ABSTRACT
Ethylene regulates plant growth, development, and stress adaptation. However, the early signaling events following ethylene perception, particularly in the regulation of ethylene receptor/CTRs (CONSTITUTIVE TRIPLE RESPONSE) complex, remains less understood. Here, utilizing the rapid phospho-shift of rice OsCTR2 in response to ethylene as a sensitive readout for signal activation, we revealed that MHZ3, previously identified as a stabilizer of ETHYLENE INSENSITIVE 2 (OsEIN2), is crucial for maintaining OsCTR2 phosphorylation. Genetically, both functional MHZ3 and ethylene receptors prove essential for OsCTR2 phosphorylation. MHZ3 physically interacts with both subfamily I and II ethylene receptors, e.g., OsERS2 and OsETR2 respectively, stabilizing their association with OsCTR2 and thereby maintaining OsCTR2 activity. Ethylene treatment disrupts the interactions within the protein complex MHZ3/receptors/OsCTR2, reducing OsCTR2 phosphorylation and initiating downstream signaling. Our study unveils the dual role of MHZ3 in fine-tuning ethylene signaling activation, providing insights into the initial stages of the ethylene signaling cascade.
Subject(s)
Ethylenes , Gene Expression Regulation, Plant , Oryza , Plant Proteins , Receptors, Cell Surface , Signal Transduction , Oryza/metabolism , Oryza/genetics , Ethylenes/metabolism , Plant Proteins/metabolism , Plant Proteins/genetics , Phosphorylation , Receptors, Cell Surface/metabolism , Receptors, Cell Surface/genetics , Plants, Genetically Modified , Membrane Proteins/metabolism , Membrane Proteins/geneticsABSTRACT
The cell wall shapes plant cell morphogenesis and affects the plasticity of organ growth. However, the way in which cell wall establishment is regulated by ethylene remains largely elusive. Here, by analyzing cell wall patterns, cell wall composition and gene expression in rice (Oryza sativa, L.) roots, we found that ethylene induces cell wall thickening and the expression of cell wall synthesis-related genes, including CELLULOSE SYNTHASE-LIKE C1, 2, 7, 9, 10 (OsCSLC1, 2, 7, 9, 10) and CELLULOSE SYNTHASE A3, 4, 7, 9 (OsCESA3, 4, 7, 9). Overexpression and mutant analyses revealed that OsCSLC2 and its homologs function in ethylene-mediated induction of xyloglucan biosynthesis mainly in the cell wall of root epidermal cells. Moreover, OsCESA-catalyzed cellulose deposition in the cell wall was enhanced by ethylene. OsCSLC-mediated xyloglucan biosynthesis likely plays an important role in restricting cell wall extension and cell elongation during the ethylene response in rice roots. Genetically, OsCSLC2 acts downstream of ETHYLENE-INSENSITIVE3-LIKE1 (OsEIL1)-mediated ethylene signaling, and OsCSLC1, 2, 7, 9 are directly activated by OsEIL1. Furthermore, the auxin signaling pathway is synergistically involved in these regulatory processes. These findings link plant hormone signaling with cell wall establishment, broadening our understanding of root growth plasticity in rice and other crops.
ABSTRACT
Texture synthesis is a fundamental problem in computer graphics that would benefit various applications. Existing methods are effective in handling 2D image textures. In contrast, many real-world textures contain meso-structure in the 3D geometry space, such as grass, leaves, and fabrics, which cannot be effectively modeled using only 2D image textures. We propose a novel texture synthesis method with Neural Radiance Fields (NeRF) to capture and synthesize textures from given multi-view images. In the proposed NeRF texture representation, a scene with fine geometric details is disentangled into the meso-structure textures and the underlying base shape. This allows textures with meso-structure to be effectively learned as latent features situated on the base shape, which are fed into a NeRF decoder trained simultaneously to represent the rich view-dependent appearance. Using this implicit representation, we can synthesize NeRF-based textures through patch matching of latent features. However, inconsistencies between the metrics of the reconstructed content space and the latent feature space may compromise the synthesis quality. To enhance matching performance, we further regularize the distribution of latent features by incorporating a clustering constraint. In addition to generating NeRF textures over a planar domain, our method can also synthesize NeRF textures over curved surfaces, which are practically useful. Experimental results and evaluations demonstrate the effectiveness of our approach.
