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Xanthomonas species are major pathogens of plants and have been studied extensively. There is increasing recognition of the importance of non-pathogenic species within the same genus. With this came the need to understand the genomic and functional diversity of non-pathogenic Xanthomonas (NPX) at the species and strain level. This study reports isolation and investigation into the genomic diversity and variation in NPX isolates, chiefly Xanthomonas indica, a newly discovered NPX species from rice. The study establishes the relationship of X. indica strains within clade I of Xanthomonads with another NPX species, X. sontii, also associated with rice seeds. Identification of highly diverse strains, open-pan genome, and systematic hyper-variation at the lipopolysaccharide biosynthetic locus when compared to pathogenic Xanthomonas indicates the acquisition of new functions for adaptation. Furthermore, comparative genomics studies established the absence of major virulence genes such as type III secretion system and effectors, which are present in the pathogens, and the presence of a known bacterial-killing type IV secretion system (X-T4SS). The diverse non-pathogenic strains of X. indica and X. sontii were found to protect rice from bacterial leaf blight pathogen, X. oryzae pv. oryzae (Xoo). The absence of phenotype of an X-T4SS mutant suggests redundancy in the genetic basis of the mechanisms involved in the bioprotection function, which may include multiple genetic loci, such as putative bacteriocin-encoding gene clusters and involvement of other factors such as nutrient and niche competition apart from induction of innate immunity through shared microbial-associated molecular patterns. The rice-NPX community and its pathogenic counterpart can be a promising model for understanding plant-microbe-microbiome interaction studies.IMPORTANCEThe Xanthomonas group of bacteria is known for its characteristic lifestyle as a phytopathogen. However, the discovery of non-pathogenic Xanthomonas (NPX) species is a major shift in understanding this group of bacteria. Multi-strain, in-depth genomic, evolutionary and functional studies on each of these NPX species are still lacking. This study on diverse non-pathogenic strains provides novel insights into genome diversity, dynamics, and evolutionary trends of NPX species from rice microbiome apart from its relationship with other relatives that form a sub-clade. Interestingly, we also uncovered that NPX species protect rice from pathogenic Xanthomonas species. The plant protection property shows their importance as a part of a healthy plant microbiome. Furthermore, finding an open pan-genome and large-scale variation at lipopolysaccharide biosynthetic locus indicates a significant role of the NPX community in host adaptation. The findings and high-quality genomic resources of NPX species and the strains will allow further systematic molecular and host-associated microbial community studies for plant health.
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Complete panicle exsertion (CPE) is an economically important quantitative trait that contributes to grain yield in rice. We deployed an integrated approach for understanding the molecular mechanism of CPE using a stable EMS mutant line, CPE-109 of Samba Mahsuri (SM) exhibiting CPE. Two consistent genomic regions have been identified for CPE through QTL mapping [qCPE-4 (28.24-31.22 Mb) and qCPE-12 (2.30-3.18 Mb)] and QTL-sequencing [Chr-4 (31.21-33.69 Mb) and Chr-12 (0.12-3.15 Mb)]. Two non-synonymous SNPs, viz; KASP 12-12 (TâC; Chr12:1269983) in Os12g0126300; AP2/ERF transcription factor and KASP 12-16 (GâA; Chr12:1515198) in Os12g0131400; F-box domain-containing protein explained 81.05 and 59.61% phenotypic variance respectively and exhibited strong co-segregation with CPE in F2 mapping populations, advanced generation lines and CPE exhibiting SM mutants through KASP assays. The downregulation of these genes in CPE-109 compared to SM was observed in transcriptome sequencing of flag leaves which was validated through qRT-PCR. We propose that the abrogation of Os12g0126300 and Os12g0131400 in CPE-109 combinatorially influences the downregulation of ethylene biosynthetic genes viz. ACC synthase, ethylene-responsive factor-2, and up-regulation of gibberellic acid synthetic genes viz. ent-kaurene synthase and two cytokinin biosynthesis genes viz. cytokinin-O-glucosyltransferase 2, carboxy-lyase which result in complete panicle exsertion.
