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As the world's fourth most deadly cancer, colorectal cancer (CRC) still needed the novel therapeutic drugs and target urgently. Although cyclin-dependent kinase 12 (CDK12) has been shown to be implicated in the malignancy of several types of cancer, its functional role and mechanism in CRC remain largely unknown. Here, we found that suppression of CDK12 inhibited tumor growth in CRC by inducing apoptosis. And CDK12 inhibition triggered autophagy by upregulating autophagy related gene 7 (ATG7) expression. Inhibition of autophagy by ATG7 knockdown and chloroquine (CQ) further decreased cell viability induced by CDK12 inhibition. Further mechanism exploration showed that CDK12 interacted with protein kinase B (AKT) regulated autophagy via AKT/forkhead box O3 (AKT/FOXO3) pathway. FOXO3 transcriptionally upregulated ATG7 expression and autophagy when CDK12 inhibition in CRC. Level of CDK12 and p-FOXO3/FOXO3 ratio were correlated with survival in CRC patients. Moreover, CDK12 inhibition improved the efficacy of anti-programmed cell death 1(PD-1) therapy in CRC murine models by enhancing CD8 + T cells infiltration. Thus, our study founded that CDK12 inhibition upregulates ATG7 triggering autophagy via AKT/FOXO3 pathway and enhances anti-PD-1 efficacy in CRC. We revealed the roles of CDK12/FOXO3/ATG7 in regulating CRC progression, suggesting potential biomarkers and therapeutic target for CRC.
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Neoplasias Colorrectales , Proteínas Proto-Oncogénicas c-akt , Humanos , Animales , Ratones , Quinasas Ciclina-Dependientes , Apoptosis , Autofagia , Neoplasias Colorrectales/tratamiento farmacológico , Proteína Forkhead Box O3RESUMEN
Refreezing the remaining genetic resources after in vitro fertilization (IVF) can conserve genetic materials. However, the precise damage inflicted by repeated freezing and thawing on bovine sperm and its underlying mechanism remain largely unexplored. Thus, this study investigates the impact of repeated freeze-thaw cycles on sperm. Our findings indicate that such cycles significantly reduce sperm viability and motility. Furthermore, the integrity of the sperm plasma membrane and acrosome is compromised during this process, exacerbating the advanced apoptosis triggered by oxidative stress. Additionally, transmission electron microscopy exposed severe damage to the plasma membranes of both the sperm head and tail. Notably, the "9 + 2" structure of the tail was disrupted, along with a significant decrease in the level of the axonemal protein DNAH10, leading to reduced sperm motility. IVF outcomes revealed that repeated freeze-thaw cycles considerably impair sperm fertilization capability, ultimately reducing the blastocyst rate. In summary, our research demonstrates that repeated freeze-thaw cycles lead to a decline in sperm viability and motility, attributed to oxidative stress-induced apoptosis and DNAH10-related dynamic deficiency. As a result, the utility of semen is compromised after repeated freezing.