ABSTRACT
Gene expression is regulated at multiple levels, including RNA processing and DNA methylation/demethylation. How these regulations are controlled remains unclear. Here, through analysis of a suppressor for the OsEIN2 over-expressor, we identified an RNA recognition motif protein SUPPRESSOR OF EIN2 (SOE). SOE is localized in nuclear speckles and interacts with several components of the spliceosome. We find SOE associates with hundreds of targets and directly binds to a DNA glycosylase gene DNG701 pre-mRNA for efficient splicing and stabilization, allowing for subsequent DNG701-mediated DNA demethylation of the transgene promoter for proper gene expression. The V81M substitution in the suppressor mutant protein mSOE impaired its protein stability and binding activity to DNG701 pre-mRNA, leading to transgene silencing. SOE mutation enhances grain size and yield. Haplotype analysis in c. 3000 rice accessions reveals that the haplotype 1 (Hap 1) promoter is associated with high 1000-grain weight, and most of the japonica accessions, but not indica ones, have the Hap 1 elite allele. Our study discovers a novel mechanism for the regulation of gene expression and provides an elite allele for the promotion of yield potentials in rice.
Subject(s)
Gene Expression Regulation, Plant , Gene Silencing , Oryza , Plant Proteins , Transgenes , Oryza/genetics , Plant Proteins/genetics , Plant Proteins/metabolism , Promoter Regions, Genetic/genetics , Mutation/genetics , Protein Domains , Haplotypes/genetics , DNA Methylation/genetics , Protein Binding , Plants, Genetically Modified , AllelesABSTRACT
INTRODUCTION: EGFR-mutated NSCLC is characterized by an immunosuppressive microenvironment that confers limited clinical effectiveness to anti-PD-1 or PD-L1 antibodies. Despite the discouraging outcomes of immunotherapy, novel immune checkpoints are constantly emerging, among which the specific vulnerability for therapeutic intervention in the context of EGFR-mutated NSCLC remains unresolved. METHODS: Data sets of patient- and cell line-levels were used for screening and mutual validation of association between EGFR mutation and a panel of immune checkpoint-related genes. Regulatory mechanism was elucidated through in vitro manipulation of EGFR signaling pathway and evaluated by immunoblot analysis, quantitative polymerase chain reaction, flow cytometry, immunofluorescence staining, and chromatin immunoprecipitation. In vivo investigation of different therapeutic strategies were conducted using both immunocompetent and immunodeficient mouse models. RESULTS: Among all screened immune checkpoints, CD47 emerged as the candidate most relevant to EGFR activation. Mechanistically, EGFR mutation constitutively activated downstream ERK and AKT pathways to respectively up-regulate the transcriptional factors c-Myc and NF-κB, both of which structurally bound to the promotor region of CD47 and actively transcribed this "don't eat me" signal. Impaired macrophage phagocytosis was observed on introduction of EGFR-sensitizing mutations in NSCLC cell line models, whereas CD47 blockade restored the phagocytic capacity and augmented tumor cell killing in both in vitro and in vivo models. Remarkably, the combination of anti-CD47 antibody with EGFR tyrosine kinase inhibitor revealed an additive antitumor activity compared with monotherapy of either antitumor agent in both immunocompetent and adaptive immunity-deficient mouse models. CONCLUSIONS: EGFR-sensitizing mutation facilitates NSCLC's escape from innate immune attack through up-regulating CD47. Combination therapy incorporating CD47 blockade holds substantial promise for clinical translation in developing more effective therapeutic approaches against EGFR-mutant NSCLC.
