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F-box protein is a subunit of the SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase complex, which plays a critical role in regulating different pathways in plant immunity. In this study, we identified the rice (Oryza sativa) F-box protein OsFBX156, which targets the heat shock protein 70 (OsHSP71.1) to regulate resistance to the rice blast fungus Magnaporthe oryzae. Overexpression of OsFBX156 or knockout of OsHSP71.1 in rice resulted in the elevation of pathogenesis-related (PR) genes and an induction burst of reactive oxygen species (ROS) after flg22 and chitin treatments, thereby enhancing resistance to M. oryzae. Furthermore, OsFBX156 can promote the degradation of OsHSP71.1 through the 26S proteasome pathway. This study sheds lights on a novel mechanism wherein the F-box protein OsFBX156 targets OsHSP71.1 for degradation to promote ROS production and PR gene expression, thereby positively regulating rice innate immunity.
Assuntos
Resistência à Doença , Proteínas F-Box , Oryza , Doenças das Plantas , Proteínas de Plantas , Ubiquitinação , Oryza/microbiologia , Oryza/metabolismo , Oryza/genética , Doenças das Plantas/microbiologia , Doenças das Plantas/imunologia , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Resistência à Doença/genética , Proteínas F-Box/metabolismo , Proteínas F-Box/genética , Espécies Reativas de Oxigênio/metabolismo , Regulação da Expressão Gênica de Plantas , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Imunidade Vegetal/genética , Ascomicetos/patogenicidadeRESUMO
Plants typically activate distinct defense pathways against various pathogens. Heightened resistance to one pathogen often coincides with increased susceptibility to another pathogen. However, the underlying molecular basis of this antagonistic response remains unclear. Here, we demonstrate that mutants defective in the transcription factor ETHYLENE-INSENSITIVE 3-LIKE 2 (OsEIL2) exhibited enhanced resistance to the biotrophic bacterial pathogen Xanthomonas oryzae pv oryzae and to the hemibiotrophic fungal pathogen Magnaporthe oryzae, but enhanced susceptibility to the necrotrophic fungal pathogen Rhizoctonia solani. Furthermore, necrotroph-induced OsEIL2 binds to the promoter of OsWRKY67 with high affinity, leading to the upregulation of salicylic acid (SA)/jasmonic acid (JA) pathway genes and increased SA/JA levels, ultimately resulting in enhanced resistance. However, biotroph- and hemibiotroph-induced OsEIL2 targets OsERF083, resulting in the inhibition of SA/JA pathway genes and decreased SA/JA levels, ultimately leading to reduced resistance. Our findings unveil a previously uncharacterized defense mechanism wherein two distinct transcriptional regulatory modules differentially mediate immunity against pathogens with different lifestyles through the transcriptional reprogramming of phytohormone pathway genes.
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Ciclopentanos , Regulação da Expressão Gênica de Plantas , Oryza , Oxilipinas , Doenças das Plantas , Imunidade Vegetal , Proteínas de Plantas , Rhizoctonia , Ácido Salicílico , Xanthomonas , Oxilipinas/metabolismo , Ácido Salicílico/metabolismo , Ciclopentanos/metabolismo , Oryza/microbiologia , Oryza/genética , Oryza/imunologia , Doenças das Plantas/microbiologia , Doenças das Plantas/imunologia , Xanthomonas/fisiologia , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Rhizoctonia/fisiologia , Imunidade Vegetal/efeitos dos fármacos , Mutação/genética , Resistência à Doença/genética , Regiões Promotoras Genéticas/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Ligação Proteica/efeitos dos fármacosRESUMO
Although the antagonistic effects of host resistance against biotrophic and necrotrophic pathogens have been documented in various plants, the underlying mechanisms are unknown. Here, we investigated the antagonistic resistance mediated by the transcription factor ETHYLENE-INSENSITIVE3-LIKE 3 (OsEIL3) in rice. The Oseil3 mutant confers enhanced resistance to the necrotroph Rhizoctonia solani but greater susceptibility to the hemibiotroph Magnaporthe oryzae and biotroph Xanthomonas oryzae pv. oryzae. OsEIL3 directly activates OsERF040 transcription while repressing OsWRKY28 transcription. The infection of R. solani and M. oryzae or Xoo influences the extent of binding of OsEIL3 to OsWRKY28 and OsERF040 promoters, resulting in the repression or activation of both salicylic acid (SA)- and jasmonic acid (JA)-dependent pathways and enhanced susceptibility or resistance, respectively. These results demonstrate that the distinct effects of plant immunity to different pathogen types are determined by two transcription factor modules that control transcriptional reprogramming and the SA and JA pathways.
