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To enable distributed multiple mobile manipulator systems to complete collaborative tasks safely and stably, this article investigates and presents a motion generation scheme that considers both orientation and position coordination based on a distributed recurrent neural network. Moreover, physical limits are also considered. Specifically, the orientation and position coordination constraints and physical limits are modeled separately as equality and inequality constraints with coupled variables. Subsequently, a motion generation scheme for multiple mobile manipulators based on quadratic programming is established. Finally, a distributed linear variational inequality-based primal-dual neural network is constructed to solve the motion generation scheme and obtain the motion trajectories of all the mobile manipulators. The simulation results demonstrate that the hybrid orientation and position collaboration motion generation scheme effectively addresses the position and orientation coordination problem for multiple mobile manipulator systems. Compared to other schemes, the proposed scheme based on a distributed computing structure greatly enhances the stability of the system. Additionally, the proposed approach introduces orientation coordination and physical limits, which increases the practicality of the system.
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This study investigated the role of O6-methylguanine-DNA methyltransferase promoter (MGMTp) methylation hierarchy and heterogeneity in grade 2-3 gliomas, focusing on variations in chemotherapy benefits and resection dependency. A cohort of 668 newly diagnosed grade 2-3 gliomas, with comprehensive clinical, radiological, and molecular data, formed the basis of this analysis. The extent of resection was categorized into gross total resection (GTR ≥100%), subtotal resection (STR >90%), and partial resection (PR ≤90%). MGMTp methylation levels were examined using quantitative pyrosequencing. Our findings highlighted the critical role of GTR in improving the prognosis for astrocytomas (IDH1/2-mutant and 1p/19q non-codeleted), contrasting with its lesser significance for oligodendrogliomas (IDH1/2 mutation and 1p/19q codeletion). Oligodendrogliomas demonstrated the highest average MGMTp methylation levels (median: 28%), with a predominant percentage of methylated cases (average methylation levels >20%). Astrocytomas were more common in the low-methylated group (10%-20%), while IDH wild-type gliomas were mostly unmethylated (<10%). Spatial distribution analysis revealed a decrement in frontal lobe involvement from methylated, low-methylated to unmethylated cases (72.8%, 59.3%, and 47.8%, respectively). In contrast, low-methylated and unmethylated cases were more likely to invade the temporal-insular region (19.7%, 34.3%, and 40.4%, respectively). Astrocytomas with intermediate MGMTp methylation were notably associated with temporal-insular involvement, potentially indicating a moderate response to temozolomide and underscoring the importance of aggressive resection strategies. In conclusion, our study elucidates the complex interplay of MGMTp methylation hierarchy and heterogeneity among grade 2-3 gliomas, providing insights into why astrocytomas and IDH wild-type lower-grade glioma might derive less benefit from chemotherapy.
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Few-layer tin (Sn)-based nanosheets (NSs) with a thickness of ≈2.5 nm are successfully prepared using a modified liquid phase exfoliation (LPE) method. Here the first exploration of photo-electrochemical (PEC) and nonlinear properties of Sn NSs is presented. The results demonstrate that the PEC properties are tunable under different experimental conditions. Additionally, Sn NSs are shown to exhibit a unique self-powered PEC performance, maintaining a good long-term stability for up to 1 month. Using electron spin resonance, active species, such as hydroxyl radicals (·OH), superoxide radicals (·O2 -), and holes (h+), are detected during operations, providing a deeper understanding of the working mechanism. Furthermore, measurements of nonlinear response reveal that Sn NSs can be effective for all-optical modulation, as it enables the realization of all-optical switching through excitation spatial cross-phase modulation (SXPM). These findings present new research insights and potential applications of Sn NSs in optoelectronics.