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KEY MESSAGE: By deploying a multi-omics approach, we unraveled the mechanisms that might help rice to combat Yellow Stem Borer infestation, thus providing insights and scope for developing YSB resistant rice varieties. Yellow Stem Borer (YSB), Scirpophaga incertulas (Walker) (Lepidoptera: Crambidae), is a major pest of rice, that can lead to 20-60% loss in rice production. Effective management of YSB infestation is challenged by the non-availability of adequate sources of resistance and poor understanding of resistance mechanisms, thus necessitating studies for generating resources to breed YSB resistant rice and to understand rice-YSB interaction. In this study, by using bulk-segregant analysis in combination with next-generation sequencing, Quantitative Trait Loci (QTL) intervals in five rice chromosomes were mapped that could be associated with YSB resistance at the vegetative phase in a resistant rice line named SM92. Further, multiple SNP markers that showed significant association with YSB resistance in rice chromosomes 1, 5, 10, and 12 were developed. RNA-sequencing of the susceptible and resistant lines revealed several genes present in the candidate QTL intervals to be differentially regulated upon YSB infestation. Comparative transcriptome analysis revealed a putative candidate gene that was predicted to encode an alpha-amylase inhibitor. Analysis of the transcriptome and metabolite profiles further revealed a possible link between phenylpropanoid metabolism and YSB resistance. Taken together, our study provides deeper insights into rice-YSB interaction and enhances the understanding of YSB resistance mechanism. Importantly, a promising breeding line and markers for YSB resistance have been developed that can potentially aid in marker-assisted breeding of YSB resistance among elite rice cultivars.
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Mapeamento Cromossômico , Mariposas , Oryza , Locos de Características Quantitativas , Oryza/genética , Oryza/parasitologia , Oryza/imunologia , Animais , Mariposas/fisiologia , Polimorfismo de Nucleotídeo Único , Doenças das Plantas/parasitologia , Doenças das Plantas/genética , Doenças das Plantas/imunologia , Resistência à Doença/genética , Genômica/métodos , Fenótipo , MultiômicaRESUMO
The determination of an optimal treatment plan for an individual patient with rectal cancer is a complex process. In addition to decisions relating to the intent of rectal cancer surgery (ie, curative or palliative), consideration must also be given to the likely functional results of treatment, including the probability of maintaining or restoring normal bowel function/anal continence and preserving genitourinary functions. Particularly for patients with distal rectal cancer, finding a balance between curative-intent therapy while having minimal impact on quality of life can be challenging. Furthermore, the risk of pelvic recurrence is higher in patients with rectal cancer compared with those with colon cancer, and locally recurrent rectal cancer is associated with a poor prognosis. Careful patient selection and the use of sequenced multimodality therapy following a multidisciplinary approach is recommended. These NCCN Guidelines Insights detail recent updates to the NCCN Guidelines for Rectal Cancer, including the addition of endoscopic submucosal dissection as an option for early-stage rectal cancer, updates to the total neoadjuvant therapy approach based on the results of recent clinical trials, and the addition of a "watch-and-wait" nonoperative management approach for clinical complete responders to neoadjuvant therapy.
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Neoplasias Retais , Humanos , Neoplasias Retais/terapia , Neoplasias Retais/diagnóstico , Neoplasias Retais/patologia , Terapia Neoadjuvante/métodos , Terapia Neoadjuvante/normas , Terapia Combinada/métodos , Estadiamento de Neoplasias , Oncologia/normas , Oncologia/métodosRESUMO
Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States. Management of disseminated metastatic CRC involves various active drugs, either in combination or as single agents. The choice of therapy is based on consideration of the goals of therapy, the type and timing of prior therapy, the mutational profile of the tumor, and the differing toxicity profiles of the constituent drugs. This manuscript summarizes the data supporting the systemic therapy options recommended for metastatic CRC in the NCCN Guidelines for Colon Cancer.
