquémico/complicaciones , Isquemia Encefálica/complicaciones , Terapia Trombolítica/efectos adversos , Terapia Trombolítica/métodosRESUMEN
Previous research has revealed that individuals with different levels of intelligence exhibit distinct patterns of event-related potentials (ERPs) related to executive functions and temporary storage. However, there is a lack of studies investigating the relative contributions of these ERPs in predicting individual differences in fluid intelligence. This study aims to examine the extent to which ERPs associated with executive functions and temporary storage can predict individual differences in fluid intelligence. Special attention is given to determining whether electrophysiological activities of temporary storage can predict fluid intelligence after accounting for executive functions, and vice versa. Both executive attention and temporary storage were measured by two experimental tasks, while electroencephalographic data were collected simultaneously. Fluid intelligence was assessed by two established tests. To address previous inconsistencies due to small sample sizes, a relatively large sample of young adults (N = 136) was recruited. The results revealed that participants with lower fluid intelligence displayed larger P3 amplitudes in the executive functions and temporary storage tasks compared to those with higher fluid intelligence. Additionally, the amplitudes of frontal and parietal P3s elicited by both executive functions and temporary storage significantly predicted fluid intelligence. Interestingly, the frontal and parietal P3s associated with temporary storage predicted fluid intelligence beyond the contributions of executive functions, supporting the storage account of individual differences in fluid intelligence. This study provides an original and fresh understanding of how executive functions and temporary storage contribute to fluid intelligence, offering new insights into the neurocognitive mechanisms underlying intelligence.
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Función Ejecutiva , Memoria a Corto Plazo , Adulto Joven , Humanos , Función Ejecutiva/fisiología , Memoria a Corto Plazo/fisiología , Inteligencia/fisiología , Potenciales Evocados/fisiología , ElectroencefalografíaRESUMEN
Background: Esophageal cancer (EC) is the 6th leading cause of cancer-related deaths worldwide, and the morbidity and mortality of EC have continued to increase in recent years. The results of the clinical application of the Fast-track recovery surgery (FTS) concept in nursing interventions for EC patients after total endoscopic esophagectomy are unconvincing. This study sought to evaluate the nursing effect of the fast-track recovery surgical nursing model on patients with EC after total cavity endoscopic esophagectomy. Methods: We searched for articles on case-control trials about nursing interventions after total endoscopic esophagectomy. The search time was set from January 2010 to May 2022. The data were independently extracted by 2 researchers. RevMan5.3 statistical software (Cochrane) was used to analyze the extracted data. All the articles included in the review were assessed for risk of bias using the Cochrane Handbook 5.3 (https://training.cochrane.org/). Results: Ultimately, 8 clinical controlled trials, comprising 613 cases, were identified. A meta-analysis was conducted of the extubation times, and the results showed that the study group's extubation times were remarkably shorter. In relation to the exhaust times, the study group had significantly shorter exhaust times than control group (P<0.05). In relation to the time, it took patients to leave bed, patients in the study group left bed in a considerably shorter time compared with controls (P<0.00001). In relation to the hospitalization time, a remarkable reduction in the length of hospital stay was observed in the study group (P<0.00001). The analysis of the funnel plots showed a small number of asymmetries, suggesting that the number of articles included was small due to the heterogeneity of the studies (P<0.00001). Conclusions: FTS care is effective at accelerating patients' postoperative recovery. This model of care needs to be further validated in the future by higher-quality and longer follow-up studies.
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Curcumin could inhibit periprosthetic osteolysis induced by wear debris and adherent endotoxin, which commonly cause prosthesis loosening and negatively influence the long-term survival of joint arthroplasty. However, its limited water solubility and poor stability pose challenges for its further clinical application. To address these issues, we developed curcumin liposomes for intraarticular injection, as liposomes possess good lubricant capacity and pharmacological synergy with curcumin. Additionally, a nanocrystal dosage form was prepared to enable comparison with the liposomes based on their ability to disperse curcumin effectively. A microfluidic method was used for its controllability, repeatability, and scalability. The Box-Behnken Design was employed to screen the formulations and flow parameters, while computational fluid dynamics was used to simulate the mixing process and predict the formation of liposomes. The optimized curcumin liposomes (Cur-LPs) had a size of 132.9 nm and an encapsulation efficiency of 97.1%, whereas the curcumin nanocrystals (Cur-NCs) had a size of 172.3 nm. Both Cur-LPs and Cur-NCs inhibited LPS-induced pro-inflammatory polarization of macrophages and reduced the expression and secretion of inflammatory factors. The mouse air pouch model further demonstrated that both dosage forms attenuated inflammatory cell infiltration and inflammatory fibrosis in subcutaneous tissues. Interestingly, the anti-inflammatory effect of Cur-LPs was more potent than that of Cur-NCs, both in vitro and in vivo, although the cellular uptake of Cur-NCs was quicker. In conclusion, the results demonstrate that Cur-LPs have great potential for the clinical treatment of inflammatory osteolysis and that the therapeutic effect is closely related to the liposomal dosage form.