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Background: Drug therapy for eye diseases has been limited by multiple protective mechanisms of the eye, which can be improved using well-designed drug delivery systems. Mesoporous silica nanoparticles (MSNs) had been used in many studies as carriers of therapeutic agents for ocular diseases treatment. However, no studies have focused on ocular biosafety. Considering that MSNs containing tetrasulfur bonds have unique advantages and have drawn increasing attention in drug delivery systems, it is necessary to explore the ocular biosafety of tetrasulfur bonds before their widespread application as ophthalmic drug carriers. Methods: In this study, hollow mesoporous silica nanoparticles (HMSNs) with different tetrasulfur bond contents were prepared and characterized. The ocular biosafety of HMSN-E was evaluated in vitro on the three selected ocular cell lines, including corneal epithelial cells, lens epithelial cells and retinal endothelial cells (HREC), and in vivo by using topical eye drops and intravitreal injections. Results: In cellular experiments, HMSNs caused obvious S content-dependent cytotoxic effect. HMSNs with the highest tetrasulfur bond content (HMSN-E), showed the highest cytotoxicity among all the HMSNs, and HREC was the most vulnerable cell to HMSN-E. It was shown that HMSN-E could react with intracellular GSH to generate H2S and decrease intracellular GSH concentration. Treatment of HREC with HMSN-E increased intracellular ROS, decreased mitochondrial membrane potential, and induced cell cycle arrest at the G1/S checkpoint, finally caused apoptosis and necrosis of HREC. Topical eye drops of HMSN-E could cause corneal damage. The intravitreal injection of HMSN-E could induce inflammation in the vitreum and ganglion cell layers, resulting in vitreous opacities and retinal abnormalities. Conclusion: The incorporation of tetrasulfur bonds into HMSN can have toxic effects on ocular tissues. Therefore, when mesoporous silica nanocarriers are designed for ophthalmic pharmaceuticals, the ocular toxicity of the tetrasulfur bonds should be considered.
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Nanopartículas , Dióxido de Silicio , Humanos , Animales , Nanopartículas/química , Dióxido de Silicio/química , Dióxido de Silicio/toxicidad , Línea Celular , Porosidad , Portadores de Fármacos/química , Apoptosis/efectos de los fármacos , Conejos , Supervivencia Celular/efectos de los fármacos , Ojo/efectos de los fármacos , Soluciones Oftálmicas/química , Soluciones Oftálmicas/farmacología , Compuestos de Organosilicio/química , Compuestos de Organosilicio/toxicidad , Especies Reactivas de Oxígeno/metabolismo , Células Epiteliales/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Inyecciones IntravítreasRESUMEN
Background: Multiple sclerosis (MS) represents a multifaceted autoimmune ailment, prompting the development and widespread utilization of numerous therapeutic interventions. However, extant medications for MS have proven inadequate in mitigating relapses and halting disease progression. Innovative drug targets for preventing multiple sclerosis are still required. The objective of this study is to discover novel therapeutic targets for MS by integrating single-cell transcriptomics and Mendelian randomization analysis. Methods: The study integrated MS genome-wide association study (GWAS) data, single-cell transcriptomics (scRNA-seq), expression quantitative trait loci (eQTL), and protein quantitative trait loci (pQTL) data for analysis and utilized two-sample Mendelian randomization study to comprehend the causal relationship between proteins and MS. Sequential analyses involving colocalization and Phenome-wide association studies (PheWAS) were conducted to validate the causal role of candidate genes. Results: Following stringent quality control preprocessing of scRNA-seq data, 1,123 expression changes across seven peripheral cell types were identified. Among the seven most prevalent cell types, 97 genes exhibiting at least one eQTL were discerned. Examination of MR associations between 28 proteins with available index pQTL signals and the risk of MS outcomes was conducted. Co-localization analyses and PheWAS indicated that FCRL3 may exert influence on MS. Conclusion: The integration of scRNA-seq and MR analysis facilitated the identification of potential therapeutic targets for MS. Notably, FCRL3, implicated in immune function, emerged as a significant drug target in the deCODE databases. This research underscores the importance of FCRL3 in MS therapy and advocates for further investigation and clinical trials targeting FCRL3.
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Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Esclerosis Múltiple , Sitios de Carácter Cuantitativo , Análisis de la Célula Individual , Transcriptoma , Humanos , Esclerosis Múltiple/genética , Esclerosis Múltiple/inmunología , Predisposición Genética a la Enfermedad , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Polimorfismo de Nucleótido Simple , Perfilación de la Expresión GénicaRESUMEN
Groundwater salinization, a major eco-environmental problem in arid and semi-arid areas, can accelerate soil salinization, reducing crop productivity and imbalances in ecosystem diversity. This study classified water samples collected from the Ulansuhai Lake basin into five clusters using self-organizing maps (SOM). On this basis, multiple isotopes (δ18Owater, δD, 87Sr/86Sr, δ18Osulfate and δ34S) and isotopic models (Rayleigh fractionation and Bayesian isotope mixing models) were used to identify and quantify the genesis and evolution of groundwater salinization. The results showed that the samples were brackish or saline water, and the hydrochemical types were dominated by Na + K-Cl (SO4). It has been proved that the processes associated with groundwater salinization in the Ulansuhai Lake basin were dominated by water-rock interaction and human inputs. Among them, evaporite dissolution contributed substantially to groundwater salinity. Furthermore, salt inputs from human activities cannot be negligible. Based on the model calculations, evaporite dissolution accounted for the most significant proportion of all sources, with a mean value of 53 %. In addition, human inputs from regular agricultural activities (28 % from sewage and manure and 8 % from fertilizers) constituted another vital source of groundwater salinization associated with extensive agricultural activities in the study area. This study's results can deepen our understanding of the genesis of groundwater salinization and the evolution of the agricultural drainage lake basin. This knowledge will assist the Environmental Protection Department in developing effective policies for groundwater management in the Yellow River Basin.
