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A facile calcination method is developed for the inâ situ synthesis of nanohybrids of Ti3+ self-doped TiO2 /graphene quantum dot nanosheets (Ti3+ -TiO2 /GQD NSs). Ti3+ sites are formed on the surface of the TiO2 nanosheets through carbothermal reduction by GQDs, using citric acid as a carbon source. Such heterojunctions exhibit enhanced visible-light absorption properties, large photocurrent current densities, and low recombination of photoinduced carriers. The methylene blue (MB) and rhodamineâ B (RhB) photodegradation result demonstrates a higher visible-light photocatalysis performance than that of the original TiO2 . On one hand, inducing Ti3+ sites is efficient for the separation of photogenerated charge carriers and for reducing electron-hole pair recombination. On the other hand, GQDs are beneficial for generating more photocurrent carriers and facilitating the charge transfer across the TiO2 surface. It is proposed that Ti3+ sites and GQDs induced in TiO2 nanosheets have a synergistic effect, leading to excellent photocatalysis properties. Finally, a theoretical calculation is provided of the carbothermal reduction for the formation mechanism of the Ti3+ defect sites.
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The identification of particular types of damage in wind turbine blades using acoustic emission (AE) techniques is a significant emerging field. In this work, a 45.7-m turbine blade was subjected to flap-wise fatigue loading for 21 days, during which AE was measured by internally mounted piezoelectric sensors. This paper focuses on using unsupervised pattern recognition methods to characterize different AE activities corresponding to different fracture mechanisms. A sequential feature selection method based on a k-means clustering algorithm is used to achieve a fine classification accuracy. The visualization of clusters in peak frequency-frequency centroid features is used to correlate the clustering results with failure modes. The positions of these clusters in time domain features, average frequency-MARSE, and average frequency-peak amplitude are also presented in this paper (where MARSE represents the Measured Area under Rectified Signal Envelope). The results show that these parameters are representative for the classification of the failure modes.
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MicroRNAs are important regulators in numerous cellular processes, including cell differentiation, proliferation, and apoptosis. Recently, miR-143 was identified as a tumor suppressor in prostate cancer (PCa). To explore the mechanism of dysregulation and anti-tumor function of miR-143 in PCa, we first found a single-nucleotide polymorphism rs4705342T>C in the promoter region of miR-143 through bioinformatics tools and then performed a case-control study including 608 PCa patients and 709 controls. Results suggested that subjects with TC/CC genotypes had significantly decreased risk of PCa compared with those with TT genotype (adjusted OR 0.68, 95 % CI 0.55-0.85). Further functional assays showed that the risk-associated T allele increased the protein-binding affinity and reduced the activity of the promoter compared with C allele. In addition, restoration of miR-143 by mimics in PCa cells significantly inhibited cell proliferation and migration and down-regulated the expression level of kallikrein-related peptidase 2 (KLK2) mRNA and protein. The miR-143-KLK2 axis was also confirmed by luciferase reporter assay in vitro. In conclusion, our findings demonstrate that there is the significant association between the functional promoter variant rs4705342T>C in miR-143 and PCa risk and newly describe the miR-143-KLK2 interaction which provided another potential mechanism for miR-143 anti-tumor function.
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MicroARNs/genética , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas , Neoplasias de la Próstata/genética , Anciano , Pueblo Asiatico/genética , Estudios de Casos y Controles , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Predisposición Genética a la Enfermedad , Humanos , Calicreínas/genética , Masculino , Neoplasias de la Próstata/patologíaRESUMEN
The linkage between biocides and antibiotic resistance has been widely suggested in laboratories and various environments. However, the action mechanism of biocides on antibiotic resistance genes (ARGs) spread is still unclear. Thus, 6 quaternary ammonium biocides (QACs) with different bonded substituents or alkyl chain lengths were selected to assess their effects on the conjugation transfer of ARGs in this study. Two conjugation models with the same donor (E. coli DH5α (RP4)) into two receptors, E. coli MG1655 and pathogenic S. sonnei SE6-1, were constructed. All QACs were found to significantly promote intra- and inter-genus conjugative transfer of ARGs, and the frequency was highly impacted by their structure and receptors. At the same environmental exposure level (4 × 10-1 mg/L), didecyl dimethyl ammonium chloride (DDAC (C10)) promoted the most frequency of conjugative transfer, while benzathine chloride (BEC) promoted the least. With the same donor, the enhanced frequency of QACs of intra-transfer is higher than inter-transfer. Then, the acquisition mechanisms of two receptors were further determined using biochemical combined with transcriptome analysis. For the recipient E. coli, the promotion of the intragenus conjugative transfer may be associated with increased cell membrane permeability, reactive oxygen species (ROS) production and proton motive force (PMF)-induced enhancement of flagellar motility. Whereas, the increase of cell membrane permeability and decreased flagellar motility due to PMF disruption but encouraged biofilm formation, maybe the main reasons for promoting intergenus conjugative transfer in the recipient S. sonnei. As one pathogenic bacterium, S. sonnei was first found to acquire ARGs by biocide exposure.