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Apoptosis , Criopreservación , Fertilización In Vitro , Congelación , Estrés Oxidativo , Preservación de Semen , Motilidad Espermática , Espermatozoides , Animales , Masculino , Bovinos , Criopreservación/veterinaria , Criopreservación/métodos , Preservación de Semen/veterinaria , Preservación de Semen/métodos , Espermatozoides/fisiología , Fertilización In Vitro/veterinaria , Congelación/efectos adversos , Membrana Celular , Supervivencia Celular , AcrosomaRESUMEN
BACKGROUND: To investigate the effects of rigid gas permeable contact lens (RGP-CL) wear on contrast visual acuity in patients after penetrating keratoplasty. METHODS: Nineteen patients (19 eyes), aged 30.45 ± 5.83 years, who had received penetrating keratoplasty and were successfully fitted with RGP-CLs at our hospital from July 2017 to June 2018 were included. Contrast visual acuities at 100%, 25%, and 10% with spectacles and RGP-CLs were analyzed using the Chi-square test. The wavefront aberrations at the anterior surface of the cornea before and 1 month after RGP-CL wear were compared using the matched sample t-test. RESULTS: The mean best spectacle-corrected visual acuities were 0.390 ± 0.135 logMAR, 0.706 ± 0.182 logMAR, and 0.952 ± 0.223 logMAR at the 100%, 25%, and 10% contrast levels, respectively, which were significantly lower than the RGP-CL-corrected visions at the three levels (0.255 ± 0.133 logMAR, 0.488 ± 0.168 logMAR, and 0.737 ± 0.159 logMAR; all P < 0.001). The vision losses with RGP-CLs were 0.231 ± 0.099 logMAR and 0.466 ± 0.094 logMAR at the 25% and 10% contrast levels, respectively. The Zernike spherical aberration Z04 was reduced from 3.734 ± 1.061 µm to 2.622 ± 0.725 µm after wearing the RGP-CLs (P ≤ 0.001). The astigmatism parameters of Z- 22 and Z22 were also reduced from 3.761 ± 2.309 µm and 3.316 ± 2.147 µm to 2.637 ± 1.722 µm and 2.016 ± 1.184 µm, respectively (P < 0.05). CONCLUSION: For post-keratoplasty patients, RGP-CLs can help to improve visual performance, especially low contrast visual acuity. The improvement may be related to the reduction of corneal aberrations, mainly the spherical and astigmatism aberrations.
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Astigmatismo , Lentes de Contacto , Humanos , Queratoplastia Penetrante , Astigmatismo/cirugía , Agudeza Visual , Córnea , Trastornos de la VisiónRESUMEN
In this study, transport behaviors of graphene oxide (GO) in saturated uncoated (i.e., clean sand) and goethite-coated sand porous media were examined as a function of the phosphate. We found that phosphate enhanced the transport of GO over a wide range of solution chemistry (i.e., pH 5.0-9.0 and the presence of 10 mmol/L Na+ or 0.5 mmol/L Ca2+). The results were mainly ascribed to the increase of electrostatic repulsion between nanoparticles and porous media. Meanwhile, deposition site competition induced by the retained phosphate was another important mechanism leading to promote GO transport. Interestingly, when the phosphate concentration increased from 0.1 to 1.0 mmol/L, the transport-enhancement effect of phosphate in goethite-coated sand was to a much larger extent than that in clean sand. The observations were primarily related to the difference in the total mass of retained phosphate between the iron oxide-coated sand and clean sand columns, which resulted in different degrees of the electrostatic repulsion and competitive effect of phosphate. When the background solution contained 0.5 mmol/L Ca2+, phosphate could be bind to sand/ goethite-coated sand surface by cation bridging; and consequently, promoted competition between phosphate and nanoparticles for deposition sites, which was an important mechanism for the enhanced effect of phosphate. Moreover, the DLVO theory was applicable to describe GO transport behaviors in porous media in the absence or presence of phosphate. Taken together, these findings highlight the important status and role of phosphate on the transport and fate of colloidal graphene oxide in the subsurface environment.
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Nanopartículas , Dióxido de Silicio , Compuestos Férricos , Grafito , Fosfatos , Porosidad , ArenaRESUMEN
In this paper, a type of effective electronic counter-countermeasures (ECCM) technique for suppressing the high-power deception jamming using an orthogonal frequency division multiplexing (OFDM) radar is proposed. Concerning the velocity deception jamming, the initial phases of the pulses transmitted in a coherent processing interval (CPI) are designed to minimize the jamming power within a specific range, forming a notch around the jamming in the Doppler spectrum. For the purpose of suppressing the range deception jamming and the joint range-velocity deception jamming, the phase codes of the subcarriers belonging to the OFDM pulses are optimized to minimize the jamming power, distributing some specific bands in the range and the range-velocity domain, respectively. According to Parseval's theorem, the phase encoding, acting as the coding manner of the OFDM subcarriers can ensure that the energy of each OFDM symbol stays the same. It is worth noticing that the phase codes of the OFDM subcarriers can influence the peak-to-average power ratio (PAPR). Thus, an optimization problem is formulated to optimize the phase codes of the subcarriers under the constraint of global PAPR, which can regulate the PAPRs of multiple OFDM symbols at the same time. The proposed problem is non-convex; therefore, it is a huge challenge to tackle. Then we present a method named by the phase-only alternating direction method multipliers (POADMM) to solve the aforementioned optimization problem. Some necessary simulation results are provided to demonstrate the effectiveness of the proposed radar signaling strategy.