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OBJECTIVE: Controversy surrounds the prognostic value of contrast-enhanced T1-weighted (T1CE) imaging-based subventricular zone (SVZ) classification in isocitrate dehydrogenase (IDH)-wildtype glioblastomas (GBMs). In this study, the authors aimed to assess the potential of incorporating FLAIR imaging into T1CE imaging-based classification for improving prognostic accuracy. METHODS: A retrospective analysis was conducted on 281 patients with IDH-wildtype GBM. T1CE imaging-based classification was performed, and T2-weighted/FLAIR imaging was integrated to evaluate its prognostic estimation ability. Based on the relationship between the tumors and SVZ, patients were categorized into SVZ+ and SVZ- cohorts based on T1CE and T2-weighted/FLAIR imaging findings. Kaplan-Meier and Cox proportional hazards regression analyses were used to assess progression-free survival (PFS) and overall survival (OS), respectively. Patients were then categorized into three subgroups based on their combined classifications: group 1 (SVZ+ on T1CE and T2-weighted/FLAIR imaging), group 2 (SVZ- on T1CE but SVZ+ on T2-weighted/FLAIR imaging), and group 3 (SVZ- on T1CE and T2-weighted/FLAIR imaging). Subgroup analysis was used to evaluate differences in clinical and molecular factors as well as in prognoses. RESULTS: The T1CE imaging-based classification failed to stratify OS between SVZ+ and SVZ- cohorts (16.0 vs 20.0 months, p = 0.36). Survival analysis revealed similar prognoses for patients in groups 1 and 2, and patients in group 2 exhibited worse OS compared with those in group 3 (19.0 vs 23.5 months, p = 0.024). Logistic regression identified lower Karnofsky Performance Status (KPS) (p = 0.011), tumor diameter (p = 0.002), and telomerase reverse transcriptase (TERT) promoter mutation (p = 0.003) to be associated with a higher incidence of group 2 GBMs. Additionally, T2-weighted/FLAIR imaging-based classification provided significant prognostic value (17.0 vs 23.5 months p = 0.021) and was found to be an independent prognostic factor in the Cox multivariate analysis (HR 1.79, 95% CI 1.08-2.96; p = 0.024). CONCLUSIONS: This study underscores the limitations of T1CE imaging-based SVZ-associated classification in predicting prognosis for IDH-wildtype GBMs. The authors therefore propose an integrated approach that involves T2-weighted/FLAIR imaging that can provide improved prognostic ability. Notably, the presence of TERT promoter mutation was identified as a critical factor in nonenhancing tumor infiltration into the SVZ. Further validation through extensive cohort studies is recommended to confirm these findings.
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Immunotherapy has been developed, which harnesses and enhances the innate powers of the immune system to fight disease, particularly cancer. PD-1 (programmed death-1) and PD-L1 (programmed death ligand-1) are key components in the regulation of the immune system, particularly in the context of cancer immunotherapy. PD-1 and PD-L1 are regulated by PTMs, including phosphorylation, ubiquitination, deubiquitination, acetylation, palmitoylation and glycosylation. PROTACs (Proteolysis Targeting Chimeras) are a type of new drug design technology. They are specifically engineered molecules that target specific proteins within a cell for degradation. PROTACs have been designed and demonstrated their inhibitory activity against the PD-1/PD-L1 pathway, and showed their ability to degrade PD-1/PD-L1 proteins. In this review, we describe how PROTACs target PD-1 and PD-L1 proteins to improve the efficacy of immunotherapy. PROTACs could be a novel strategy to combine with radiotherapy, chemotherapy and immunotherapy for cancer patients.