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Conjugación Genética , Desinfectantes , Escherichia coli , Compuestos de Amonio Cuaternario , Desinfectantes/farmacología , Compuestos de Amonio Cuaternario/farmacología , Escherichia coli/efectos de los fármacos , Escherichia coli/genética , Farmacorresistencia Bacteriana/genética , Antibacterianos/farmacología , Farmacorresistencia Microbiana/genética , Transferencia de Gen HorizontalRESUMEN
Proton exchange membrane water electrolysers promise to usher in a new era of clean energy, but they remain a formidable obstacle in designing active and durable electrocatalysts for the acidic oxygen evolution reaction (OER). In this study, a protonated iridium oxide embedded with single-atom dispersed ruthenium atoms (H3.8Ir1- xRuxO4) that demonstrates exceptional activity and stability in acidic water oxidation is introduced. The single Ru dopants favorably induce localized oxygen vacancies in the IrâO lattice, synergistically strengthening the adsorption of OOH* intermediates and enhancing the intrinsic OER activity. In addition, the preferential oxidation of Ru and the electronegativity of the oxygen vacancies significantly stabilize the IrâO active sites, improving the OER stability. Consequently, the H3.8Ir1â xRuxO4 catalyst shows an overpotential of 255 mV at 10 mA cm-2 and displays exceptional catalytic endurance in acidic electrolytes, surpassing 1100 h, representing a remarkable one-order-of-magnitude increase in stability compared to that of pristine H3.8IrO4. A proton exchange membrane electrolyser utilizing the H3.8Ir1- xRuxO4 catalyst as an anode exhibits stable performance for more than 1280 h under a high current density of 2 A cm-2.
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Background: Cuproptosis-related long-stranded non-coding RNAs (lncRNAs) have several implications for the prognosis of multiple myeloma (MM). This research aimed to construct a prognostic risk model for MM patients and explore the potential signaling pathways in the risk group. Methods: Cuproptosis-related lncRNAs were obtained from the co-expression analysis of cuproptosis-related genes and lncRNAs. Subsequently, twelve cuproptosis-related lncRNAs were selected to construct a prognostic risk model of MM patients by the least absolute shrinkage and selection operator (LASSO) regression. Then, the clinical data of these patients were randomly divided into the training group and the testing group. Next, patients were divided into the low- and high-risk groups according to the median risk score. The Kaplan-Meier survival analysis was performed to clarify the prognostic differences between risk subtypes. Besides, the Cox analysis was conducted to identify whether the risk score can be used as an independent prognostic factor. In addition, the receiver operating characteristic (ROC) curve analysis and the concordance index (C-index) curve analysis were performed to elucidate the value of risk score as a prognostic indicator. Finally, the differential risk analysis and functional enrichment analysis were carried out to identify the potential signaling pathways in the low- and high-risk groups. Results: The results demonstrated that the overall survival (OS) of patients in the high-risk group was shorter than that in the low-risk group. There were significant differences in the expression of genes in MM patients between the high- and low-risk groups. The Gene Ontology (GO) analysis results showed that the differentially expressed risk-related genes (DERGs) were mainly concentrated on the collagen-containing extracellular matrix. According to the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis results, the DERGs may be related to the neuroactive ligand-receptor interaction and mitogen-activated protein kinase (MAPK) signaling pathway, indicating that they may be involved in the progression of tumors. Conclusions: The findings of this study suggest that cuproptosis-related lncRNAs may be effective biomarkers for predicting the prognosis of MM patients, which is anticipated to contribute to the improvement of clinical outcomes.