Assuntos
Ciclopentanos , Regulação da Expressão Gênica de Plantas , Oryza , Oxilipinas , Doenças das Plantas , Imunidade Vegetal , Proteínas de Plantas , Ácido Salicílico , Xanthomonas , Ciclopentanos/metabolismo , Oryza/microbiologia , Oryza/genética , Oryza/imunologia , Oryza/metabolismo , Oxilipinas/metabolismo , Ácido Salicílico/metabolismo , Doenças das Plantas/microbiologia , Doenças das Plantas/imunologia , Xanthomonas/patogenicidade , Imunidade Vegetal/genética , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Rhizoctonia , Transdução de Sinais , Resistência à Doença/genética , Regiões Promotoras Genéticas/genética , Magnaporthe , Transcrição GênicaRESUMO
In the past few years, two-dimensional (2D) high-temperature ferromagnetic semiconductor (FMS) materials with novelty and excellent properties have attracted much attention due to their potential in spintronics applications. In this work, using first-principles calculations, we predict that the H-MnN2 monolayer with the H-MoS2-type structure is a stable intrinsic FMS with an indirect band gap of 0.79 eV and a high Curie temperature (Tc) of 380 K. The monolayer also has a considerable in-plane magnetic anisotropy energy (IMAE) of 1005.70 µeV/atom, including a magnetic shape anisotropy energy induced by the dipole-dipole interaction (shape-MAE) of 168.37 µeV/atom and a magnetic crystalline anisotropy energy resulting from spin-orbit coupling (SOC-MAE) of 837.33 µeV/atom. Further, based on the second-order perturbation theory, its in-plane SOC-MAE of 837.33 µeV/atom is revealed to mainly derive from the couplings of Mn-dxz,dyz and Mn-dx2-y2,dxy orbitals through Lz in the same spin channel. In addition, the biaxial strain and carrier doping can effectively tune the monolayer's magnetic and electronic properties. Such as, under the hole and few electrons doping, the transition from semiconductor to half-metal can be realized, and its Tc can go up to 520 and 620 K under 5% tensile strain and 0.3 hole doping, respectively. Therefore, our research will provide a new, promising 2D FMS for spintronics devices.
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Due to the inconsistent absorption and scattering effects of different wavelengths of light, underwater images often suffer from color casts, blurred details, and low visibility. To address this image degradation problem, we propose a robust and efficient underwater image enhancement method named UIEOGP. It can be divided into the following three steps. First, according to the light attenuation effect presented by Lambert Beer's law, combined with the variance change after attenuation, we estimate the depth of field in the underwater image. Then, we propose a local-based color correction algorithm to address the color cast issue in underwater images, employing the statistical distribution law. Finally, drawing inspiration from the law of light propagation, we propose detail enhancement algorithms, each based on the geometric properties of circles and ellipses, respectively. The enhanced images produced by our method feature vibrant colors, improved contrast, and sharper detail. Extensive experiments show that our method outperforms current state-of-the-art methods. In further experiments, we found that our method is beneficial for downstream tasks of underwater image processing, such as the detection of keypoints and edges in underwater images.
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Background: To study the effect of cycloplegia on ocular parameters in children with myopia and hyperopia. Methods: Forty-two myopia and forty-four hyperopia eyes in children between 5 and 10 years of age were included. Measurements were taken before and after cycloplegia using 1% atropine sulfate ointment. The ocular parameters included central corneal thickness (CCT), corneal curvature (CC), anterior chamber depth (ACD), pupil diameter (PD), axial length (AL), and central retinal thickness (CRT). Results: There was no significant difference in CCT, CC, and CRT between the two groups without cycloplegia, but the ACD of the myopia (3.64 ± 0.28 mm) group was significantly higher than that of hyperopia (3.40 ± 0.24 mm; t = -4.522; P < 0.0001). The average PD of the myopia (4.85 ± 0.87 mm) group was significantly smaller than that of the hyperopia group (5.47 ± 1.15 mm; t = 2.903; P < 0.0046). The average AL of myopia (24.25 ± 0.77 mm) was significantly higher than that of hyperopia (21.73 ± 1.24 mm; t = 12.084; P < 0.0001). However, it was found that the average PD of myopia (7.68 ± 0.51 mm) was significantly larger than that of hyperopia (7.41 ± 0.57 mm; t = 2.364; P=0.0202) under cycloplegia. As for the changes in refractive factors before and after cycloplegia, deepened ACD and enlarged PD were noted in both the groups after cycloplegia. Conclusions: Cycloplegia not only affects ACD and PD but also leads to the reversal of PD differences between the two groups. Cycloplegia effects enabled us to study changes in all known ocular parameters in a short period.