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Antígeno B7-H1 , Neoplasias , Humanos , Antígeno B7-H1/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Quimera Dirigida a la Proteólisis , Neoplasias/tratamiento farmacológico , InmunoterapiaRESUMEN
BACKGROUND: Although the COVID-19 pandemic has exerted potential impact on patients with glioblastomas (GBMs), it remains unclear whether the survival and its related risk factors of GBM patients would be altered or not during the period spanning from pre-COVID-19 to post-COVID-19 pandemic era. This study aimed to clarify the important issues above. METHODS: Two observational cohorts were utilized, including the nationwide American cohort from the Surveillance, Epidemiology, and End-Results (SEER) and the Chinese glioblastoma cohort (CGC) at our institution during 2018-2020. Demographics, tumour features, treatment regimens and clinical outcomes were collected. Cox regression model, competing risk model, and subgroup and sensitivity analysis were used to dynamically estimate the survival and its relevant risk factors over different diagnosis years from the pre-COVID-19 (2018 and 2019) to post-COVID-19 (2020) pandemic. Causal mediation analysis was further adopted to explore the potential relationship between risk factors and mortality. RESULTS: This study included 11321 GBM cases in SEER and 226 GBM patients in CGC, respectively. Instead of the diagnostic years of 2018-2020, the prognostic risk factors, such as advanced age, bilateral tumour and absence of comprehensive therapy (surgery combined with chemoradiotherapy), were identified to persistently affect GBM survival independently during the period from 2018 to 2020 in the SEER cohort (all P < 0.05). In CGC, lack of comprehensive therapy for GBM patients were restated as survival risk factors during the same timeframe. Causal mediation analysis showed that the effect of comprehensive therapy on all-cause mortality played a determinant role (direct effect value -0.227, 95% CI -0.248 to -0.207), which was partially mediated by age (9.11%) rather than tumour laterality. CONCLUSIONS: As the timeframe shifted from pre-COVID-19 to post-COVID-19 pandemic, survival of GBM patients remained stable, yet advanced age, bilateral tumours, and passive treatment continuingly impacted GBM survival. It is necessary to optimize the comprehensive treatment for GBM patients even in the post-pandemic era.
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Neoplasias Encefálicas , COVID-19 , Glioblastoma , Humanos , COVID-19/epidemiología , COVID-19/mortalidad , COVID-19/terapia , Glioblastoma/terapia , Glioblastoma/epidemiología , Glioblastoma/mortalidad , Masculino , Femenino , Persona de Mediana Edad , China/epidemiología , Estados Unidos/epidemiología , Factores de Riesgo , Neoplasias Encefálicas/epidemiología , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/mortalidad , Anciano , Adulto , Estudios de Cohortes , Programa de VERFRESUMEN
Tracing lacustrine groundwater discharge (LGD) is essential for understanding the hydrological cycle and water chemistry behaviour of lakes. LGD usually exhibits large spatial variability, but there are few reports on quantitatively revealing the spatial patterns of LGD at the whole lake scale. This study investigated the spatial patterns of LGD in Daihai Lake, a typical closed inland lake in northern China, based on the stable isotopes (δ2H and δ18O) of groundwater, surface water, and sediment pore water (SPW). The results showed that there were significant differences between the δ2H and δ18O values of different water bodies in the Daihai Lake Basin: groundwater < SPW < lake water. The LGD through SPW was found to be an important recharge pathway for the lake. Accordingly, stable isotopes of SPW showed that LGD in the northeastern and northwestern of Daihai Lake was significantly greater both horizontally and vertically than that in the other regions, and the proportions of groundwater in SPW in these two regions were 55.53% and 29.84%, respectively. Additionally, the proportion of groundwater in SPW showed a significant increase with profile depth, and the proportion reached 100% at 50 cm below the sediment surface in the northeastern of the lake where the LGD intensity was strongest. The total LGD to Daihai Lake was 1.47 × 107 m3/a, while the LGD in the northeastern and northwestern of the lake exceeded 1.9 × 106 m3/a. This study provides new insights into assessing the spatial patterns of LGD and water resource management in lakes.