Subject(s)
CD47 Antigen , Carcinoma, Non-Small-Cell Lung , ErbB Receptors , Lung Neoplasms , Macrophages , Mutation , Phagocytosis , Up-Regulation , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/immunology , Carcinoma, Non-Small-Cell Lung/drug therapy , CD47 Antigen/genetics , Humans , Mice , Animals , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Lung Neoplasms/drug therapy , Lung Neoplasms/immunology , ErbB Receptors/genetics , Macrophages/metabolism , Macrophages/immunology , Immunity, Innate , Immune Evasion , Xenograft Model Antitumor AssaysABSTRACT
INTRODUCTION: The literature on de novo EGFRT790M-mutant patients diagnosed with lung cancer is limited, and there is currently no consensus concerning the most effective treatment protocols. This study aimed to investigate the genomic characteristics of de novoEGFRT790M-mutant non-small cell lung cancer (NSCLC) and provide insights into its clinical response and resistance mechanism to third-generation EGFR-TKIs. METHODS: Next-generation sequencing was utilized to screen a substantial cohort of 4,228 treatment-naïve patients from the Mygene genomic database to identifythe de novo EGFR-T790M mutation. Meanwhile, we recruited 83 individuals diagnosed with lung cancer who harbored de novo EGFRT790M mutation in the real world. In addition, 166 patients who acquired EGFR-T790M mutation after becoming resistant to first- or second-generation EGFR-TKIs were included as a comparison cohort. RESULTS: De novo EGFRT790M mutation identified by next-generation sequencing is rare (â¼1.3 %) in Chinese lung cancer patients. The relative variant allele frequency (VAF) of de novo EGFRT790M mutation was either comparable to or significantly lower than those of EGFR-activating mutations. Patients with de novo-T790M mutations exhibited less favorable clinical outcomes when administered third-generation EGFR-TKIs as first-line therapy thanthose with 19del mutationsdue to a high overlap rate in EGFR p.L858R mutation. In patients with a de novo EGFRT790M mutation, no correlation was observed between T790M clonality and treatment outcomes with third-generation EGFR-TKIs. In contrast, the sub-clonality of the T790M mutation detrimentally affected the third-generation EGFR-TKI treatment efficacy in patients with acquired T790M mutation. Potential resistance mechanisms of third-generation EGFR TKIs in NSCLC patients with de novo or acquired EGFRT790M mutations included EGFR p.C797S in cis or EGFR p.E709X mutation, as well as activation of bypass pathways. CONCLUSIONS: The present study characterized the uncommon but unique de novo EGFRT790M-mutant NSCLC and laid a foundation for designing future clinical trials in the setting of uncommon EGFR mutation.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , ErbB Receptors/genetics , ErbB Receptors/metabolism , Drug Resistance, Neoplasm/genetics , Mutation , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/pharmacologyABSTRACT
Patients with mild cognitive impairment (MCI) are at a high risk of developing future dementia. However, early identification and active intervention could potentially reduce its morbidity and the incidence of dementia. Functional near-infrared spectroscopy (fNIRS) has been proposed as a noninvasive modality for detecting oxygenation changes in the time-varying hemodynamics of the prefrontal cortex. This study sought to provide an effective method for detecting patients with MCI using fNIRS and the Wisconsin card sorting test (WCST) to evaluate changes in blood oxygenation. The results revealed that all groups with a lower mini-mental state examination grade had a higher increase in HHb concentration during a modified WCST (MCST). The increase in the change in oxygenated hemoglobin concentration in the stroke group was smaller than that in the normal group due to weak cerebrovascular reactivity.
Subject(s)
Cognitive Dysfunction , Dementia , Humans , Spectroscopy, Near-Infrared/methods , Cognitive Dysfunction/diagnostic imaging , Prefrontal Cortex , Oxyhemoglobins , Dementia/complicationsABSTRACT
Ethylene plays essential roles in rice growth, development and stress adaptation. Translational control of ethylene signaling remains unclear in rice. Here, through analysis of an ethylene-response mutant mhz9, we identified a glycine-tyrosine-phenylalanine (GYF) domain protein MHZ9, which positively regulates ethylene signaling at translational level in rice. MHZ9 is localized in RNA processing bodies. The C-terminal domain of MHZ9 interacts with OsEIN2, a central regulator of rice ethylene signaling, and the N-terminal domain directly binds to the OsEBF1/2 mRNAs for translational inhibition, allowing accumulation of transcription factor OsEIL1 to activate the downstream signaling. RNA-IP seq and CLIP-seq analyses reveal that MHZ9 associates with hundreds of RNAs. Ribo-seq analysis indicates that MHZ9 is required for the regulation of ~ 90% of genes translationally affected by ethylene. Our study identifies a translational regulator MHZ9, which mediates translational regulation of genes in response to ethylene, facilitating stress adaptation and trait improvement in rice.