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Traditional rice blast resistance breeding largely depends on utilizing typical resistance (R) genes. However, the lack of durable R genes has prompted rice breeders to find new resistance resources. Susceptibility (S) genes are potential new targets for resistance genetic engineering using genome-editing technologies, but identifying them is still challenging. Here, through the integration of genome-wide association study (GWAS) and transcriptional analysis, we identified two genes, RNG1 and RNG3, whose polymorphisms in 3'-untranslated regions (3'-UTR) affected their expression variations. These polymorphisms could serve as molecular markers to identify rice blast-resistant accessions. Editing the 3'-UTRs using CRISPR/Cas9 technology affected the expression levels of two genes, which were positively associated with rice blast susceptibility. Knocking out either RNG1 or RNG3 in rice enhanced the rice blast and bacterial blight resistance, without impacting critical agronomic traits. RNG1 and RNG3 have two major genotypes in diverse rice germplasms. The frequency of the resistance genotype of these two genes significantly increased from landrace rice to modern cultivars. The obvious selective sweep flanking RNG3 suggested it has been artificially selected in modern rice breeding. These results provide new targets for S gene identification and open avenues for developing novel rice blast-resistant materials.
Assuntos
Genes de Plantas , Oryza , Oryza/genética , Oryza/microbiologia , Estudo de Associação Genômica Ampla , Edição de Genes , Resistência à Doença/genética , Melhoramento VegetalRESUMO
BACKGROUND: Ubiquitination is essential for many cellular processes in eukaryotes, including 26S proteasome-dependent protein degradation, cell cycle progression, transcriptional regulation, and signal transduction. Although numerous ubiquitinated proteins have been empirically identified, their cognate ubiquitin E3 ligases remain largely unknown. RESULTS: Here, we generate a complete ubiquitin E3 ligase-encoding open reading frames (UbE3-ORFeome) library containing 98.94% of the 1515 E3 ligase genes in the rice (Oryza sativa L.) genome. In the test screens with four known ubiquitinated proteins, we identify both known and new E3s. The interaction and degradation between several E3s and their substrates are confirmed in vitro and in vivo. In addition, we identify the F-box E3 ligase OsFBK16 as a hub-interacting protein of the phenylalanine ammonia lyase family OsPAL1-OsPAL7. We demonstrate that OsFBK16 promotes the degradation of OsPAL1, OsPAL5, and OsPAL6. Remarkably, we find that overexpression of OsPAL1 or OsPAL6 as well as loss-of-function of OsFBK16 in rice displayed enhanced blast resistance, indicating that OsFBK16 degrades OsPALs to negatively regulate rice immunity. CONCLUSIONS: The rice UbE3-ORFeome is the first complete E3 ligase library in plants and represents a powerful proteomic resource for rapid identification of the cognate E3 ligases of ubiquitinated proteins and establishment of functional E3-substrate interactome in plants.
Assuntos
Oryza , Ubiquitina-Proteína Ligases , Oryza/genética , Oryza/metabolismo , Proteômica , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Ubiquitinadas/genética , Proteínas Ubiquitinadas/metabolismo , Ubiquitinação , Ubiquitinas/genética , Ubiquitinas/metabolismoRESUMO
Mitochondria are energy factories of cells and are important for intracellular interactions with other organelles. Emerging evidence indicates that mitochondria play essential roles in the response to pathogen infection. During infection, pathogens deliver numerous enzymes and effectors into host cells, and some of these effectors target mitochondria, altering mitochondrial morphology, metabolism, and functions. To defend against pathogen attack, mitochondria are actively involved in changing intracellular metabolism, hormone-mediated signaling, and signal transduction, producing reactive oxygen species and reactive nitrogen species and triggering programmed cell death. Additionally, mitochondria coordinate with other organelles to integrate and amplify diverse immune signals. In this review, we summarize recent advances in understanding how mitochondria function in plant immunity and how pathogens target mitochondria for host defense suppression.