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Curcumina , Nanopartículas , Osteólisis , Ratones , Animales , Liposomas , Curcumina/farmacología , Curcumina/uso terapéutico , Curcumina/química , Osteólisis/tratamiento farmacológico , Lipopolisacáridos , Nanopartículas/químicaRESUMEN
Renal cell carcinoma (RCC) is a serious threat to people's health due to its rapid progression, and patients easily develop resistance to targeted therapy. The absent in melanoma 2 (AIM2) is a receptor protein that has recently been proposed to play an important role in various diseases. In this study, AIM2 was identified as a new biomarker of RCC and promoted RCC progression and sunitinib resistance in an inflammasome-independent manner. Mechanistically, AIM2 promoted FOXO3a phosphorylation and proteasome degradation, thereby reducing its transcriptional effect on ACSL4 and inhibiting ferroptosis. In summary, AIM2 promoted RCC progression and sunitinib resistance through FOXO3a-ACSL4 axis-regulated ferroptosis, which could provide new ideas and therapeutic targets for RCC diagnosis and treatment.
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Carcinoma de Células Renales , Ferroptosis , Neoplasias Renales , Melanoma , Humanos , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Sunitinib/farmacología , Sunitinib/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Ferroptosis/genética , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Proteínas de Unión al ADNRESUMEN
Zirconium (Zr) hydrides threaten the reliability of fuel assembly and have repeatedly induced failures in cladding tubes and pressure vessels. Thus, they attract a broad range of research interests. For example, delayed hydride cracking induced a severe fracture and failure in a Zircaloy-2 pressure tube in 1983, causing the emergency shutdown of the Pickering nuclear reactor. Hydride has high hardness and very low toughness, and it tends to aggregate toward cooler or tensile regions, which initiates localized hydride precipitation and results in delayed hydride cracking. Notably, hydride reorientation under tensile stress substantially decreases the fracture toughness and increases the ductile-to-brittle transition temperature of Zr alloys, which reduces the safety of the long-term storage of spent nuclear fuel. Therefore, improving our knowledge of Zr hydrides is useful for effectively controlling hydride embrittlement in fuel assembly. The aim of this review is to reorganize the mechanisms of hydride nucleation and growth behaviors, hydride reorientation under external stress, and hydride-induced embrittlement. We revisit important examples of progress of research in this field and emphasize the key future aspects of research on Zr hydrides.
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A recent study confirmed that thiolutin is effective in the treatment of nucleotide-binding domain-like receptor protein 3 (NLRP3)-related inflammatory diseases. Nevertheless, whether thiolutin (THL) is involved in the regulation of NLRP3 inflammasome in ischemic stroke is not known. The murine neuronal cell oxygen-glucose deprivation (OGD) model was first established, and then different concentrations (25 nM and 50 nM) of THL were administered for 48 h incubation, respectively. Subsequently, cell viability and toxicity, and the levels of intracellular inflammatory factors interleukin-1ß (IL-1ß), interleukin-18 (IL-18), oxidative stress factors superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT) and malondialdehyde (MDA), and NLRP3 inflammasome activation-related proteins pro-caspase, caspase-1, apoptosis-associated speck like-protein (ASC) and NLRP3 were examined, respectively. We further established the mouse middle cerebral artery occlusion (MCAO) model to evaluate the therapeutic effects of THL on cerebral infarction like behaviors in mice and the preventive effects on NLRP3 inflammasome activation in vivo. Cell cytotoxic, and the levels of inflammatory factors and oxidative stress were conspicuously increased, and NLRP3 inflammasome was materially activated in the OGD-induced cell model and MCAO-established mouse model, which were partially countered by THL treatment. Besides, intraperitoneal injection of THL could prominently reduce the cerebral infarct volume and neuromotor deficit scores in MCAO mice. The present study confirmed that THL attenuated neuronal and cerebral inflammatory injury caused by OGD and MCAO models in mice through restraining NLRP3 inflammasome activation in vitro and in vivo.