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Joint angle and frequency estimation is an important branch in array signal processing with numerous applications in radar, sonar, wireless communications, etc. Extensive attention has been paid and numerous algorithms have been developed. However, existing algorithms rely on accurately quantified measurements. In this paper, we stress the problem of angle and frequency estimation for sensor arrays using one-bit measurements. The relationship between the covariance matrices of one-bit measurement and that of the accurately quantified measurement is extended to the tensor domain. Moreover, a one-bit parallel factor analysis (PARAFAC) estimator is proposed. The simulation results show that the angle and frequency estimation can be quickly achieved and correctly paired.
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BACKGROUND: Many migrants from rural China seek work in urban areas and leave their children in their home villages to be raised by relatives. These children are often referred to as 'left-behind children'. Parental migration tends to have a profound impact on a child's growth. This study sought to assess the prevalence of illness and malnutrition among children in rural areas raised with different parenting patterns and to explore factors affecting their health and development. METHOD: A cross-sectional survey was conducted to examine the physical health of children raised with different parenting patterns and to explore associated risk factors. In total, this study examined 735 children ages 3-6 years in eight rural villages in two counties of Shandong Province. Their primary caregivers were interviewed with a semi-structured questionnaire. Anthropometric measurements of the children were taken and their nutritional status was determined according to WHO Child Growth Standards. RESULTS: This study found a relatively high prevalence of wasting, overweight and obesity among left-behind children. After potential confounders were controlled for, the parenting pattern, annual household income and health literacy of the primary caregiver significantly influenced the health and developmental indicators of children. CONCLUSIONS: This study highlighted the impact of the characteristics of the primary caregiver on a child's health and development and the importance of practical interventions for preschool-aged children who are left behind and raised with different parenting patterns.
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Desarrollo Infantil , Composición Familiar , Sobrepeso/epidemiología , Responsabilidad Parental , Población Rural/estadística & datos numéricos , Síndrome Debilitante/epidemiología , Pesos y Medidas Corporales , Cuidadores , Niño , Preescolar , China/epidemiología , Estudios Transversales , Femenino , Conocimientos, Actitudes y Práctica en Salud , Estado de Salud , Humanos , Lactante , Masculino , Obesidad Infantil/epidemiología , Factores de Riesgo , Factores SocioeconómicosRESUMEN
PURPOSE: Previous studies that assessed the relationship between obesity, overweight, and survival in colorectal cancer (CRC) have provided conflicting results. Therefore, we quantitatively summarized existing evidence to estimate the association between obesity/overweight and overall survival (OS) in CRC patients and explored potentially important sources of variability. METHODS: Eligible studies were identified via PubMed and EMBASE searches. The summary hazard ratio (sHR) was estimated using a fixed-effects or random-effects model according to the heterogeneity between the studies. Meta-regression and subgroup analyses were performed to explore potential sources of heterogeneity. RESULTS: A total of 29 eligible studies, with 51,303 CRC patients, were finally included. The overall analysis showed worse OS among obese patients [sHR 1.10, 95 % confidence intervals (CI) 1.06-1.15], but not among overweight patients (sHR 0.92, 95 % CI 0.86-1.00), than in normal-weight patients. Considerable heterogeneity was observed across studies, which was primarily attributed to the timing of body mass index (BMI) assessment (meta-regression p < 0.05). The association between obesity and worse OS was strengthened when BMI was assessed before diagnosis (sHR 1.30, 95 % CI, 1.17-1.44). Conversely, post-diagnostic, in particular post-treatment, overweight was associated with a better OS (sHR 0.79, 95 % CI 0.70-0.91). Other factors, including gender, geographic location, and stage, may also modify the prognostic value of obesity or overweight. CONCLUSIONS: Obese but not overweight patients appear to have worse OS than normal-weight patients with CRC. The associations of obesity and overweight with OS in CRC patients majorly depend upon the timing of BMI assessment.