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Mitocôndrias , Imunidade Vegetal , Hormônios/metabolismo , Mitocôndrias/metabolismo , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
Cold tolerance at the bud burst stage (CTB) is a key trait for direct-seeded rice. Although quantitative trait loci (QTL) affecting CTB in rice have been mapped using traditional linkage mapping and genome-wide association study (GWAS) methods, the underlying genes remain unknown. In this study, we evaluated the CTB phenotype of 339 cultivars in the Rice Diversity Panel II (RDP II) collection. GWAS identified four QTLs associated with CTB (qCTBs), distributed on chromosomes 1-3. Among them, qCTB-1-1 overlaps with Osa-miR319b, a known cold tolerance micro RNA gene. The other three qCTBs have not been reported. In addition, we characterised the candidate gene OsRab11C1 for qCTB-1-2 that encodes a Rab protein belonging to the small GTP-binding protein family. Overexpression of OsRab11C1 significantly reduced CTB, while gene knockout elevated CTB as well as cold tolerance at the seedling stage, suggesting that OsRab11C1 negatively regulates rice cold tolerance. Molecular analysis revealed that OsRab11C1 modulates cold tolerance by suppressing the abscisic acid signalling pathway and proline biosynthesis. Using RDP II and GWAS, we identified four qCTBs that are involved in CTB and determined the function of the candidate gene OsRab11C1 in cold tolerance. Our results demonstrate that OsRab11C1 is a negative regulator of cold tolerance and knocking out of the gene by genome-editing may provide enhanced cold tolerance in rice.
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Mitochondria are essential for animal and plant immunity. Here, we report that the effector MoCDIP4 of the fungal pathogen Magnaporthe oryzae targets the mitochondria-associated OsDjA9-OsDRP1E protein complex to reduce rice immunity. The DnaJ protein OsDjA9 interacts with the dynamin-related protein OsDRP1E and promotes the degradation of OsDRP1E, which functions in mitochondrial fission. By contrast, MoCDIP4 binds OsDjA9 to compete with OsDRP1E, resulting in OsDRP1E accumulation. Knockout of OsDjA9 or overexpression of OsDRP1E or MoCDIP4 in transgenic rice results in shortened mitochondria and enhanced susceptibility to M. oryzae Overexpression of OsDjA9 or knockout of OsDRP1E in transgenic rice, in contrast, leads to elongated mitochondria and enhanced resistance to M. oryzae Our study therefore reveals a previously unidentified pathogen-infection strategy in which the pathogen delivers an effector into plant cells to target an HSP40-DRP complex; the targeting leads to the perturbation of mitochondrial dynamics, thereby inhibiting mitochondria-mediated plant immunity.
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Magnaporthe , Oryza , Dinaminas/metabolismo , Resposta ao Choque Térmico , Interações Hospedeiro-Patógeno/genética , Magnaporthe/metabolismo , Dinâmica Mitocondrial , Oryza/genética , Oryza/metabolismo , Doenças das Plantas/genética , Doenças das Plantas/microbiologia , Imunidade Vegetal/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismoRESUMO
Because of the frequent breakdown of major resistance (R) genes, identification of new partial R genes against rice blast disease is an important goal of rice breeding. In this study, we used a core collection of the Rice Diversity Panel II (C-RDP-II), which contains 584 rice accessions and are genotyped with 700 000 single-nucleotide polymorphism (SNP) markers. The C-RDP-II accessions were inoculated with three blast strains collected from different rice-growing regions in China. Genome-wide association study identified 27 loci associated with rice blast resistance (LABRs). Among them, 22 LABRs were not associated with any known blast R genes or QTLs. Interestingly, a nucleotide-binding site leucine-rich repeat (NLR) gene cluster exists in the LABR12 region on chromosome 4. One of the NLR genes is highly conserved in multiple partially resistant rice cultivars, and its expression is significantly up-regulated at the early stages of rice blast infection. Knockout of this gene via CRISPR-Cas9 in transgenic plants partially reduced blast resistance to four blast strains. The identification of this new non-strain specific partial R gene, tentatively named rice blast Partial Resistance gene 1 (PiPR1), provides genetic material that will be useful for understanding the partial resistance mechanism and for breeding durably resistant cultivars against blast disease of rice.