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Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Ratones , Animales , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Caspasa 1/metabolismo , Oxígeno , Isquemia Encefálica/tratamiento farmacológicoRESUMEN
Grapholita molesta is one of the most damaging pests worldwide in stone and pome fruits. Application of chemical pesticides is still the main method to control this pest, which results in resistance to several types of insecticides. Carboxylesterase (CarE) is one of the important enzymes involved in the detoxification metabolism and tolerance of xenobiotics and insecticides. However, the roles of CarEs in insecticides susceptibility of G. molesta are still unclear. In the present study, the enzyme activity of CarEs and the mRNA expression of six CarE genes were consistently elevated after treatment with three insecticides (emamectin benzoate, lambda-cyhalothrin, and chlorantraniliprole). According to spatio-temporal expression profiles, six CarE genes expressed differently in different developmental stages, and highly expressed in some detoxification metabolic organs. RNAi-mediated knockdown of these six CarE genes indicated that the susceptibility of G. molesta to all these three insecticides were obviously raised after GmCarE9, GmCarE14, GmCarE16, and GmCarE22 knockdown, respectively. Overall, these results demonstrated that GmCarE9, GmCarE14, GmCarE16, and GmCarE22 play a role in the susceptibility of G. molesta to emamectin benzoate, lambda-cyhalothrin, and chlorantraniliprole treatment. This study expands our understanding of CarEs in insects, that the same CarE gene could participate in the susceptibility to different insecticides.
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Insecticidas , Mariposas Nocturnas , Animales , Insecticidas/farmacología , Insecticidas/metabolismo , Carboxilesterasa/genética , Mariposas Nocturnas/genética , Larva/metabolismoRESUMEN
PURPOSE: Angiogenesis is involved in many pathological and physiological processes and is mainly driven by hypoxia. Karyopherin subunit alpha 2 (KPNA2), a member of the nuclear transport protein family, was recently shown to be induced by hypoxia in various types of tumours, so we aimed to investigate the role and mechanism of KPNA2 in angiogenesis under hypoxia. MATERIALS AND METHODS: After overexpression or knockdown of KPNA2 in human umbilical vein endothelial cells (HUVEC) by adenovirus vector infection, the tube formation, proliferation and migration of HUVEC under hypoxia were detected by tubule formation assay, 5-ethynyl-2'-deoxyuridine (EdU) staining and Transwell assay, respectively. After overexpression or knockdown of KPNA2 in a murine hindlimb ischemia model by local injection of purified adenovirus vector into the gastrocnemius muscle, blood flow changes were examined with a laser Doppler system. Changes in KPNA2-binding proteins under hypoxia were detected by immunoprecipitation-mass spectrometry (IP-MS) and co-immunoprecipitation (Co-IP). The effect of KPNA2 on signal transducer and activator of transcription 3 (STAT3) was detected by Western blotting and quantitative RTâPCR. RESULTS: KPNA2 was upregulated in the HUVEC hypoxia model and murine hindlimb ischemia model. Overexpression of KPNA2 increased the proliferation, migration and tube formation of HUVEC under hypoxia, while knockdown of KPNA2 reduced the proliferation, migration and tube formation of HUVEC. Overexpression of KPNA2 promoted the restoration of blood flow in the murine hindlimb ischemia model, while knockout of KPNA2 inhibited the restoration of blood flow in the murine hindlimb ischemia model. Mechanistically, hypoxia promoted the binding of STAT3 to KPNA2. Overexpression of KPNA2 promoted STAT3 phosphorylation and then upregulated vascular endothelial growth factor (VEGF) and angiopoietin 2(ANGPT2), whereas knockdown of KPNA2 inhibited STAT3 phosphorylation and then downregulated VEGF and ANGPT2. CONCLUSION: Our study demonstrates that hypoxia promotes the binding of STAT3 to KPNA2 and KPNA2 promotes angiogenesis under hypoxia by promoting the binding of STAT3 and JAK1 and regulating STAT3 phosphorylation.
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Factor de Transcripción STAT3 , Factor A de Crecimiento Endotelial Vascular , Humanos , Ratones , Animales , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor de Transcripción STAT3/metabolismo , Fosforilación , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Neovascularización Fisiológica , Isquemia , Hipoxia/metabolismo , alfa CarioferinasRESUMEN
With the development of nanomedicine technology, stimuli-responsive nanocarriers play an increasingly important role in antitumor therapy. Compared with the normal physiological environment, the tumor microenvironment (TME) possesses several unique properties, including acidity, high glutathione (GSH) concentration, hypoxia, over-expressed enzymes and excessive reactive oxygen species (ROS), which are closely related to the occurrence and development of tumors. However, on the other hand, these properties could also be harnessed for smart drug delivery systems to release drugs specifically in tumor tissues. Stimuli-responsive nanoparticles (srNPs) can maintain stability at physiological conditions, while they could be triggered rapidly to release drugs by specific stimuli to prolong blood circulation and enhance cancer cellular uptake, thus achieving excellent therapeutic performance and improved biosafety. This review focuses on the design of srNPs based on several stimuli in the TME for the delivery of antitumor drugs. In addition, the challenges and prospects for the development of srNPs are discussed, which can possibly inspire researchers to develop srNPs for clinical applications in the future.