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Neoplasias do Colo , Humanos , Neoplasias do Colo/diagnóstico , Neoplasias do Colo/terapia , Neoplasias do Colo/patologia , Neoplasias do Colo/tratamento farmacológico , Oncologia/normas , Oncologia/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Estados UnidosRESUMO
There is a continuous and pressing need to establish new brain-penetrant bioactive compounds with anti-cancer properties. To this end, a new series of 4'-((4-substituted-4,5-dihydro-1H-1,2,3-triazol-1-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile (OTBN-1,2,3-triazole) derivatives were synthesized by click chemistry. The series of bioactive compounds were designed and synthesized from diverse alkynes and N3-OTBN, using copper (II) acetate monohydrate in aqueous dimethylformamide at room temperature. Besides being highly cost-effective and significantly reducing synthesis, the reaction yielded 91-98 % of the target products without the need of any additional steps or chromatographic techniques. Two analogues exhibit promising anti-cancer biological activities. Analogue 4l shows highly specific cytostatic activity against lung cancer cells, while analogue 4k exhibits pan-cancer anti-growth activity. A kinase screen suggests compound 4k has single-digit micromolar activity against kinase STK33. High STK33 RNA expression correlates strongly with poorer patient outcomes in both adult and pediatric glioma. Compound 4k potently inhibits cell proliferation, invasion, and 3D neurosphere formation in primary patient-derived glioma cell lines. The observed anti-cancer activity is enhanced in combination with specific clinically relevant small molecule inhibitors. Herein we establish a novel biochemical kinase inhibitory function for click-chemistry-derived OTBN-1,2,3-triazole analogues and further report their anti-cancer activity in vitro for the first time.
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Antineoplásicos , Proliferação de Células , Química Click , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Proteínas Quinases , Proteínas Serina-Treonina Quinases , Triazóis , Humanos , Triazóis/química , Triazóis/farmacologia , Triazóis/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Estrutura Molecular , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Linhagem Celular Tumoral , Nitrilas/química , Nitrilas/farmacologia , Nitrilas/síntese químicaRESUMO
In the face of escalating challenges of microbial resistance strains, this study describes the design and synthesis of 5-({1-[(1H-1,2,3-triazol-4-yl)methyl]-1H-indol-3-yl}methylene)thiazolidine-2,4-dione derivatives, which have demonstrated significant antimicrobial properties. Compared with the minimum inhibitory concentrations (MIC) values of ciprofloxacin on the respective strains, compounds 5a, 5d, 5g, 5l, and 5m exhibited potent antibacterial activity with MIC values ranging from 16 to 25 µM. Almost all the synthesized compounds showed lower MIC compared to standards against vancomycin-resistant enterococcus and methicillin-resistant Staphylococcus aureus strains. Additionally, the majority of the synthesized compounds demonstrated remarkable antifungal activity, against Candida albicans and Aspergillus niger, as compared to nystatin, griseofulvin, and fluconazole. Furthermore, the majority of compounds exhibited notable inhibitory effects against the Plasmodium falciparum strain, having IC50 values ranging from 1.31 to 2.79 µM as compared to standard quinine (2.71 µM). Cytotoxicity evaluation of compounds 5a-q on SHSY-5Y cells at up to 100 µg/mL showed no adverse effects. Comparison with control groups highlights their noncytotoxic characteristics. Molecular docking confirmed compound binding to target active sites, with stable protein-ligand complexes displaying drug-like molecules. Molecular dynamics simulations revealed dynamic stability and interactions. Rigorous tests and molecular modeling unveil the effectiveness of the compounds against drug-resistant microbes, providing hope for new antimicrobial compounds with potential safety.
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Antimaláricos , Staphylococcus aureus Resistente à Meticilina , Tiazolidinedionas , Antibacterianos/química , Antimaláricos/farmacologia , Triazóis/farmacologia , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Indóis/farmacologia , Testes de Sensibilidade Microbiana , Estrutura MolecularRESUMO
Lodging, a phenomenon characterized by the bending or breaking of rice plants, poses substantial constraints on productivity, particularly during the harvesting phase in regions susceptible to strong winds. The rice strong culm trait is influenced by the intricate interplay of genetic, physiological, epigenetic, and environmental factors. Stem architecture, encompassing morphological and anatomical attributes, alongside the composition of both structural and non-structural carbohydrates, emerges as a critical determinant of lodging resistance. The adaptive response of the rice culm to various biotic and abiotic environmental factors further modulates the propensity for lodging. Advancements in next-generation sequencing technologies have expedited the genetic dissection of lodging resistance, enabling the identification of pertinent genes, quantitative trait loci, and novel alleles. Concurrently, contemporary breeding strategies, ranging from biparental approaches to more sophisticated methods such as multi-parent-based breeding, gene pyramiding, genomic selection, genome-wide association studies, and haplotype-based breeding, offer perspectives on the genetic underpinnings of culm strength. This review comprehensively delves into physiological attributes, culm histology, epigenetic determinants, and gene expression profiles associated with lodging resistance, with a specialized focus on leveraging next-generation sequencing for candidate gene discovery.