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Magnaporthe , Oryza , China , Mapeamento Cromossômico , Resistência à Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Oryza/genética , Doenças das Plantas/genéticaRESUMO
BACKGROUND: Src, an oncoprotein that drives progression of head and neck squamous cell carcinoma (HNSCC), is commonly hyperactivated in this disease. Unfortunately, the clinical benefit of targeting Src is significantly dampened in HNSCC patients, because the cytotoxic effects of anti-Src therapy and tumor resistance to it are less predictable. Thus, understanding the mechanism of tumor resistance to Src inhibition and seeking a way to overcome it are warranted. METHODS: Dual drug-loaded nanoparticles (NPs) were developed to co-deliver Src inhibitor saracatinib (AZD0530) and AKT inhibitor capivasertib (AZD5363) into the same population of tumor cells. An orthotopic tongue tumor model was generated to evaluate the in vivo therapeutic effects. Cell growth was determined by CellTiter-Glo® Luminescent Cell Viability Kit, colony formation, and 3D culture, and tumor growth was determined by bioluminescence and tumor size. The molecular changes induced by the treatments were assessed by Western blotting and immunohistochemistry. RESULTS: Capivasertib inactivated the AKT-S6 signaling and re-sensitized saracatinib-resistant HNSCC cells to saracatinib. Combination of capivasertib with saracatinib suppressed HNSCC growth more efficiently than either drug alone. Cathepsin B-sensitive NPs for co-delivering saracatinib and capivasertib significantly improved the efficacy of tumor repression without increasing side effects, which were due to highly specific tumor-targeting drug delivery system and synergistic anticancer effects by co-inactivation of AKT and Src in HNSCC cells. CONCLUSIONS: Addition of AKT blockade improves anti-HNSCC efficacy of anti-Src therapy, and co-delivery of capivasertib and saracatinib by tumor-targeting NPs has the potential to achieve better treatment outcomes than the free drug combination.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Sistemas de Liberação de Medicamentos , Sinergismo Farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Nanopartículas/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Quinases da Família src/antagonistas & inibidores , Animais , Apoptose , Benzodioxóis/administração & dosagem , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Movimento Celular , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Nanopartículas/química , Invasividade Neoplásica , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Quinazolinas/administração & dosagem , Transdução de Sinais , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoAssuntos
Antineoplásicos/uso terapêutico , Bortezomib/uso terapêutico , Imunoglobulina D , Lenalidomida/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Talidomida/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/mortalidade , Fatores de Risco , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: Combinations of bortezomib (Velcade), cyclophosphamide and dexamethasone have shown significant efficacy and safety for patients of newly diagnosed multiple myeloma (NDMM). In this study, we compared the efficacy and safety of modified VCD regimens with novel changes in bortezomib dose and schedule for NDMM. METHODS: Eighty-five NDMM patients from multiple centers were randomly assigned to a high-dose (1.6 mg/m2) (group A) or a low-dose (1.3 mg/m2) (group B) bortezomib, administrated on days 1, 6, 11, and 16 subcutaneously in a 4-week cycle for nine cycles, combined with 40 mg dexamethasone on bortezomib days and cyclophosphamide 300 mg/m2 on days 1-3 intravenously. RESULTS: After four cycles, complete response (CR) or better in group A (43.6%) was higher than that in group B (12.8%) (P = 0.002). During induction, for patients with R-ISS stage III, the CR or better rate in group A was superior to that in group B (P = 0.01). Of patients < 65, the CR or better rate of group A was superior to that of group B (P = 0.004). Rapid onset of CR occurred in group A (P < 0.01). Meanwhile, rate of 3-4 diarrhea was higher in group A (P = 0.03), which caused higher rate of dose reduction for patients ≥ 65 (P = 0.041). No significant difference between the two groups in PFS and OS. CONCLUSIONS: The studied high-dose VCD as induction regimen had an improved CR rate, especially in patients < 65 or with R-ISS stage III, and is feasible for young and high-risk patients. Trial registration ClinicalTrials.gov: NCT02086942.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bortezomib/administração & dosagem , Ciclofosfamida/administração & dosagem , Dexametasona/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Bortezomib/efeitos adversos , Ciclofosfamida/efeitos adversos , Dexametasona/efeitos adversos , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Teniposídeo/administração & dosagem , Resultado do TratamentoRESUMO