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A high-performance piezoelectric photocatalyst (V-BiOIO3/FTCN) was constructed to improve removal efficiency of tetracycline hydrochloride (TCH). The role of V-BiOIO3 in the composite was to introduce piezoelectric effect and construct S-scheme heterojunction photocatalyst with fish scale tubular carbon nitride (FTCN). The morphology, structure, chemical composition and optoelectronic characteristics of the as-prepared photocatalysts were studied by SEM, TEM, XRD, XPS and UV-Vis DRS. Combined with UV-Vis DRS, XPS valence band, Mott-schottky curve and theoretical calculations, the mechanism of TCH degradation was deeply analyzed. A series of degradation experiments showed that the V-BiOIO3/FTCN could effectively degrade TCH, and the removal efficiency was further improved under the action of ultrasound. Importantly, the further immobilized V-BiOIO3/FTCN/MS could float on the water surface to degrade TCH without additional stirring, which facilitated the recovery of photocatalysts and showed excellent practical application value. This work provided a reference for the design and immobilization of carbon nitride-based piezoelectric photocatalysts.
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Antibacterianos , Tetraciclina , Tetraciclina/química , Catálisis , Antibacterianos/químicaRESUMEN
BACKGROUND: The addition of immune checkpoint inhibitors to perioperative chemotherapy in operable gastric or gastroesophageal junction (GEJ) cancer has become one of the research hotspots, while reliable biomarkers for efficacy are lacking. We conducted a phase 1 trial to assess the safety and efficacy of LP002, an anti-PD-L1 antibody, plus chemotherapy as perioperative treatment in patients with gastric or GEJ cancer. METHODS: We enrolled patients with resectable and PD-L1 positive gastric or GEJ cancers. Eligible patients received three preoperative and six postoperative cycles of intravenous LP002 with cisplatin and 5-fluorouracil, repeated every 2 weeks. The primary endpoint was safety. Secondary endpoints included rate of margin-free (R0) resection and pathological complete response (pCR). We also characterized changes in the tumor immune microenvironment using multiplex immunofluorescence (MIF) staining and next-generation sequencing (NGS) with pre- and post-treatment tumor samples. RESULTS: Thirty patients were enrolled, of whom 28 had GEJ cancer. With a median follow-up of 7.9 months, all patients completed preoperative treatment, and 27 patients underwent surgery. Twenty-four patients underwent R0 resection. Six patients (20.0%) had Mandard tumor regression grade (TRG) 1-3, including one achieving pCR. Twenty-seven patients had treatment-related adverse events (TRAEs), while grade 3-4 TRAEs were observed in 11 patients. No treatment-related deaths occurred. MIF staining revealed that TRG 1-3 group was associated with a higher density of PD-L1+/CD68+ cells in the pre-treatment tumor parenchyma than TRG 4-5 group (p = 0.048). NGS studies with paired pre- and post-treatment tumor samples revealed the disappearance of pre-existing mutations, the emergence of new mutations, and variations in the abundance of mutations after preoperative LP002 and chemotherapy. Meanwhile, tumor mutational burden decreased in patients with TRG 1-3 (p = 0.0313). CONCLUSIONS: LP002 plus cisplatin and 5-fluorouracil are safe in patients with gastric or GEJ cancer, and patient selection via appropriate biomarkers is needed in the future.
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Adenocarcinoma , Neoplasias Esofágicas , Neoplasias Gástricas , Humanos , Cisplatino/uso terapéutico , Adenocarcinoma/patología , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/cirugía , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/cirugía , Unión Esofagogástrica/cirugía , Unión Esofagogástrica/patología , Fluorouracilo/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Microambiente TumoralRESUMEN
Electrochemically reducing CO2 to more reduced chemical species is a promising way that not only enables the conversion of intermittent energy resources to stable fuels, but also helps to build a closed-loop anthropogenic carbon cycle. Among various electrocatalysts for electrochemical CO2 reduction, multifunctional metal-organic frameworks (MOFs) have been employed as highly efficient and selective heterogeneous electrocatalysts due to their ultrahigh porosity and topologically diverse structures. Up to now, great progress has been achieved in the design and synthesis of highly active and selective MOF-related catalysts for electrochemical CO2 reduction reaction (CO2RR), and their corresponding reaction mechanisms have been thoroughly studied. In this review, we summarize the recent progress of applying MOFs and their derivatives in CO2RR, with a focus on the design strategies for electrocatalysts and electrolyzers. We first discussed the reaction mechanisms for different CO2RR products and introduced the commonly applied electrolyzer configurations in the current CO2RR system. Then, an overview of several categories of products (CO, HCOOH, CH4, CH3OH, and multi-carbon chemicals) generated from MOFs or their derivatives via CO2RR was discussed. Finally, we offer some insights and perspectives for the future development of MOFs and their derivatives in electrochemical CO2 reduction. We aim to provide new insights into this field and further guide future research for large-scale applications.