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This discussion summarizes the NCCN Clinical Practice Guidelines for managing squamous cell anal carcinoma, which represents the most common histologic form of the disease. A multidisciplinary approach including physicians from gastroenterology, medical oncology, surgical oncology, radiation oncology, and radiology is necessary. Primary treatment of perianal cancer and anal canal cancer are similar and include chemoradiation in most cases. Follow-up clinical evaluations are recommended for all patients with anal carcinoma because additional curative-intent treatment is possible. Biopsy-proven evidence of locally recurrent or persistent disease after primary treatment may require surgical treatment. Systemic therapy is generally recommended for extrapelvic metastatic disease. Recent updates to the NCCN Guidelines for Anal Carcinoma include staging classification updates based on the 9th edition of the AJCC Staging System and updates to the systemic therapy recommendations based on new data that better define optimal treatment of patients with metastatic anal carcinoma.
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Neoplasias do Ânus , Carcinoma de Células Escamosas , Humanos , Biópsia , OncologiaRESUMO
Complete panicle exsertion (CPE) in rice is an important determinant of yield and a desirable trait in breeding. However, the genetic basis of CPE in rice still remains to be completely characterized. An ethyl methane sulfonate (EMS) mutant line of an elite cultivar Samba Mahsuri (BPT 5204), displaying stable and consistent CPE, was identified and named as CPE-110. MutMap and RNA-seq were deployed for unraveling the genomic regions, genes, and markers associated with CPE. Two major genomic intervals, on chromosome 8 (25668481-25750456) and on chromosome 11 (20147154-20190400), were identified to be linked to CPE through MutMap. A non-synonymous SNP (G/A; Chr8:25683828) in the gene LOC_Os08g40570 encoding pyridoxamine 5'-phosphate oxidase with the SNP index 1 was converted to Kompetitive allele-specific PCR (KASP) marker. This SNP (KASP 8-1) exhibited significant association with CPE and further validated through assay in the F2 mapping population, released varieties and CPE exhibiting BPT 5204 mutant lines. RNA-seq of the flag leaves at the booting stage, 1100 genes were upregulated and 1305 downregulated differentially in CPE-110 and BPT 5204. Metabolic pathway analysis indicated an enrichment of genes involved in photosynthesis, glyoxylate, dicarboxylate, porphyrin, pyruvate, chlorophyll, carotenoid, and carbon metabolism. Further molecular and functional studies of the candidate genes could reveal the mechanistic aspects of CPE. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-023-01412-1.
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Xanthomonas oryzae pv. oryzae (Xoo) is a major rice pathogen, and its genome harbors extensive inter-strain and inter-lineage variations. The emergence of highly virulent pathotypes of Xoo that can overcome major resistance (R) genes deployed in rice breeding programs is a grave threat to rice cultivation. The present study reports on a long-read Oxford nanopore-based complete genomic investigation of Xoo isolates from 11 pathotypes that are reported based on their reaction toward 10 R genes. The investigation revealed remarkable variation in the genome structure in the strains belonging to different pathotypes. Furthermore, transcription activator-like effector (TALE) proteins secreted by the type III secretion system display marked variation in content, genomic location, classes, and DNA-binding domain. We also found the association of tal genes in the vicinity of regions with genome structural variations. Furthermore, in silico analysis of the genome-wide rice targets of TALEs allowed us to understand the emergence of pathotypes compatible with major R genes. Long-read, cost-effective sequencing technologies such as nanopore can be a game changer in the surveillance of major and emerging pathotypes. The resource and findings will be invaluable in the management of Xoo and in appropriate deployment of R genes in rice breeding programs.