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Neoplasias Colorrectales/mortalidad , Obesidad , Índice de Masa Corporal , Humanos , Pronóstico , Análisis de SupervivenciaRESUMEN
Self-assembled functionalized multiwalled carbon nanotube (MWNT) films were successfully constructed, linked by a kind of strong binding strength from the self-complementary hydrogen-bonding array of ureidopyrimidinone-based modules (UPM) attached. Employing the feasible reaction of isocyanate containing ureidopyrimidinone with amine modified MWNTs, the UPMs composed of ureidopyrimidinone and ureido were attached to MWNTs with the content as low as 0.6 mmol/g MWNTs. Upon multiple hydrogen-bonding interactions from incorporation of the AADD (A, hydrogen-bonding acceptor; D, hydrogen-bonding donor) quadruple hydrogen bonds of ureidopyrimidinone and the double hydrogen bonds of ureido group, UPM functionalized MWNTs (MWNT-UPM) can be well dispersed in the polar solvent of N,N-dimethylformamide (DMF), while they tend to self-assemble to give a self-supported film in the apolar solvent of CHCl3. In addition, by using the multiple hydrogen-bonding interactions as the driving force, the layer-by-layer (LBL) MWNT-UPM films with high coverage on solid slides can be processed. Because of the self-association of MWNT-UPM in apolar solvent, it was found that the LBL assembly of MWNT-UPM was more favorable in the polar solvent of DMF than in the apolar solvent of CHCl3. Moreover, the hydrogen-bonding linked MWNT-UPM films showed good stability upon soaking in different solvents. Furthermore, the as-prepared LBL films showed electrochemical active behaviors, exhibiting a remarkable catalytic effect on the reduction of nifedipine.
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The complex seabed conditions and ocean environment pose significant challenges to the material selection and construction of bottom liners for offshore final disposal sites. To overcome the challenges, this study proposed a novel isolation particle layer for offshore final disposal sites. The isolation particle was composed by salt-resistant bentonite coating material and cement core material (D10 was 10 mm in core diameter and 2 mm in coating thickness; D20 was 20 mm and 4 mm). Upon immersion in artificial seawater, the isolation particles underwent expansion, leading to the formation of the novel isolation particle layers with low hydraulic conductivity less than 1 × 10-7 cm/s and adsorption of heavy metals in bentonite interlayers. Large column tests showed that both D10 and D20 isolation particle layers exhibited remarkable swelling capacity and low hydraulic conductivity (4.3 × 10-9 cm/s and 2.6 × 10-8 cm/s) under 3 m seawater pressure. During one year of observation, water tank test demonstrated that both isolation particle layers displayed remarkable stability and low hydraulic conductivity of 2.73 × 10-10 cm/s and 8.36 × 10-10 cm/s with load. The maximum adsorption capacities of salt-resistant bentonite were 123.55 mg/g for Pb2+, 60.29 mg/g for Cd2+ and 54.22 mg/g for Cu2+. Both isolation particle layers exhibited a high removal rate of over 95 % for heavy metals in water tank tests. The large-scale laboratory tests indicated the significant potential of the novel isolation particle layer for offshore final disposal sites. Subsequently, a testing ocean site will be selected to further investigate its practical engineering performance.
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Bentonita , Metales Pesados , Agua , Agua de Mar , AdsorciónRESUMEN
WG-5 is a lightweight stream cipher proposed for usage in the resource-constrained devices, e.g., passive RFID tags, industrial controllers, contactless smart cards and sensors. In this paper, a weakness called slide property of WG-5 which has not been discovered in previous works is for the first time explored and analyzed. The result shows that the probability that two related key-IV pairs of WG-5 generate the shifted keystreams can be up to 2-20, which is significantly high compared with an ideal stream cipher that generates the random keystreams. The correctness and accuracy of this theoretical probability is confirmed experimentally. Based on the slide property of WG-5, some key recovery attacks on WG-5 in the related key setting are proposed. The cryptanalytic result shows that the 80-bit secret key of WG-5 can be recovered with a time complexity of 225.615, requiring 6 related keys and 80 keystream bits for each of 224.585 chosen IVs. The experimental result validates our attack and shows that WG-5 can be broken within about 92.054 seconds on a common PC in the related key setting. These results imply that the design of WG-5 is far from optimal and needs to be strengthened to provide enough security for the lightweight constrained applications.