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Parental histones, the carriers of posttranslational modifications, are deposited evenly onto the replicating DNA of sister chromatids in a process dependent on the Mcm2 subunit of DNA helicase and the Pole3 subunit of leading-strand DNA polymerase. The biological significance of parental histone propagation remains unclear. Here we show that Mcm2-mutated or Pole3-deleted mouse embryonic stem cells (ESCs) display aberrant histone landscapes and impaired neural differentiation. Mutation of the Mcm2 histone-binding domain causes defects in pre-implantation development and embryonic lethality. ESCs with biased parental histone transfer exhibit increased epigenetic heterogeneity, showing altered histone variant H3.3 and H3K27me3 patterning at genomic sites regulating differentiation genes. Our results indicate that the lagging strand pattern of H3.3 leads to the redistribution of H3K27me3 in Mcm2-2A ESCs. We demonstrate that symmetric parental histone deposition to sister chromatids contributes to cellular differentiation and development.
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Histonas , Células Madre Embrionarias de Ratones , Animales , Ratones , Histonas/genética , Células Madre Embrionarias , Diferenciación Celular/genética , ADN HelicasasRESUMEN
Recently, a C>T polymorphism (rs1434536) in a miR-125b binding site in the 3' untranslated region (3'UTR) of bone morphogenetic protein membrane receptor type IB gene (BMPR1B) has been found to contribute to cancer susceptibility. To investigate whether it plays an important role in the development of prostate cancer in southern Chinese Han population, we performed a case-control study. 247 prostate cancer and 278 control subjects were included in the cancer association study and dual-luciferase reporter assay was used to test the binding ability of miR-125b to BMPR1B-C or -T vectors. The effect of CT/TT genotype on prostate cancer risk was found to be significant for localized disease (OR=1.60, 95% CI=1.01-2.53, P=0.044) and among subgroups of aged>70 years (OR=1.90, 95% CI=1.15-3.15, P=0.015) compared with CC genotype. Moreover, C-allele gave a reduced luciferase activity relative to T-allele in dual-luciferase reporter assay. Our findings show that rs1434536 in the 3'UTR of BMPR1B gene affects the binding ability of miR-125b to BMPR1B mRNA and contributes to the genetic predisposition to localized prostate cancer and patients aged>70 years.
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Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/genética , Predisposición Genética a la Enfermedad/genética , Neoplasias de la Próstata/genética , Regiones no Traducidas 3'/genética , Factores de Edad , Anciano , Sitios de Unión/genética , Estudios de Casos y Controles , Humanos , Luciferasas , Masculino , MicroARNs/genética , MicroARNs/metabolismo , Oportunidad Relativa , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
Various physical information can be leaked while the encryption algorithm is running in the device. Side-channel analysis exploits these leakages to recover keys. Due to the sensitivity of deep learning to the data features, the efficiency and accuracy of side channel analysis are effectively improved with the application of deep learning algorithms. However, a considerable part of existing reserches are based on traditional neural networks. The effectiveness of key recovery is improved by increasing the size of the network. However, the computational complexity of the algorithm increases accordingly. Problems such as overfitting, low training efficiency, and low feature extraction ability also occur. In this paper, we construct an improved lightweight convolutional neural network based on the feature fusion network. The new network and the traditional neural networks are respectively applied to the side-channel analysis for comparative experiments. The results show that the new network has faster convergence, better robustness and higher accuracy. No overfitting has occurred. A heatmap visualization method was introduced for analysis. The new network has higher heat value and more concentration in the key interval. Side-channel analysis based on feature fusion network has better performance, compared with the ones based on traditional neural networks.