Subject(s)
Oryza , Oryza/metabolism , Plant Proteins/genetics , Plant Proteins/metabolism , Mutation , Ethylenes/metabolism , RNA/metabolism , Gene Expression Regulation, PlantABSTRACT
The recently proposed neural radiance fields (NeRF) use a continuous function formulated as a multi-layer perceptron (MLP) to model the appearance and geometry of a 3D scene. This enables realistic synthesis of novel views, even for scenes with view dependent appearance. Many follow-up works have since extended NeRFs in different ways. However, a fundamental restriction of the method remains that it requires a large number of images captured from densely placed viewpoints for high-quality synthesis and the quality of the results quickly degrades when the number of captured views is insufficient. To address this problem, we propose a novel NeRF-based framework capable of high-quality view synthesis using only a sparse set of RGB-D images, which can be easily captured using cameras and LiDAR sensors on current consumer devices. First, a geometric proxy of the scene is reconstructed from the captured RGB-D images. Renderings of the reconstructed scene along with precise camera parameters can then be used to pre-train a network. Finally, the network is fine-tuned with a small number of real captured images. We further introduce a patch discriminator to supervise the network under novel views during fine-tuning, as well as a 3D color prior to improve synthesis quality. We demonstrate that our method can generate arbitrary novel views of a 3D scene from as few as 6 RGB-D images. Extensive experiments show the improvements of our method compared with the existing NeRF-based methods, including approaches that also aim to reduce the number of input images.
ABSTRACT
BACKGROUND & OBJECTIVE: "Anti-angiogenetic drugs plus chemotherapy" (anti-angio-chemo) and "immune checkpoint inhibitors plus chemotherapy" (ICI-chemo) are superior to traditional chemotherapy in the first-line treatment of patients with advanced non-small-cell lung cancer (NSCLC). However, in the absence of a direct comparison of ICI-chemo with anti-angio-chemo, the superior one between them has not been decided, and the benefit of adding anti-angiogenetic agents to ICI-chemo remains controversial. This study aimed to investigate the role of antiangiogenic agents for advanced NSCLC in the era of immunotherapy. METHODS: Eligible randomized controlled trials (RCTs) comparing chemotherapy versus therapeutic regimens involving ICIs or anti-angiogenetic drugs were included. Outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and rate of grade 3-4 toxicity assessment. R-4.3.1 was utilized to perform the analysis. RESULTS: A total of 54 studies with a sample size of 25,046 were finally enrolled. "Atezolizumab + Bevacizumab + Chemotherapy" significantly improved the ORR compared with "Atezolizumab + Chemotherapy" (Odds ratio (OR) = 2.73, 95% confidence interval (CI): 1.27-5.87). The trend also favored "Atezolizumab + Bevacizumab + Chemotherapy" in PFS and OS (hazard ratio (HR) = 0.71, 95% CI: 0.39-1.31; HR = 0.94, 95% CI: 0.77-1.16, respectively). In addition, "Pembrolizumab + Chemotherapy" and "Camrelizumab + Chemotherapy" significantly prolonged the PFS compared to "Bevacizumab + Chemotherapy" (HR = 0.65, 95% CI: 0.46-0.92; HR = 0.63, 95% CI: 0.41-0.97; respectively). Meanwhile, "Pembrolizumab + Chemotherapy" and "Sintilimab + Chemotherapy" yielded more OS benefits than "Bevacizumab + Chemotherapy" (HR = 0.69, 95% CI: 0.56-0.83; HR = 0.64, 95%CI: 0.46-0.91; respectively). Scheme between "Atezolizumab + Bevacizumab + Chemotherapy" and "Atezolizumab + Chemotherapy" made no significant difference (OR = 1.18, 95%CI: 0.56-2.42) concerning the rate of grade 3-4 toxicity. It seemed that ICI-chemo yielded more improvement in quality-adjusted life-year (QALY) than "Bevacizumab + Chemotherapy" in cost-effectiveness analysis. CONCLUSION: Our results suggest that ICI-chemo is associated with potentially longer survival, better cost-effectiveness outcomes, and comparable safety profiles than anti-angio-chemo. Also, adding bevacizumab to ICI-chemo seemed to provide additional therapeutic benefits without adding treatment burden. Our findings would supplement the current standard of care and help the design of future clinical trials for the first-line treatment of patients with advanced NSCLC.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Angiogenesis Inhibitors/adverse effects , Bevacizumab/therapeutic use , Immunotherapy/methods , Antineoplastic Combined Chemotherapy Protocols/adverse effectsABSTRACT