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BACKGROUND: The cancers of the digestive tract, including colorectal cancer (CRC), gastric cancer, and esophageal cancer, are part of the most common cancers as well as one of the most important leading causes of cancer death worldwide. SUMMARY: Despite the emergence of immune checkpoint inhibitors (e.g., anti-CTLA-4 and anti-PD-1/PD-L1) in the past decade, offering renewed optimism in cancer treatment, only a fraction of patients derive benefit from these therapies. This limited efficacy may stem from tumor heterogeneity and the impact of metabolic reprogramming on both tumor cells and immune cells within the tumor microenvironment (TME). The metabolic reprogramming of glucose, lipids, amino acids, and other nutrients represents a pivotal hallmark of cancer, serving to generate energy, reducing equivalent and biological macromolecule, thereby fostering tumor proliferation and invasion. Significantly, the metabolic reprogramming of tumor cells can orchestrate changes within the TME, rendering patients unresponsive to immunotherapy. KEY MESSAGES: In this review, we predominantly encapsulate recent strides on metabolic reprogramming among digestive tract cancer, especially CRC, in the TME with a focus on how these alterations influence anti-tumor immunity. Additionally, we deliberate on potential strategies to address these abnormities in metabolic pathways and the viability of combined therapy within the realm of anti-cancer immunotherapy.
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Microambiente Tumoral , Humanos , Microambiente Tumoral/inmunología , Neoplasias Gastrointestinales/inmunología , Neoplasias Gastrointestinales/metabolismo , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Inmunoterapia/métodos , Neoplasias del Sistema Digestivo/inmunología , Neoplasias del Sistema Digestivo/metabolismo , Animales , Reprogramación MetabólicaRESUMEN
Geopolymer is an environmentally friendly solidification/stabilization (S/S) binder, exhibiting significant potential for immobilizing heavy metals in municipal solid waste incineration fly ash (MSWIFA). However, due to the diversity in geopolymer raw materials and heavy metal properties, predicting the heavy metal immobilization rate proves to be challenging. In order to enhance the application of geopolymers in immobilizing heavy metals in MSWIFA, a universal method is required to predict the heavy metal immobilization rate. Therefore, this study employs machine learning to predict the heavy metal immobilization rate in S/S of MSWIFA by geopolymers. A gradient boosting regression (GB) model with superior performance (R2 = 0.9214) was obtained, and a graphical user interface (GUI) software was developed to facilitate the convenient accessibility of researchers. The feature categories influencing heavy metal immobilization rate are ranked in order of importance as heavy metal properties > geopolymer raw material properties > curing conditions > alkali activator properties. This study facilitates the rapid prediction, improvement, and optimization of heavy metal immobilization in S/S of MSWIFA by geopolymers, and also provides a theoretical basis for the resource utilization of industrial solid waste, contributing to the environmental protection.
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This study aims to understand how surfactants affect the mobility of tetracycline (TC), an antibiotic, through different aquifer media. Two anionic and cationic surfactants, sodium dodecylbenzene sulfonate (SDBS) and cetyltrimethyl ammonium bromide (CTAB), were used to study their influence on TC mobility through clean sand and humic acid (HA)-coated sand. HA coating inhibits TC mobility due to its strong interaction with TC. Both surfactants promoted TC mobility at pH 7.0 due to competitive deposition, steric effect, and increased hydrophilicity of TC. CTAB had a more substantial effect than SDBS, related to the surfactants' molecular properties. Each surfactant's promotion effects were greater in HA-coated sand than in quartz sand due to differences in surfactant retention. CTAB inhibited TC transport at pH 9.0 due to its significant hydrophobicity effect. Furthermore, in the presence of Ca2+, SDBS enhanced TC transport by forming deposited SDBS-Ca2+-TC complexes. On the other hand, CTAB increased TC mobility due to its inhibition of cation bridging between TC and porous media. The findings highlight surfactants' crucial role in influencing the environmental behaviors of tetracycline antibiotics in varied aquifers.