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Algoritmos , Redes Neurales de la ComputaciónRESUMEN
Novel lotus root starch (LRS)-myristic acid (MA) complexes were prepared using an ultrasound-assisted hydrothermal method (UHM) to investigate its nutritional intervention in type 2 diabetes mellitus (T2DM). Ultrasonic treatment promoted the formation of the V-type crystal structure of the complex and improved the intermolecular interaction force, the order of the short-range starch molecules, and crystallinity. The volume of the ultrasound-assisted LRS-MA composite (U-LRS-MA) particles was enlarged, the particle distribution showed non-uniformity, and the surface grooves were deepened. The resistant starch content of U-LRS-MA was greatly increased from 34.58 % of native starch to 68.20 %. Dietary Supplements of 5 % and 15 % U-LRS-MA significantly reduced the body weight, the organ index and fasting blood glucose of T2DM mice, effectively adjusted its blood lipid level, alleviated its liver damage and increased the levels of colonic short-chain fatty acids. The addition of 5 % U-LRS-MA was more effective in T2DM than 15 % U-LRS-MA. Ultrasound could be effectively employed to prepare lipid-starch complexes, namely type 5 resistant starch, which was proved for the first time to have an excellent intervention effect on T2DM.
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Diabetes Mellitus Tipo 2 , Almidón , Ratones , Animales , Almidón/química , Almidón Resistente , Lípidos , Suplementos DietéticosRESUMEN
Non-homologous end joining (cNHEJ) is a major pathway to repair double-strand breaks (DSBs) in DNA. Several core cNHEJ are involved in the progress of the repair such as KU70 and 80, DNA-dependent protein kinase catalytic subunit (DNA-PKcs), Artemis, X-ray repair cross-complementing protein 4 (XRCC4), DNA ligase IV, and XRCC4-like factor (XLF). Recent studies have added a number of new proteins during cNHEJ. One of the newly identified proteins is Paralogue of XRCC4 and XLF (PAXX), which acts as a scaffold that is required to stabilize the KU70/80 heterodimer at DSBs sites and promotes the assembly and/or stability of the cNHEJ machinery. PAXX plays an essential role in lymphocyte development in XLF-deficient background, while XLF/PAXX double-deficient mouse embryo died before birth. Emerging evidence also shows a connection between the expression levels of PAXX and cancer development in human patients, indicating a prognosis role of the protein. This review will summarize and discuss the function of PAXX in DSBs repair and its potential role in cancer development.
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Roturas del ADN de Doble Cadena , Neoplasias , Animales , ADN , Reparación del ADN , Proteínas de Unión al ADN/genética , Humanos , Ratones , Neoplasias/genéticaRESUMEN
Recently, with the rapid development of artificial intelligence, image generation based on deep learning has advanced significantly. Image generation based on Generative Adversarial Networks (GANs) is a promising study. However, because convolutions are limited by spatial-agnostic and channel-specific, features extracted by conventional GANs based on convolution are constrained. Therefore, GANs cannot capture in-depth details per image. Moreover, straightforwardly stacking of convolutions causes too many parameters and layers in GANs, yielding a high overfitting risk. To overcome the abovementioned limitations, in this study, we propose a GANs called GIU-GANs (where Global Information Utilization: GIU). GIU-GANs leverages a new module called the GIU module, which integrates the squeeze-and-excitation module and involution to focus on global information via the channel attention mechanism, enhancing the generated image quality. Moreover, Batch Normalization (BN) inevitably ignores the representation differences among noise sampled by the generator and thus degrades the generated image quality. Thus, we introduce the representative BN to the GANs' architecture. The CIFAR-10 and CelebA datasets are employed to demonstrate the effectiveness of the proposed model. Numerous experiments indicate that the proposed model achieves state-of-the-art performance.