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RATIONALE: Central retinal artery occlusion (CRAO) sparing the cilioretinal artery (CLRA) with severe subretinal fluid and non-characteristic cherry-red spot is uncommon. In the present case, the patient received an intravitreal injection of anti- vascular endothelial growth factor, which is very rare. PATIENT CONCERNS: A 59-year-old man underwent vitrectomy of the left eye for diabetic retinopathy and vitreous hemorrhage. Six months after the operation, the patient presented with sudden painless visual-acuity decline in his left eye and was diagnosed with CRAO; his best corrected visual acuity was weak light perception. Whole retinal edema was seen on the fundus, and macular gray retinal opacification was present without a characteristic cherry-red spot. Optical coherence tomography revealed subretinal fluid (SRF) in the papillomacular bundle and inner retinal thickening. Fundus fluorescein angiography confirmed that the central retinal artery was not filled at 40 seconds and that the CLRA supplied a part of the macular area. Eight months after the second intravitreal injection of ranibizumab, Optical coherence tomography showed a significant reduction in inner retinal hyperreflectivity and the thickness of the nasal macular retina. The SRF was clearly absorbed, and the visual acuity improved to 1.1 logMAR units. DIAGNOSIS: Atypical CRAO. INTERVENTIONS: The patient was treated with intravitreal injection of anti-VEGF in his left eye. The thickness of the nasal macular retina decreased. OUTCOMES: The SRF was clearly absorbed, and the patient's visual acuity significantly improved. LESSONS: When CRAO occurs in patients with diabetic retinopathy sparing the CLRA, the non-characteristic cherry-red spot may be due to macular inner retinal edema, SRF and other factors. According to the patient's condition, anti-vascular endothelial growth factor can be administered as appropriate to inhibit choroidal neovascularization, reduce SRF in the macular retina, and save some vision.
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Retinopatía Diabética , Edema Macular , Papiledema , Oclusión de la Arteria Retiniana , Masculino , Humanos , Persona de Mediana Edad , Líquido Subretiniano , Retinopatía Diabética/complicaciones , Retinopatía Diabética/tratamiento farmacológico , Papiledema/complicaciones , Oclusión de la Arteria Retiniana/etiología , Arterias Ciliares , Inhibidores de la Angiogénesis/uso terapéutico , Edema Macular/etiología , Edema Macular/complicaciones , Factores de Crecimiento Endotelial Vascular/uso terapéutico , Anticuerpos Monoclonales/uso terapéuticoRESUMEN
Chimeric receptor T cells (CAR-T) can effectively cure leukemia; however, there are two limitations: a complicated preparation process ex vivo and cytokine release syndrome (CRS). In this study, we constructed a lipid nanoparticle system modified by CD3 antibody on the surface, loading with the plasmid containing the combination gene of interleukin 6 short hairpin RNA (IL-6 shRNA) and CD19-CAR (AntiCD3-LNP/CAR19 + shIL6). The system targeted T cells by the mediation of CD3 antibody and stably transfected T cells to transform them into CAR-T cells with IL-6 knockdown, thus killing CD19-highly expressed leukemia tumor cells and reducing CRS caused by IL-6. In vivo experiments showed that AntiCD3-LNP/CAR19 + shIL6 could stably transfect T cells and produce CAR-T within 90 days to kill the tumor. This significantly prolonged the survival time of leukemia model mice and demonstrated the prepared LNP exhibited the same anti-tumor effect as the traditional CAR-T cells prepared ex vivo. In this study, CAR-T cells were directly produced in vivo after intravenous injection of the lipid nanoparticles, without the need of using the current complex process ex vivo. Additionally, IL-6 expression was silenced, which would be helpful to reduce the CRS and improve the safety of CAR-T therapy. This method improves the convenience of using CAR-T technology and is helpful in further promoting the clinical application of CAR-T.