Pulmonary lymphoepithelioma-like carcinoma (PLELC) is a rare and histologically distinctive subtype of nonsmall cell lung cancer (NSCLC). High expression of programmed death ligand 1 (PD-L1) and scarcity of druggable driver mutations raise the potential of immunotherapy for advanced PELEC. However, evidence on the clinical impact of immune-checkpoint inhibitors (ICIs) remained limited and unconvincing. The present study retrospectively enrolled advanced PLELC patients who received ICIs either as up-front or salvage therapy in SYSUCC between March 15, 2017 and March 15, 2022. The comparative efficacy of chemoimmunotherapy vs chemotherapy in the first-line setting and chemoimmunotherapy vs ICIs monotherapy in the ≥2 line setting was investigated. A total of 96 patients were finally enrolled; 49 PLELC patients received immunotherapy plus platinum-based chemotherapy, while 45 patients received platinum-based chemotherapy as first-line treatment. Patients with chemoimmunotherapy significantly obtain more survival benefits than those receiving chemotherapy (median progression-free survival [PFS]: 15.6 vs 8.6 months, P = .0015). Additionally, patients with chemoimmunotherapy obtained more PFS benefits than those with ICIs monotherapy in the ≥2 line of therapy (median PFS: 21.7 months vs 7.8 months, P = .094). A significant correlation was observed between prognostic nutritional index (PNI) and favorable treatment outcomes in patients receiving first-line chemoimmunotherapy (median PFS: 17.8 months vs 7.6 months, P < .0001). Likewise, patients in the monocyte-to-lymphocyte ratio (MLR)-high group had significantly shorter PFS than the MLR-low group (median PFS: 11.2 months vs not reached, P = .0009). Our study elucidated the superior efficacy of ICIs therapy, especially chemoimmunotherapy in advanced PLELC, which may provide new insight into the role of immunotherapy in advanced PLELC.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Carcinoma, Squamous Cell , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Retrospective Studies , Lung Neoplasms/drug therapy , ImmunotherapyABSTRACT
Rice is an important food crop in the world and the study of its growth and plasticity has a profound influence on sustainable development. Ethylene modulates multiple agronomic traits of rice as well as abiotic and biotic stresses during its lifecycle. It has diverse roles, depending on the organs, developmental stages and environmental conditions. Compared to Arabidopsis (Arabidopsis thaliana), rice ethylene signalling pathway has its own unique features due to its special semiaquatic living environment and distinct plant structure. Ethylene signalling and responses are part of an intricate network in crosstalk with internal and external factors. This review will summarize the current progress in the mechanisms of ethylene-regulated coleoptile growth in rice, with a special focus on ethylene signaling and interaction with other hormones. Insights into these molecular mechanisms may shed light on ethylene biology and should be beneficial for the genetic improvement of rice and other crops.
Subject(s)
Arabidopsis , Oryza , Plant Growth Regulators/metabolism , Seedlings/metabolism , Oryza/genetics , Cotyledon/metabolism , Ethylenes/metabolism , Arabidopsis/metabolism , Gene Expression Regulation, PlantABSTRACT
Deformation component analysis is a fundamental problem in geometry processing and shape understanding. Existing approaches mainly extract deformation components in local regions at a similar scale while deformations of real-world objects are usually distributed in a multi-scale manner. In this article, we propose a novel method to exact multiscale deformation components automatically with a stacked attention-based autoencoder. The attention mechanism is designed to learn to softly weight multi-scale deformation components in active deformation regions, and the stacked attention-based autoencoder is learned to represent the deformation components at different scales. Quantitative and qualitative evaluations show that our method outperforms state-of-the-art methods. Furthermore, with the multiscale deformation components extracted by our method, the user can edit shapes in a coarse-to-fine fashion which facilitates effective modeling of new shapes.
ABSTRACT
Photoconduction (PC) properties were investigated for ternary indium aluminium nitride (In x Al1-x N) nanorods (NRs) with different indium compositions (x) from 0.35 to 0.68, as grown by direct-current reactive magnetron sputter epitaxy. Cross-sectional scanning transmission electron microscopy (STEM) reveals single-crystal quality of the vertically aligned In x Al1-x N NRs. Single-rod photodetector devices with good ohmic contacts were fabricated using the focused-ion-beam technique (FIB), where the In-rich In0.68Al0.32N NR exhibits an optimal photocurrent responsivity of 1400 A W-1 and photoconductive gain of 3300. A transition from a positive photoresponse to a negative photoresponse was observed, while increasing the In composition x from 0.35 to 0.57. The negative PC was further enhanced by increasing x to 0.68. A model based on the coexistence and competition of deep electron trap states and recombination centers was proposed to explain the interesting composition-dependent PC in these ternary III-nitride 1D nanostructures.