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Oryza , Xanthomonas , Efetores Semelhantes a Ativadores de Transcrição/genética , Efetores Semelhantes a Ativadores de Transcrição/metabolismo , Doenças das Plantas/genética , Melhoramento Vegetal , Xanthomonas/genética , Oryza/genéticaRESUMO
This selection from the NCCN Guidelines for Rectal Cancer focuses on management of malignant polyps and resectable nonmetastatic rectal cancer because important updates have been made to these guidelines. These recent updates include redrawing the algorithms for stage II and III disease to reflect new data supporting the increasingly prominent role of total neoadjuvant therapy, expanded recommendations for short-course radiation therapy techniques, and new recommendations for a "watch-and-wait" nonoperative management technique for patients with cancer that shows a complete response to neoadjuvant therapy. The complete version of the NCCN Guidelines for Rectal Cancer, available online at NCCN.org, covers additional topics including risk assessment, pathology and staging, management of metastatic disease, posttreatment surveillance, treatment of recurrent disease, and survivorship.
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Neoplasias Retais , Humanos , Oncologia , Terapia Neoadjuvante , Neoplasias Retais/diagnóstico , Neoplasias Retais/patologia , Neoplasias Retais/terapiaRESUMO
Exoribonuclease R (RNase R) is a 3' hydrolytic exoribonuclease that can degrade structured RNA. Mutation in RNase R affects virulence of certain human pathogenic bacteria. The aim of this study was to determine whether RNase R is necessary for virulence of the phytopathogen that causes bacterial blight in rice, Xanthomonas oryzae pv. oryzae (Xoo). In silico analysis has indicated that RNase R is highly conserved among various xanthomonads. Amino acid sequence alignment of Xoo RNase R with RNase R from various taxa indicated that Xoo RNase R clustered with RNase R of order Xanthomonadales. To study its role in virulence, we generated a gene disruption mutant of Xoo RNase R. The Xoo rnr- mutant is moderately virulence deficient, and the complementing strain (rnr-/pHM1::rnr) rescued the virulence deficiency of the mutant. We investigated swimming and swarming motilities in both nutrient-deficient minimal media and nutrient-optimal media. We observed that RNase R mutation has adversely affected the swimming and swarming motilities of Xoo in optimal media. However, in nutrient-deficient media only swimming motility was noticeably affected. Growth curves in optimal media at suboptimal temperature (15°C cold stress) indicate that the Xoo rnr- mutant grows more slowly than the Xoo wild type and complementing strain (rnr-/pHM1::rnr). Given these findings, we report for the first time that RNase R function is necessary for complete virulence of Xoo in rice. It is also important for motility of Xoo in media and for growth of Xoo at suboptimal temperature.
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Oryza , Xanthomonas , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Exorribonucleases/metabolismo , Oryza/microbiologia , Doenças das Plantas/microbiologia , VirulênciaRESUMO
Xanthomonas is a major group of pathogenic bacteria infecting staple food crops like rice. Increasingly it is being recognized that non-pathogenic Xanthomonas (NPX) are also important members of a healthy plant microbiome. However, the vast majority of the species described in this genus are of pathogenic nature, and only a few NPX species have been reported till now. Genomic and taxonogenomic analysis of NPX is needed for the management of this important group of bacteria. In this study, two yellow-pigmented bacterial isolates were obtained from healthy rice seeds in Punjab, India. The isolates designated PPL560T and PPL568 were identified as members of the genus Xanthomonas based on biochemical tests and 16S rRNA gene sequence analysis retrieved from the whole-genome sequences. Isolates formed a distinct monophyletic lineage with Xanthomonas sontii and Xanthomonas sacchari as the closest relatives in the phylogenetic tree based on core gene content shared by the representative species of the genus Xanthomonas. Pairwise ortho Average Nucleotide Identity and digital DNA-DNA hybridization values calculated against other species of Xanthomonas were below their respective cut-offs. In planta studies revealed that PPL560T and PPL568 are non-pathogenic to rice plants upon leaf clip inoculation. The absence of type III secretion system-related genes and effectors further supported their non-pathogenic status. Herein, we propose Xanthomonas indica sp. nov. as novel species of the genus Xanthomonas with PPL560T = MTCC 13185 = CFBP 9039 = ICMP 24394 as its type strain and PPL568 as another constituent member.