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Agua Subterránea , Lagos , Isótopos , Agua , Movimientos del Agua , China , Monitoreo del Ambiente/métodosRESUMEN
A rarely discussed phenomenon in the realm of photocatalytic materials involves the presence of gradient distributed dopants and defects from the interior to the surface. This intriguing characteristic has been successfully achieved in the case of ZnS through the incorporation of atomic monovalent copper ions (Cu+) and concurrent sulfur vacancies (Vs), resulting in a photocatalyst denoted as G-CZS1-x. Through the cooperative action of these atomic Cu dopants and Vs, G-CZS1-x significantly extends its photoabsorption range to encompass the full spectrum (200-2100 nm), which improves the solar utilization ability. This alteration enhances the efficiency of charge separation and optimizes Δ(H*) (free energy of hydrogen adsorption) to approach 0 eV for the hydrogen evolution reaction (HER). It is noteworthy that both surface-exposed atomic Cu and Vs act as active sites for photocatalysis. G-CZS1-x exhibits a significant H2 evolution rate of 1.01 mmol h-1 in the absence of a cocatalyst. This performance exceeds the majority of previously reported photocatalysts, exhibiting approximately 25-fold as ZnS, and 5-fold as H-CZS1-x with homogeneous distribution of equal content Cu dopants and Vs. In contrast to G-CZS1-x, the H adsorption on Cu sites for H-CZS1-x (ΔG(H*) = -1.22 eV) is excessively strong to inhibit the H2 release, and the charge separation efficiency for H-CZS1-x is relatively sluggish, revealing the positive role of a gradient distribution model of dopants and defects on activity enhancement. This work highlights the synergy of atomic dopants and defects in advancing photoactivity, as well as the significant benefit of the controllable distribution model of dopants and defects for photocatalysis.
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The reliable and accurate detection of unauthorized additives in food is significant to prevent health risks. In recent years, surface-enhanced Raman spectroscopy (SERS) with fast, simple, and sensitive capabilities has been widely used for food safety analysis. In order to detect illegally added dye molecule rhodamine 6G and small molecule melamine in food, we have proposed a fast, convenient, and label-free SERS detection technology using flower-like Ag/ZnO as the SERS substrate. The structure and morphology of the flower-like Ag/ZnO were characterized by scanning electron microscopy, energy dispersive spectrometery, transmission electron microscopy, and X-ray diffraction analysis. We investigated the SERS effect and sensitivity of flower-like Ag/ZnO toward rhodamine 6G and melamine. The synergistic effect of flower-like Ag/ZnO provides high SERS activity for the detection of rhodamine 6G and melamine at the lowest detection concentrations of 0.5 ng mL-1 and 1.0 ng mL-1, respectively. Therefore, flower-like Ag/ZnO with good sensitivity and uniformity has potential for improving the detection of illegal food additives.
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Rodaminas , Espectrometría Raman , Triazinas , Óxido de Zinc , Óxido de Zinc/química , Plata/químicaRESUMEN
A highly immunosuppressive tumor microenvironment (TME) and the presence of the bloodâbrain barrier are the two major obstacles to eliciting an effective immune response in patients with high-grade glioma (HGG). Here, we tried to enhance the local innate immune response in relapsed HGG by intracranially injecting poly(I:C) to establish a robust antitumor immune response in this registered clinical trial (NCT03392545). During the follow-up, 12/27 (44.4%) patients who achieved tumor control concomitant with survival benefit were regarded as responders in our study. We found that the T-cell receptor (TCR) repertoire in the TME was reshaped after poly(I:C) treatment. Based on the RNA-seq analysis of tumor samples, the expression of annexin A1 (ANXA1) was significantly upregulated in the tumor cells of nonresponders, which was further validated at the protein level. In vitro and in vivo experiments showed that ANXA1 could induce the production of M2-like macrophages and microglia via its surface receptor formyl peptide receptor 1 (FPR1) to establish a Treg cell-driven immunosuppressive TME and suppress the antitumor immune response facilitated by poly(I:C). The ANXA1/FPR1 signaling axis can inhibit the innate immune response of glioma patients by promoting an anti-inflammatory and Treg-driven TME. Moreover, ANXA1 could serve as a reliable predictor of response to poly(I:C), with a notable predictive accuracy rate of 92.3%. In light of these notable findings, this study unveils a new perspective of immunotherapy for gliomas.