The aim of our study was to evaluate the prognostic impact of minimal residual disease (MRD) and high-risk cytogenetics (HRCs) on outcomes in multiple myeloma (MM) patients. We applied multiparameter flow cytometry (MFC) to detect MRD in 123 consecutive patients diagnosed with MM for the first time who achieved very good partial remission (VGPR) or better after bortezomib or thalidomide-based induction therapy. Moreover, we examined the cytogenetic features of MM patients using magnetic-activated cell sorting and interphase fluorescence in situ hybridization (MACS-iFISH) at diagnosis. In all 123 MM patients, progression-free survival (PFS) and overall survival (OS) were better in the MRD- group (n = 31) than in the MRD+ group (n = 92) (median PFS: not reached (NR) vs. 26 months (m), P = 0.0002; 4-year OS, 91.7% vs. 66.3%, P = 0.008). PFS and OS were significantly shorter for each increase of one log per MRD level (P < 0.0001 and P = 0.001). The median PFS of the four groups according to the ratio of aberrant plasma cells (less than 0.01%, 0.01-0.1%, 0.1-1%, and more than 1%) were NR, 37 m, 26 m, and 15 m, respectively, and the 4-year OS rates were 91.7%, 69.3%, 76.1%, and 54.0%, respectively. In addition, our results show that PFS and OS were better for the standard-risk cytogenetic (SRC) patients than the HRC patients (median PFS: NR vs. 26 m, P = 0.004; 3-year OS: 95.8% vs. 76.0%, P = 0.006). The independent predictors of PFS were HRC and MRD+, which had hazard ratios of 1.901 (95% CI 1.094-3.303) and 3.486 (95% CI 1.449-8.386), respectively; while those for OS were an LDH level ≥ 250 U/L, HRC, and MRD+, which had hazard ratios of 2.789 (95% CI 1.080-7.199), 2.697 (95% CI 1.053-6.907), and 7.714 (95% CI 1.040-57.227), respectively. Furthermore, for SRC patients or HRC patients, PFS and OS were all longer in MRD- than in MRD+ patients. Strikingly, there was no significant difference in PFS or OS between the MRD-HRC and MRD+SRC groups (median PFS 45 vs. 34 m, P = 0.300; 4-year OS 100% vs. 83.6%, P = 0.196). PFS was superior in MRD-SRC than in MRD-HRC (NR vs. 45 m, P = 0.035); however, there was no significant difference in the 4-year OS between MRD-SRC and MRD-HRC (87.5% vs 100%, P = 0.480). MRD+ and HRCs were both independent prognostic factors in MM patients. Moreover, achieving MRD- may ameliorate a poor prognosis in MM patients with HRCs.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Aberrações Cromossômicas , Citometria de Fluxo , Mieloma Múltiplo , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Mieloma Múltiplo/mortalidade , Neoplasia Residual , Fatores de Risco , Taxa de SobrevidaAssuntos
Corpos Estranhos , Gastroscopia , Estômago , Instrumentos Cirúrgicos , Dor Abdominal/diagnóstico , Dor Abdominal/etiologia , Adulto , Corpos Estranhos/diagnóstico , Corpos Estranhos/fisiopatologia , Corpos Estranhos/cirurgia , Gastroscopia/instrumentação , Gastroscopia/métodos , Humanos , Masculino , Radiografia Abdominal/métodos , Estômago/diagnóstico por imagem , Estômago/cirurgia , Resultado do TratamentoRESUMO
BACKGROUND: Inhibition of metastasis of head and neck squamous cell carcinoma (HNSCC) is one of the most important challenges in cancer treatment. Src, a non-receptor tyrosine kinase, has been implicated as a key promoter in tumor progression and metastasis of HNSCC. However, Src therapy for HNSCC is limited by lack of efficient in vivo delivery and underlying mechanisms remain elusive. METHODS: Src knockdown cells were achieved by lentiviral-mediated interference. Cell migration and invasion were examined by wound healing and Transwell assays. Protein levels were determined by Western blot and/or immunohistochemistry. The Src inhibitor saracatinib was loaded into self-assembling nanoparticles by the solvent evaporation method. An experimental metastasis mouse model was generated to investigate the drug efficacy in metastasis. RESULTS: Blockade of Src kinase activity by saracatinib effectively suppressed invasion and metastasis of HNSCC. Mechanistic assessment of the drug effects in HNSCC cells showed that saracatinib induced suppression of Src-dependent invasion/metastasis through downregulating the expression levels of Vimentin and Snail proteins. In tests in mice, saracatinib loaded into the novel multifunctional nanoparticles exhibited superior effects on suppression of HNSCC metastasis compared with the free drug, which is mainly attributed to highly specific and efficient tumor-targeted drug delivery system. CONCLUSIONS: These findings and advances are of great importance to the development of Src-targeted nanomedicine as a more effective therapy for metastatic HNSCC.