ABSTRACT
This study aims to reveal the buckling behavior of filament-wound composite cylindrical shells subjected to external pressure. The boundary conditions of the cylindrical shells were one end fixed and the other free. The carbon fiber stacking sequences were [±90]2/([±20]/[±90]/[±40]/[±90]/[±60]/[±90])2/[±90]. Finite element software ANSYS 16.2 was used for the numerical simulation to predict the critical buckling pressure and buckling behavior of composite cylindrical shell. External hydrostatic pressure tests were conducted, where the buckling behavior and strain response were observed. Numerical simulation accurately predicted the critical buckling pressure of carbon fiber/epoxy filament composite cylindrical shells under external pressure with 3.5% deviation from the experimental results. The buckling modes simulated by the finite element method agreed well with the deformed shape observed in the experiment, which was characterized by the uniform distribution of the three hoop waves. Comparing the axial compressive strain and hoop compressive strain of the composite shell, it was found that the circumferential stiffness of the shell was weaker than the axial stiffness. In addition, a comparative study of the strains of the fixed-end and free-end metal control sleeves was carried out. The results show that the boundary conditions have a significant influence on the strain response of control sleeves.
ABSTRACT
BACKGROUND: Afatinib is the only currently approved EGFR-tyrosine kinase inhibitors for advanced non-small cell lung cancer (NSCLC) patients with EGFR G719X/L861Q/S768I. However, there are limited real-world data concerning the benefits and resistance mechanisms of afatinib in patients with these nonclassical mutations. To fill this gap, the present study was conducted. METHODS: All NSCLC patients treated with afatinib were screened, and patients with EGFR G719X/L861Q/S768I were enrolled into the analysis. Either tumor tissue or blood specimens were detected by the commercial next-generation sequencing (NGS) panels or amplification-refractory mutation system (ARMS)-polymerase chain reaction (PCR) to figure out the mutation genotype. RESULTS: A total of 106 advanced NSCLC patients with EGFR G719X/L861Q/S768I received afatinib treatment. The benefits of afatinib exhibited heterogeneity in different mutation genotypes. Notably, at baseline, NGS testing was performed in 59 patients, and TP53 was the most frequently coexisting mutation. Patients with TP53 mutations obtained fewer survival benefits than those with TP53 wild-type. A total of 68 patients ultimately experienced progression, and 27 patients received NGS testing to clarify the potential resistance mechanisms. EGFR-T790M, CDK4 amplification, FGFR1 amplification, PIK3CA, MET amplification, RET fusions, HER2, and BRAF mutations were identified in three (11.1%), three (11.1%), three (11.1%), three (11.1%), three (11.1%), one (3.7%), one (3.7%), and one (3.7%) of the cases, respectively. Five patients underwent ARMS-PCR testing for detecting EGFR-T790M mutation, and only one patient was T790M-positive. CONCLUSIONS: The present study elucidated the differential benefits of afatinib within different mutation genotypes and first revealed the spectrum of potential resistance mechanisms in patients with EGFR G719X/L861Q/S768I. The results of this study may provide practical clinical information that can guide optimal treatment in this setting.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Afatinib/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Class I Phosphatidylinositol 3-Kinases/genetics , ErbB Receptors/genetics , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mutation , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins B-raf/geneticsABSTRACT
Ethylene plays essential roles in adaptive growth of rice (Oryza sativa). Understanding of the crosstalk between ethylene and auxin (Aux) is limited in rice. Here, from an analysis of the root-specific ethylene-insensitive rice mutant mao hu zi 10 (mhz10), we identified the tryptophan aminotransferase (TAR) MHZ10/OsTAR2, which catalyzes the key step in indole-3-pyruvic acid-dependent Aux biosynthesis. Genetically, OsTAR2 acts downstream of ethylene signaling in root ethylene responses. ETHYLENE INSENSITIVE3 like1 (OsEIL1) directly activated OsTAR2 expression. Surprisingly, ethylene induction of OsTAR2 expression still required the Aux pathway. We also show that Os indole-3-acetic acid (IAA)1/9 and OsIAA21/31 physically interact with OsEIL1 and show promotive and repressive effects on OsEIL1-activated OsTAR2 promoter activity, respectively. These effects likely depend on their EAR motif-mediated histone acetylation/deacetylation modification. The special promoting activity of OsIAA1/9 on OsEIL1 may require both the EAR motifs and the flanking sequences for recruitment of histone acetyltransferase. The repressors OsIAA21/31 exhibit earlier degradation upon ethylene treatment than the activators OsIAA1/9 in a TIR1/AFB-dependent manner, allowing OsEIL1 activation by activators OsIAA1/9 for OsTAR2 expression and signal amplification. This study reveals a positive feedback regulation of ethylene signaling by Aux biosynthesis and highlights the crosstalk between ethylene and Aux pathways at a previously underappreciated level for root growth regulation in rice.