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Anexina A1 , Glioma , Humanos , Anexina A1/metabolismo , Antiinflamatorios , Inmunidad , Receptor Toll-Like 3/metabolismo , Microambiente TumoralRESUMEN
Atomically dispersed metal and nitrogen co-doped carbon catalysts (M-N-C) have been attracting tremendous attentions thanks to their unique MNx active sites and fantastic catalytic activities in advanced oxidation technologies (AOTs) for water remediation. However, precisely tailoring the microenvironment of active sites at atomic level is still an intricate challenge so far, and understanding of the non-radical mechanisms in persulfate activation exists many uncertainties. In this review, latest developments on the microenvironment modulation strategies of atomically dispersed M-N-C catalysts including regulation of central metal atoms, regulation of coordination numbers, regulation of coordination heteroatoms, and synergy between single-atom catalysts (SACs) with metal species are systematically highlighted and discussed. Afterwards, progress and underlying limitations about the typical non-radical pathways from production of singlet oxygen, electron transfer mechanism to generation of high-valent metal species are well demonstrated to inspire intrinsic insights about the mechanisms of M-N-C/persulfate systems. Lastly, perspectives for the remaining challenges and opportunities about the further development of carbon-based SACs in environment remediation are also pointed out. It is believed that this review will be much valuable for the further design of active sites in M-N-C/persulfate catalytic systems and promote the wide application of SACs in various fields.
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PURPOSE: This study aimed to assess the ability of [11C]methionine (MET) PET in distinguishing between tumor progression (TP) and treatment-related changes (TRCs) among different types of adult-type diffuse gliomas according to the 2021 World Health Organization classification and predict overall survival (OS). METHODS: We retrospectively selected 113 patients with adult-type diffuse gliomas with suspected TP who underwent MET PET imaging. Maximum and mean tumor-to-background ratios (TBRmax, TBRmean) and metabolic tumor volume (MTV) were calculated. Diagnoses were verified by histopathology (n = 50) or by clinical/radiological follow-up (n = 63). The diagnostic performance of MET PET parameters was evaluated through receiver operating characteristic (ROC) analysis and area under the curve (AUC) calculation. Survival analysis employed the Kaplan-Meier method and Cox proportional-hazards regression. RESULTS: TP and TRCs were diagnosed in 76 (67%) and 37 (33%) patients, respectively. ROC analysis revealed TBRmax had the best performance in differentiating TP from TRCs with a cut-off of 1.96 in IDH-mutant astrocytoma (AUC, 0.87; sensitivity, 93%; specificity 69%), 1.80 in IDH-mutant and 1p/19q-codeleted oligodendroglioma (AUC, 0.96; sensitivity, 100%; specificity, 89%), and 2.13 in IDH wild-type glioblastoma (AUC, 0.89; sensitivity, 89%; specificity, 78%), respectively. On multivariate analysis, higher TBRmean and MTV were significantly correlated with shorter OS in all IDH-mutant gliomas, as well as in IDH-mutant astrocytoma subgroup. CONCLUSION: This work confirms that MET PET has varying diagnostic performances in distinguishing TP from TRCs within three types of adult-type diffuse gliomas, and highlights its high diagnostic accuracy in IDH-mutant and 1p/19q-codeleted oligodendroglioma and potential prognostic value for IDH-mutant gliomas, particularly IDH-mutant astrocytoma.
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Astrocitoma , Neoplasias Encefálicas , Glioma , Oligodendroglioma , Adulto , Humanos , Metionina , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Estudios Retrospectivos , Glioma/diagnóstico por imagen , Glioma/genética , Glioma/terapia , Racemetionina , Tomografía de Emisión de Positrones , Isocitrato Deshidrogenasa/genética , MutaciónRESUMEN
OBJECTIVE: Calcification is a hallmark characteristic of oligodendroglioma (ODG) that may be used as a diagnostic factor, but its prognostic implications remain unclear. This study aimed to investigate the features of calcified ODGs and to evaluate the differences in survival between patients with calcified and noncalcified ODGs. METHODS: We retrospectively reviewed the records of 305 consecutive patients who were diagnosed with IDH-mutant, 1p/19q codeleted ODG at our institution from July 2009 to August 2020. Patients with intratumoral calcification were identified. The clinical, radiologic, and molecular features of the patients in the calcified group and noncalcified group were recorded. Univariate and multivariate analyses were performed to identify prognostic factors. RESULTS: Of the 305 patients, 112 (36.7%) were confirmed to have intratumoral calcification. Compared to ODGs without calcification, ODGs with calcifications had a larger tumor diameter; lower degree of resection; higher tumor grade; higher MGMT methylation level; higher Ki-67 index; and higher rates of