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Oryza , Xanthomonas , DNA Bacteriano/química , DNA Bacteriano/genética , Oryza/microbiologia , Filogenia , RNA Ribossômico 16S/genética , Sementes , Xanthomonas/genéticaRESUMO
INTRODUCTION: The minimally invasive UroLift® System procedure in moderate-to-severe benign prostate hyperplasia (BPH) refractory to medical treatment may be superior over other prostate procedures regarding its preserved sexual function post-operatively. We aimed to optimise patient selection criteria for the UroLift® System. MATERIAL AND METHODS: Fifty-one men that underwent UroLift® System surgery were retrospectively reviewed over >24 months. We evaluated the efficacy and safety of UroLift® System, pre-operatively and at three, six, 12, and 24 months post-operatively, assessing the International Prostate Symptom Score (IPPS), urinary flow rates (Qmax), post void residual (PVR) bladder scan volumes and the International Index of Erectile Function (IIEF). Adverse events were assessed by Clavien-Dindo Classification. RESULTS: The 51 men undergoing UroLift® System had a success rate of 92.2% over 2 years, with improvements in Qmax, IPSS and PVR. IIEF was preserved in all cases. Adverse events were Clavien-Dindo grade 1, most commonly mild-to-severe dysuria (19.6%), and resolved spontaneously. Four patients failed to improve. CONCLUSION: Patient-related selection criteria to optimise the UroLift® System clinical outcomes include age, Qmax, PVR urine, median lobe, PSA levels, prostate volume, IPSS and IIEF scores. The UroLift® System is safe and effective in moderate-to-severe BPH refractory to pharmacological treatments and avoids retrograde ejaculation.
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Sintomas do Trato Urinário Inferior , Hiperplasia Prostática , Sistema Urinário , Humanos , Sintomas do Trato Urinário Inferior/diagnóstico , Sintomas do Trato Urinário Inferior/etiologia , Sintomas do Trato Urinário Inferior/cirurgia , Masculino , Seleção de Pacientes , Hiperplasia Prostática/cirurgia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Xanthomonas oryzae pv. oryzae uses several type III secretion system (T3SS) secreted effectors, namely XopN, XopQ, XopX and XopZ, to suppress rice immune responses that are induced following treatment with cell wall degrading enzymes. Here we show that a T3SS secreted effector XopX interacts with two of the eight rice 14-3-3 proteins. Mutants of XopX that are defective in 14-3-3 binding are also defective in suppression of immune responses, suggesting that interaction with 14-3-3 proteins is required for suppression of host innate immunity. However, Agrobacterium-mediated delivery of both XopQ and XopX into rice cells results in induction of rice immune responses. These immune responses are not observed when either protein is individually delivered into rice cells. XopQ-XopX-induced rice immune responses are not observed with a XopX mutant that is defective in 14-3-3 binding. Yeast two-hybrid, bimolecular fluorescence complementation and co-immunoprecipitation assays indicate that XopQ and XopX interact with each other. A screen for Xanthomonas effectors that can suppress XopQ-XopX-induced rice immune responses led to the identification of five effectors, namely XopU, XopV, XopP, XopG and AvrBs2, that could individually suppress these immune responses. These results suggest a complex interplay of Xanthomonas T3SS effectors in suppression of both pathogen-triggered immunity and effector-triggered immunity to promote virulence on rice.