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Procesamiento de Imagen Asistido por Computador , Redes Neurales de la Computación , Inteligencia Artificial , Procesamiento de Imagen Asistido por Computador/métodosRESUMEN
The design of a photocatalyst for efficient algal inactivation under visible light is essential for the application of photocatalysis to the control of harmful algal blooms. In this study, a novel Z-scheme heterojunction tubular photocatalyst, Ag2O@PG, was synthesized by chemically depositing silver oxide compounded with P-doped hollow tubular graphitic carbon nitride for the photocatalytic inactivation of Microcystis aeruginosa (M. aeruginosa). The photocatalytic algal inactivation experiments showed that the photocatalytic activity of Ag2O@PG was influenced by the ratio of the composition of the obtained materials. The optimal algal inactivation efficiency was observed when using Ag2O@PG-0.4 at a dosage of 0.2â¯g/L. It was able to achieve a 99.1â¯%â¯M. aeruginosa inactivation at an initial concentration of 4.5â¯×â¯106 cells/mL following 5â¯h' visible light irradiation. During the process, the cell membrane permeability and cell morphology changed. Furthermore, under the constant attack of superoxide radicals and holes caused by Ag2O@PG, the superoxide dismutase, glutathione and malondialdehyde of algae cells increased during the experiments to alleviate oxidative damage. Eventually, the antioxidant system of algae cells was destroyed. To further validate the potential application of Ag2O@PG-0.4 in real algal bloom environment, an experiment in real water samples was carried out. Overall, the Ag2O@PG-0.4 as an efficient photocatalyst has a promising potential for emergency treatment measures to alleviate algal blooms.
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Microcystis , Luz , Microcystis/químicaRESUMEN
The Fenton-like processes are considered to be one of the most promising strategies for inactivating bacteria due to their capacity to produce reactive oxygen species (ROS). Herein, a catalytic system for efficient inactivation of Escherichia coli (E. coli) was developed by anchoring single-atom Ru on layered double hydroxides (LDH). The Ru/NiFe-LDH catalyst showed excellent performance in activating peroxymonosulfate (PMS) to inactivate E. coli. Under the combined action of the ultra-low concentrations of Ru/NiFe-LDH (40 mg/L) and PMS (5 mg/L), 7 log E. coli can be totally inactivated within 90 s. This was attributed to the combined effect of single-atom Ru adsorption to E. coli and the ROS produced in situ. Mechanism studies indicated that the 1O2 with electrophilic properties was the key active species responsible for the rapid inactivation of E. coli. The E. coli inactivation process suggested that the ROS produced first attacked the outer membrane of the cell, then the antioxidant enzymes in the cell were induced, the macromolecule substances were released and mineralized, eventually leading to irreversible cell death. This work firstly loads monoatomic Ru on LDH for bacterial inactivation, providing a feasible method for rapid inactivation of E. coli.
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Antioxidantes , Escherichia coli , Hidróxidos , Peróxidos , Especies Reactivas de OxígenoRESUMEN
BACKGROUND: Apoptosis is the physiological mechanism of programmed cell death and abnormal regulation of this pathway can lead to carcinogenesis. We hypothesized that the FAS -1377G>A, -670A>G, and FASL -844T>C polymorphisms are associated with risk of prostate cancer (PCa). MATERIALS AND METHODS: We genotyped polymorphisms in a hospital-based case-control study of 602 patients diagnosed with PCa and 703 cancer-free controls in a Chinese population using polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: We found a significantly decreased risk associated with FAS -1377GA [adjusted odds ratio (OR) = 0.71, 95% confidence interval (CI) = 0.56-0.90] genotype compared with the -1377GG genotype and decreased risk associated with FAS -670AG and -670GG genotypes (OR 0.75, 95% CI: 0.59-0.95; OR 0.70, 95% CI: 0.50-0.96) compared with the -670AA genotype. Consistently, we found that individuals carrying haplotype genotype with 0 or 1 risk allele (-1377G and -670A) had a lower risk of PCa than those with two risk alleles (OR 0.48, 95% CI: 0.28-0.80; OR 0.60, 95% CI: 0.41-0.87; OR 0.82, 95% CI: 0.69-0.97 for the AA, GG, and AG haplotype, respectively). In addition, when we evaluated these two FAS polymorphisms together, we found that the combined genotype with 4 risk alleles was associated with a significantly increased risk of PCa compared with those with 0-3 variants (OR 1.51, 95% CI: 1.19-1.91), and this increased risk was more pronounced among subgroups of Gleason score <7 and >7, and PSA > 20 ng/ml (OR 1.49, 95% CI: 1.08-2.04; OR 1.72, 95% CI: 1.25-2.44; OR 1.61, 95% CI: 1.23-2.13, respectively). CONCLUSIONS: These results suggested that the FAS polymorphisms may contribute to PCa risk in a Chinese population.