midline crossing, enhancement, cyst, and 1q/19p copolysomy, and patients with calcification were more likely to receive chemoradiotherapy. ODGs with T2 hypointense calcification had a higher Hounsfield unit (HU) value on CT scans, and a lower degree of resection. Patients with T2 hypointense calcification ODGs had a shorter survival than those with non-hypointense calcification ODGs. ODGs with calcification and cysts showed a higher Ki-67 index, tumor grade, and enhanced rate, and the patients had an unfavorable overall survival (OS). Calcification was found to be a negative prognostic factor for both progression-free survival (PFS) and OS by univariate analysis, which was confirmed by the Cox proportional hazard model. CONCLUSIONS: Calcification is a useful negative prognostic factor for PFS and OS in patients with ODGs and could therefore be helpful in guiding personalized treatment and predicting patient prognosis. CLINICAL RELEVANCE STATEMENT: Calcification can serve as an independent prognostic factor for patients with oligodendroglioma and shows a vital role in guiding individualized treatment. KEY POINTS: ⢠Intratumoral calcification is an independent negative prognostic risk factor for progression-free survival and overall survival in oligodendroglioma patients. ⢠Calcifications in oligodendroglioma can be divided into hypointense and non-hypointense subtypes based on T2-weighted imaging, and patients with T2-hypointense calcification oligodendrogliomas have worse prognosis. ⢠Calcification concurrent with cysts indicates a more aggressive phenotype of oligodendrogliomas and a significantly reduced survival rate.
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Senescent cells remain metabolically active, but their metabolic landscape and resulting implications remain underexplored. Here, we report upregulation of pyruvate dehydrogenase kinase 4 (PDK4) upon senescence, particularly in some stromal cell lines. Senescent cells display a PDK4-dependent increase in aerobic glycolysis and enhanced lactate production but maintain mitochondrial respiration and redox activity, thus adopting a special form of metabolic reprogramming. Medium from PDK4+ stromal cells promotes the malignancy of recipient cancer cells in vitro, whereas inhibition of PDK4 causes tumor regression in vivo. We find that lactate promotes reactive oxygen species production via NOX1 to drive the senescence-associated secretory phenotype, whereas PDK4 suppression reduces DNA damage severity and restrains the senescence-associated secretory phenotype. In preclinical trials, PDK4 inhibition alleviates physical dysfunction and prevents age-associated frailty. Together, our study confirms the hypercatabolic nature of senescent cells and reveals a metabolic link between cellular senescence, lactate production, and possibly, age-related pathologies, including but not limited to cancer.
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Ácido Láctico , Neoplasias , Proteínas Quinasas , Regulación hacia Arriba , Senescencia CelularRESUMEN
Frequent outbreaks of harmful cyanobacterial blooms and the microcystins (MCs) they produce seriously affect the survival of aquatic organisms. Interactions between gut microbiota and hosts often play crucial roles in driving the adaptation of aquatic organisms to environmental changes. In this study, we investigated the phenotypic indicators of the freshwater gastropod Bellamya aeruginosa, after uptake of Microcystis aeruginosa and explored its gut microbial composition and gut metabolites in response to toxic cyanobacterial stress. Results showed that the MCs concentration in the hepatopancreas of snails fed with toxic cyanobacteria decreased from 2.64 ± 0.14 µg·g-1 on day 7 to 1.16 ± 0.10 µg·g-1 on day 14. The compositions of the intestinal microbiota of snails fed with different algae significantly differed, and the relative abundance of gut microbes such as Lactobacillus and Sphingobium significantly increased after feeding toxic cyanobacteria. Significant differences also existed in intestinal metabolites, the relative abundance of the following metabolites significantly increased: l-proline, 5,6-DHET, stachyose, raffinose, and 3-isopropylmalate. Sankey network diagrams showing links between gut microbes and gut metabolites. The association of Lactobacillus and Sphingobium with amino acids may be related to host tolerance to toxicity, and the linkages of gut microbes with metabolites such as levan, imidazolepropionic acid, and eicosanoids may be associated with involvement in host immune responses. The association of microbes with stachyose and raffinose can help the host to regulate energy homeostasis. These results reveal the underlying mechanisms of gut microbes in the snail adaptation to toxic cyanobacterial stress. This study could be great important for gaining new insights into toxic cyanobacteria-induced changes in snail gut microbes and metabolites and their roles in snail adaptation to toxic cyanobacterial stress, and may provide important insights into the use of freshwater gastropods for the prevention and control of cyanobacterial blooms.