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Leucemia , Receptores Quiméricos de Antígenos , Animales , Antígenos CD19 , Inmunoterapia Adoptiva/métodos , Interleucina-6/genética , Liposomas , Ratones , Nanopartículas , ARN Interferente Pequeño/genética , Receptores Quiméricos de Antígenos/genética , Linfocitos TRESUMEN
PURPOSE: Chimeric antigen receptor (CAR) T cell therapy has demonstrated clinical success in treating haematologic malignancies but has not been effective against solid tumours thus far. Trop2 is a tumour-related antigen broadly overexpressed on a variety of tumours and has been reported as a promising target for pancreatic cancers. Our study aimed to determine whether CAR T cells designed with a fully human Trop2-specific single-chain fragment variable (scFv) can be used in the treatment of Trop2-positive pancreatic tumours. METHODS: We designed Trop2-targeted chimeric antigen receptor engineered T cells with a novel human anti-Trop2 scFv (2F11) and then investigated the cytotoxicity, degranulation, and cytokine secretion profiles of the anti-Trop2 CAR T cells when they were exposed to Trop2 + cancer cells in vitro. We also studied the antitumour efficacy and toxicity of Trop2-specific CAR T cells in vivo using a BxPC-3 pancreatic xenograft model. RESULTS: Trop2-targeted CAR T cells designed with 2F11 effectively killed Trop2-positive pancreatic cancer cells and produced high levels of cytotoxic cytokines in vitro. In addition, Trop2-targeted CAR T cells, which persistently circulate in vivo and efficiently infiltrate into tumour tissues, significantly blocked and even eliminated BxPC-3 pancreatic xenograft tumour growth without obvious deleterious effects observed after intravenous injection into NSG mice. Moreover, disease-free survival was efficiently prolonged. CONCLUSION: These results show that Trop2-targeted CAR T cells equipped with a fully human anti-Trop2 scFv could be a potential treatment strategy for pancreatic cancer and could be useful for clinical evaluation.
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Neoplasias Pancreáticas , Receptores Quiméricos de Antígenos , Animales , Antígenos de Neoplasias , Línea Celular Tumoral , Humanos , Inmunoterapia Adoptiva/métodos , Ratones , Neoplasias Pancreáticas/terapia , Linfocitos T , Ensayos Antitumor por Modelo de Xenoinjerto , Neoplasias PancreáticasRESUMEN
Persistence of CAR-T cell function is associated with relapse rate after CAR-T therapy, while co-stimulatory agents are highly concerned with the persistence of CAR-T cells. In this study, we designed and constructed a series of BCMA-targeting second-generation CAR constructs containing CD28, 41BB, and OX40 molecules, respectively, to identify the costimulatory domains most favorable for persistence. The results of routine in vitro studies showed that OX40-CAR-T and 41BB-CAR-T had similar antitumor effects and were superior to CD28-CAR-T in terms of proliferation and cytotoxicity. Although difficult to distinguish by conventional functional assays, OX40-CAR-T cells exhibited greater proliferation and enhanced immune memory than 41BB-CAR-T cells with the repeated stimulation assay by BCMA-expressing target cells. In vivo studies further demonstrated that OX40-CAR-T cells had stronger proliferative activity than 41BB-CAR-T cells, which was highly consistent with the in vitro antitumor activity and proliferation results. Our study provides for the first time a scientific basis for designing OX40-CAR-T cell therapy to improve relapse in patients with MM after CAR-T treatment.
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Mieloma Múltiple , Receptores Quiméricos de Antígenos , Humanos , Inmunoterapia Adoptiva/métodos , Mieloma Múltiple/terapia , Recurrencia Local de Neoplasia , Linfocitos TRESUMEN
Although chimeric antigen receptor (CAR) T cell immunotherapy has shown promising significance in B cell malignancies, success against T cell malignancies remains unsatisfactory because of shared antigenicity between normal and malignant T cells, resulting in fratricide and hindering CAR production for clinical treatment. Here, we report a new strategy of blocking the CD7 antigen on the T cell surface with a recombinant anti-CD7 antibody to obtain a sufficient amount of CD7-targeting CAR-T cells for T cell acute lymphoblastic leukemia (T-ALL) treatment. Feasibility was evaluated systematically, revealing that blocking the CD7 antigen with an antibody effectively blocked CD7-derived fratricide, increased the expansion rate, reduced the proportion of regulatory T (Treg) cells, maintained the stem cell-like characteristics of T cells, and restored the proportion of the CD8+ T cell population. Ultimately, we obtained anti-CD7 CAR-T cells that were specifically and effectively able to kill CD7 antigen-positive target cells, obviating the need for complex T cell modifications. This approach is safer than previous methods and provides a new, simple, and feasible strategy for clinical immunotherapies targeting CD7-positive malignant tumors.