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Benzodioxóis/uso terapêutico , Neoplasias de Cabeça e Pescoço/patologia , Metástase Neoplásica/tratamento farmacológico , Quinazolinas/uso terapêutico , Quinases da Família src/antagonistas & inibidores , Animais , Antineoplásicos/uso terapêutico , Benzodioxóis/administração & dosagem , Modelos Animais de Doenças , Portadores de Fármacos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Camundongos , Nanomedicina/métodos , Nanopartículas/uso terapêutico , Quinazolinas/administração & dosagem , Fatores de Transcrição da Família Snail/antagonistas & inibidores , Vimentina/antagonistas & inibidoresRESUMO
BACKGROUND: Silicon (Si) can confer plant resistance to both abiotic and biotic stress. In the present study, the priming effect of Si on rice (Oryza sativa cv Nipponbare) against the root-knot nematode Meloidogyne graminicola and its histochemical and molecular impact on plant defense mechanisms were evaluated. RESULTS: Si amendment significantly reduced nematodes in rice roots and delayed their development, while no obvious negative effect on giant cells was observed. Increased resistance in rice was correlated with higher transcript levels of defense-related genes (OsERF1, OsEIN2 and OsACS1) in the ethylene (ET) pathway. Si amendment significantly reduced nematode numbers in rice plants with enhanced ET signaling but had no effect in plants deficient in ET signaling, indicating that the priming effects of Si were dependent on the ET pathway. A higher deposition of callose and accumulation of phenolic compounds were observed in rice roots after nematode attack in Si-amended plants than in the controls. CONCLUSION: These findings indicate that the priming effect may partially depend on the production of phenolic compounds and hydrogen peroxide. Further research is required to model the ethylene signal transduction pathway that occurs in the Si-plant-nematode interaction system and gain a better understanding of Si-induced defense in rice.
Assuntos
Oryza/efeitos dos fármacos , Oryza/parasitologia , Doenças das Plantas/prevenção & controle , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/parasitologia , Silício/farmacologia , Tylenchoidea/patogenicidade , Animais , Lignina/metabolismo , Doenças das Plantas/parasitologia , Tylenchoidea/efeitos dos fármacosRESUMO
Rice blast, caused by Magnaporthe oryzae (synonym: Pyricularia oryzae), severely reduces rice production and grain quality. The molecular mechanism of rice resistance to M. oryzae is not fully understood. In this study, we identified a chaperone DnaJ protein, OsDjA6, which is involved in basal resistance to M. oryzae in rice. The OsDjA6 protein is distributed in the entire rice cell. The expression of OsDjA6 is significantly induced in rice after infection with a compatible isolate. Silencing of OsDjA6 in transgenic rice enhances resistance to M. oryzae and also results in an increased burst of reactive oxygen species after flg22 and chitin treatments. In addition, the expression levels of WRKY45, NPR1 and PR5 are increased in OsDjA6 RNAi plants, indicating that OsDjA6 may mediate resistance by affecting the salicylic acid pathway. Finally, we found that OsDjA6 interacts directly with the E3 ligase OsZFP1 in vitro and in vivo. These results suggest that the DnaJ protein OsDjA6 negatively regulates rice innate immunity, probably via the ubiquitination proteasome degradation pathway.