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Sustainable and renewable biomass-derived porous carbon (BPC) have garnered considerable attention owing to their low cost, high specific surface area, and outstanding electrochemical performance. However, the subpar energy density severely restricts the applications of BPC in high-energy-density devices. Herein, a high-surface-area porous carbon with multiple heteroatoms doping was derived from rapeseed meals by hydrothermal carbonization and high-temperature activation. The rapeseed meal-derived activated carbon (RMAC) exhibits a remarkable surface area of 3291 m2 g-1 and is doped with nitrogen (1.05 at.%), oxygen (7.4 at.%), phosphorus (0.31 at.%), and sulfur, resulting in an impressive specific capacitance of 416 F g-1 at 1 A g-1. Furthermore, even after 10,000 cycles, the optimized RMAC-800 electrode maintains 92 % of its initial capacitance, attesting to its exceptional performance. Through comprehensive density functional theory (DFT) calculations, the elements O, N, P, and S can significantly enhance the electron negativity and density, improving the adsorption and diffusion of K+ to attain a high capacitance. To assess the RMAC-800's practical performance, an asymmetric supercapacitor with 1 M [BMIM]BF4/AN electrolyte was produced that delivered a high energy density of 195.94 Wh kg-1 at a power density of 1125 W kg-1. Thus, we propose an eco-friendly strategy for producing BPC materials with outstanding electrochemical performance for supercapacitors.
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Brassica napus , Brassica rapa , Adsorción , Potasio , Biomasa , Porosidad , Fenómenos Físicos , Carbón OrgánicoRESUMEN
Aqueous alkaline zinc-based batteries (AAZBs) are promising for large-scale applications due to their high working voltage, safety, and low cost. However, the further development of AAZBs has been significantly hindered by the low electronic conductivity and poor cycling stability of traditional nickel/cobalt-based cathode materials. In this work, a binder-free electrode was successfully designed by electrodepositing NiCo-LDH nanosheets on NiCoS nanotube arrays that were grown on nickel foam (NiCoS@NiCo-LDH). The unique three-dimensional core-shell heterostructures not only enhance electrical conductivity but also offer abundant active sites and rapid ion/electron transport channels, thereby improving its electrochemical performance. The as-fabricated NiCoS@NiCo-LDH electrode delivers a capacity of 312 mA h g-1 (0.624 mA h cm-2) at 2 mA cm-2 and exhibits high rate capability with 90% capacity retention at 10 mA cm-2. Additionally, the assembled NiCoS@NiCo-LDH//Zn battery exhibits a high energy density of 435.3 W h kg-1 at a power density of 4.1 kW kg-1 and maintains 95.9% of its capacity after 3000 cycles at a current density of 20 mA cm-2.
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As a natural adsorbent material, bentonite is widely used in the field of heavy metal adsorption. The heavy metal adsorption capacity of bentonite varies significantly in studies due to the differences in the properties of bentonite, solution, and heavy metal. To achieve accurate predictions of bentonite's heavy metal adsorption capacity, this study employed six machine learning (ML) regression algorithms to investigate the adsorption characteristics of bentonite. Finally, an eXtreme Gradient Boosting Regression (XGB) model with outstanding predictive performance was constructed. Explanation analysis of the XGB model further reveal the importance and influence manner of each input feature in predicting the heavy metal adsorption capacity of bentonite. The feature categories influencing heavy metal adsorption capacity were ranked in order of importance as adsorption conditions > bentonite properties > heavy metal properties. Furthermore, a web-based graphical user interface (GUI) software was developed, facilitating researchers and engineers to conveniently use the XGB model for predicting the heavy metal adsorption capacity of bentonite. This study provides new insights into the adsorption behaviors of bentonite for heavy metals, offering guidance and support for enhancing its application efficiency and addressing heavy metal pollution remediation.