Subject(s)
Ethylenes , Indoleacetic Acids , Oryza , Plant Roots , Tryptophan Transaminase , Ethylenes/metabolism , Gene Expression Regulation, Plant , Indoleacetic Acids/metabolism , Oryza/growth & development , Oryza/metabolism , Plant Roots/growth & development , Plant Roots/metabolism , Tryptophan Transaminase/genetics , Tryptophan Transaminase/metabolismABSTRACT
OBJECTIVE: This study aimed to compare the efficacy and safety of different platinum adjuvant chemotherapy regimens for early-stage resected non-small-cell lung cancer (NSCLC). DESIGN: Systematic review with network meta-analysis of randomised trials. DATA SOURCES: PubMed, EMBASE, The Cochrane Library, Web of Science and Scopus Google Scholar were searched through 12 March 2021. ELIGIBILITY CRITERIA: Eligible randomised controlled trials (RCTs) comparing the postoperative platinum chemotherapy regimen with the observation-controlled group or comparing two platinum chemotherapy regimens head-to-head were included. DATA EXTRACTION AND SYNTHESIS: The primary outcome was the efficacy of adjuvant chemotherapy regimens including relapse-free survival (RFS), overall survival (OS), 2-year, 3-year, 5-year RFS rate and OS rate. The secondary outcome was the rate of grade 3-4 toxicity assessments. Cochrane Handbook (V.5) was used for the risk of bias assessment. Analyses were performed using R software V.4.3.1. RESULTS: 20 RCTs with a sample size of 5483 were enrolled in meta-analysis. The chemotherapy group had a significant RFS and OS advantage compared with the observation group (HR 0.67; 95% CI 0.56 to 0.81, p<0.0001; HR 0.80; 95% CI, 0.73 to 0.88, p<0.0001, respectively). Compared with the observation arm, only the 'cisplatin_vinorelbine' regimen had a significant RFS and OS advantage (HR 0.63; 95% CI 0.43 to 0.87; HR 0.74; 95% CI 0.63 to 0.87, respectively) while the remaining chemotherapy regimens had no significant difference of efficacy compared with the observation group. In terms of the safety of adjuvant chemotherapy, the incidence of haematological toxicities and nausea/vomiting was not significantly higher in the 'cisplatin_vinorelbine' arm than in other chemotherapy group. CONCLUSION: This study summarised the adjuvant cytotoxicity chemotherapy regimens for patients with early-stage resected NSCLC. Our analysis may provide some guiding significance for the clinicians when determining the optimal chemotherapy regimen.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/surgery , Chemotherapy, Adjuvant , Cisplatin/therapeutic use , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/surgery , Neoplasm Recurrence, Local/drug therapy , Network Meta-Analysis , Platinum/therapeutic use , Vinorelbine/therapeutic useABSTRACT
Human connectome describes the complicated connection matrix of nervous system among human brain. It also possesses high potential of assisting doctors to monitor the brain injuries and recoveries in patients. In order to unravel the enigma of neuron connections and functions, previous research has strived to dig out the relations between neurons and brain regions. Verbal fluency test (VFT) is a general neuropsychological test, which has been used in functional connectivity investigations. In this study, we employed convolutional neural network (CNN) on a brain hemoglobin concentration changes (ΔHB) map obtained during VFT to investigate the connections of activated brain areas and different mental status. Our results show that feature of functional connectivity can be identified accurately with the employment of CNN on ΔHB mapping, which is beneficial to improve the understanding of brain functional connections.