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Proteínas de Bactérias/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Oryza/imunologia , Oryza/microbiologia , Xanthomonas/patogenicidade , Proteínas 14-3-3/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/imunologia , Sítios de Ligação , Núcleo Celular/metabolismo , Mutação , Fosforilação , Doenças das Plantas/imunologia , Doenças das Plantas/microbiologia , Imunidade Vegetal , Proteínas de Plantas/imunologia , Proteínas de Plantas/metabolismo , Serina/genética , Xanthomonas/metabolismoRESUMO
Plant pathogens secrete cell wall-degrading enzymes that degrade various components of the plant cell wall. Plants sense this cell wall damage as a mark of infection and induce immune responses. However, the plant functions that are involved in the elaboration of cell wall damage-induced immune responses remain poorly understood. Transcriptome analysis revealed that a rice (Oryza sativa) receptor-like kinase, WALL-ASSOCIATED KINASE-LIKE21 (OsWAKL21.2), is up-regulated following treatment with either Xanthomonas oryzae pv oryzae (a bacterial pathogen) or lipaseA/esterase (LipA; a cell wall-degrading enzyme of X. oryzae pv oryzae). Overexpression of OsWAKL21.2 in rice induces immune responses similar to those activated by LipA treatment. Down-regulation of OsWAKL21.2 attenuates LipA-mediated immune responses. Heterologous expression of OsWAKL21.2 in Arabidopsis (Arabidopsis thaliana) also activates plant immune responses. OsWAKL21.2 is a dual-activity kinase that has in vitro kinase and guanylate cyclase activities. Interestingly, kinase activity of OsWAKL21.2 is necessary to activate rice immune responses, whereas in Arabidopsis, OsWAKL21.2 guanylate cyclase activity activates these responses. Our study reveals a rice receptor kinase that activates immune responses in two different species via two different mechanisms.
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Oryza/enzimologia , Oryza/imunologia , Imunidade Vegetal , Proteínas de Plantas/metabolismo , Proteínas Quinases/metabolismo , Arabidopsis/genética , Ciclopentanos/metabolismo , Regulação para Baixo/genética , Regulação da Expressão Gênica de Plantas , Lipase/metabolismo , Oryza/microbiologia , Oxilipinas/metabolismo , Folhas de Planta/metabolismo , Proteínas de Plantas/genética , Plantas Geneticamente Modificadas , Ácido Salicílico/metabolismo , Xanthomonas/fisiologiaRESUMO
This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colon Cancer focuses on systemic therapy options for the treatment of metastatic colorectal cancer (mCRC), because important updates have recently been made to this section. These updates include recommendations for first-line use of checkpoint inhibitors for mCRC, that is deficient mismatch repair/microsatellite instability-high, recommendations related to the use of biosimilars, and expanded recommendations for biomarker testing. The systemic therapy recommendations now include targeted therapy options for patients with mCRC that is HER2-amplified, or BRAF V600E mutation-positive. Treatment and management of nonmetastatic or resectable/ablatable metastatic disease are discussed in the complete version of the NCCN Guidelines for Colon Cancer available at NCCN.org. Additional topics covered in the complete version include risk assessment, staging, pathology, posttreatment surveillance, and survivorship.
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Neoplasias do Colo , Medicamentos Biossimilares , Neoplasias do Colo/diagnóstico , Neoplasias do Colo/genética , Neoplasias do Colo/terapia , Reparo de Erro de Pareamento de DNA , Humanos , Instabilidade de Microssatélites , MutaçãoRESUMO
In this study, we report on antiproliferative benzyloxy dihydropyrimidinones (DHPMs) produced by the Biginelli reaction of benzyloxy benzaldehyde, urea, and diverse 1,3-diones. The reaction was catalyzed by lanthanum triflate and completed within 1-1.5 h, with 74-97% yield. The antiproliferative assay was carried out for all synthesized dihydropyrimidinones against six human solid tumor cell lines. Six compounds showed good antiproliferative activity with GI50 values below 5 µM. Among all the synthesized compounds, the most potent derivative showed good antiproliferative activity against all cell lines with GI50 values in the range of 1.1-3.1 µM. These DHPMs comply with druglikeness. Furthermore, ADMET prediction and the effect of P-glycoprotein on the antiproliferative activity were also studied. Overall, our method allows eco-friendly access to benzyloxy DHPMs as potential anticancer drugs.
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Antineoplásicos , Proliferação de Células/efeitos dos fármacos , Pirimidinonas , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Lantânio/química , Estrutura Molecular , Pirimidinonas/síntese química , Pirimidinonas/química , Pirimidinonas/farmacologia , Relação Estrutura-Atividade , Ureia/químicaRESUMO
The NCCN Guidelines for Rectal Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with rectal cancer. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines. These updates include clarifying the definition of rectum and differentiating the rectum from the sigmoid colon; the total neoadjuvant therapy approach for localized rectal cancer; and biomarker-targeted therapy for metastatic colorectal cancer, with a focus on new treatment options for patients with BRAF V600E- or HER2 amplification-positive disease.