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Proteína Ligando Fas/genética , Neoplasias de la Próstata/genética , Receptor fas/genética , Anciano , Alelos , Pueblo Asiatico/genética , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , China/epidemiología , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Haplotipos , Humanos , Masculino , Oportunidad Relativa , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , Polimorfismo de Longitud del Fragmento de Restricción , Neoplasias de la Próstata/epidemiología , RiesgoRESUMEN
PURPOSE: This phase I trial was performed to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), preliminary efficacy, and pharmacokinetics (PK) of LY01610, a novel liposome-encapsulated irinotecan, in patients with advanced esophageal squamous cell carcinoma (ESCC). METHODS: This trial was conducted in two stages. In the dose-escalation stage, patients with advanced ESCC refractory or intolerant to previous chemotherapy received escalating doses of LY01610. A recommended dose based on patient tolerance was then expanded in the second stage. LY01610 was administered intravenously every 2 weeks, except that the first cycle in dose escalation was 3 weeks to allow observation of DLTs. RESULTS: Twenty-four patients were enrolled across 4 dose levels (30, 60, 90 and 120 mg/m2). The DLTs included vomiting and febrile neutropenia, and the MTD was 90 mg/m2. The most common grade 3/4 adverse events were leukopenia in six patients (25.0%), anemia in six patients (25.0%) and neutropenia in five patients (20.8%). One patient achieved complete response, and four had partial response, including one patient receiving LY01610 at the starting dose of 30 mg/m2. Compared with conventional irinotecan, the PK profile of LY01610 was characterized by increased and prolonged exposure of total irinotecan and the active metabolite SN-38 in plasma. CONCLUSION: LY01610 demonstrated manageable toxicity and promising anti-tumor activity in patients with advanced ESCC. Future clinical development of LY01610 as single agent or in combination with other anti-cancer agents in treating ESCC patients is warranted. TRIAL REGISTRATION: NCT04088604 at ClinicalTrials.gov.
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Neoplasias Esofágicas/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Irinotecán/administración & dosificación , Inhibidores de Topoisomerasa I/administración & dosificación , Adulto , Relación Dosis-Respuesta a Droga , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/patología , Femenino , Humanos , Irinotecán/efectos adversos , Irinotecán/farmacocinética , Liposomas , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neutropenia/inducido químicamente , Inhibidores de Topoisomerasa I/efectos adversos , Inhibidores de Topoisomerasa I/farmacocinéticaRESUMEN
BACKGROUND: OH2 is a genetically engineered oncolytic herpes simplex virus type 2 designed to selectively amplify in tumor cells and express granulocyte-macrophage colony-stimulating factor to enhance antitumor immune responses. We investigated the safety, tolerability and antitumor activity of OH2 as single agent or in combination with HX008, an anti-programmed cell death protein 1 antibody, in patients with advanced solid tumors. METHODS: In this multicenter, phase I/II trial, we enrolled patients with standard treatment-refractory advanced solid tumors who have injectable lesions. In phase I, patients received intratumoral injection of OH2 at escalating doses (106, 107 and 108CCID50/mL) as single agent or with fixed-dose HX008. The recommended doses were then expanded in phase II. Primary endpoints were safety and tolerability defined by the maximum-tolerated dose and dose-limiting toxicities (DLTs) in phase I, and antitumor activity assessed per Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) and immune-RECIST in phase II. RESULTS: Between April 17, 2019 and September 22, 2020, 54 patients with metastatic cancers were enrolled. Forty patients were treated with single agent OH2, and 14 with OH2 plus HX008. No DLTs were reported with single agent OH2 in phase I. Four patients, having metastatic mismatch repair-proficient rectal cancer or metastatic esophageal cancer, achieved immune-partial response, with two from the single agent cohort and two from the combination cohort. The duration of response were 11.25+ and 14.03+ months for the two responders treated with single agent OH2, and 1.38+ and 2.56+ months for the two responders in the combination cohort. The most common treatment-related adverse event (TRAE) with single agent OH2 was fever (n=18, 45.0%). All TRAEs were of grade 1-2, except one case of grade 3 fever in the 108CCID50/mL group. No treatment-related serious AEs occurred. Single agent OH2 induced alterations in the tumor microenvironment, with clear increases in CD3+ and CD8+ cell density and programmed death-ligand 1 expression in the patients' post-treatment biopsies relative to baseline. CONCLUSIONS: Intratumoral injection of OH2 was well-tolerated, and demonstrated durable antitumor activity in patients with metastatic esophageal and rectal cancer. Further clinical development of OH2 as single agent or with immune checkpoint inhibitors in selected tumor types is warranted.