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BACKGROUND: The efficacy of anti-PD-1 therapy is primarily hindered by the limited T-cell immune response rate and immune evasion capacity of tumor cells. Autophagy-related protein 7 (ATG7) plays an important role in autophagy and it has been linked to cancer. However, the role of ATG7 in the effect of immune checkpoint blockade (ICB) treatment on high microsatellite instability (MSI-H)/mismatch repair deficiency (dMMR) CRC is still poorly understood. METHODS: In this study, patients from the cancer genome altas (TCGA) COAD/READ cohorts were used to investigate the biological mechanism driving ATG7 development. Several assays were conducted including the colony formation, cell viability, qRT-PCR, western blot, immunofluorescence, flow cytometry, ELISA, immunohistochemistry staining and in vivo tumorigenicity tests. RESULTS: We found that ATG7 plays a crucial role in MSI-H CRC. Its knockdown decreased tumor growth and caused an infiltration of CD8+ T effector cells in vivo. ATG7 inhibition restored surface major histocompatibility complex I (MHC-I) levels, causing improved antigen presentation and anti-tumor T cell response by activating reactive oxygen species (ROS)/NF-κB pathway. Meanwhile, ATG7 inhibition also suppressed cholesterol accumulation and augmentation of anti-tumor immune responses. Combining ATG7 inhibition and statins improved the therapeutic benefit of anti-PD-1 in MSI-H CRC. Importantly, CRC patients with high expression of both ATG7 and recombinant 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) experienced worse prognosis compared to those with low ATG7 and HMGCR expression. CONCLUSIONS: Inhibition of ATG7 leads to upregulation of MHC-I expression, augments immune response and suppresses cholesterol accumulation. These findings demonstrate that ATG7 inhibition has therapeutic potential and application of statins can increase the sensitivity to immune checkpoint inhibitors.
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Neoplasias Encefálicas , Neoplasias Colorrectales , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Síndromes Neoplásicos Hereditarios , Humanos , Proteína 7 Relacionada con la Autofagia/genética , Colesterol , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Reparación de la Incompatibilidad de ADN , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Inmunidad , Inestabilidad de MicrosatélitesRESUMEN
The N-N atropisomer, as an important and intriguing chiral system, was widely present in natural products, pharmaceutical lead compounds, and advanced material skeletons. The anisotropic structural characteristics caused by its special axial rotation have always been one of the challenges that chemists strive to overcome. Herein, we report an efficient method for the enantioselective synthesis of N-N axially chiral frameworks via a cobalt-catalyzed atroposelective C-H activation/annulation process. The reaction proceeds under mild conditions by using Co(OAc)2·4H2O as the catalyst with a chiral salicyl-oxazoline (Salox) ligand and O2 as an oxidant, affording a variety of N-N axially chiral products with high yields and enantioselectivities. This protocol provides an efficient approach for the facile construction of N-N atropisomers and further expands the range of of N-N axially chiral derivatives. Additionally, under the conditions of electrocatalysis, the desired N-N axially chiral products were also successfully achieved with good to excellent efficiencies and enantioselectivities.
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Aqueous sodium-ion batteries (ASIB) offer many potential applications in large-scale power grids since they are inexpensive, safe, and environmentally friendly. Sodium superionic conductors (NASICON), especially carbon-coated Na3 V2 (PO4 )3 (NVP), have attracted much attention due to the full use of their high ion migration speed. However, the poor cycle lifespan and capacity retention of NVP hinder its application in ASIB. Herein, a novel bimetal-doped Na3 V1.3 Fe0.5 W0.2 (PO4 )3 (NV1.3 Fe0.5 W0.2 P) cathode is designed and synthesized to achieve outstanding cycling stability (95 % of initial capacity at 50thâ cycle). The electrochemical behavior and charge storage mechanism of NV1.3 Fe0.5 W0.2 P are systematically investigated by various inâ situ and ex situ characterizations. The Fe and W codoping could stabilize the NASICON framework to suppress the proton attack on the Na site in the aqueous electrolyte, thus resulting in excellent cycling stability. DFT calculations show that bimetallic doping increases the structural stability of NVP. Moreover, an ASIB fabricated using a NV1.3 Fe0.5 W0.2 P cathode and a NaTi2 (PO4 )3 anode delivers 64â mAh g-1 at room temperature, 95 % capacity retention after 50â cycles (1â A g-1 ).