RESUMO
The potato's most devastating disease is late blight, which is caused by Phytophthora infestans. Whereas various resistance (R) genes are known, most are typically defeated by this fast-evolving oomycete pathogen. However, the broad-spectrum and durable R8 is a vital gene resource for potato resistance breeding. To support an educated deployment of R8, we embarked on a study on the corresponding avirulence gene Avr8. We overexpressed Avr8 by transient and stable transformation, and found that Avr8 promotes colonization of P. infestans in Nicotiana benthamiana and potato, respectively. A yeast-two-hybrid (Y2H) screen showed that AVR8 interacts with a desumoylating isopeptidase (StDeSI2) of potato. We overexpressed DeSI2 and found that DeSI2 positively regulates resistance to P. infestans, while silencing StDeSI2 downregulated the expression of a set of defense-related genes. By using a specific proteasome inhibitor, we found that AVR8 destabilized StDeSI2 through the 26S proteasome and attenuated early PTI responses. Altogether, these results indicate that AVR8 manipulates desumoylation, which is a new strategy that adds to the plethora of mechanisms that Phytophthora exploits to modulate host immunity, and StDeSI2 provides a new target for durable resistance breeding against P. infestans in potato.
Assuntos
Phytophthora infestans , Solanum tuberosum , Melhoramento Vegetal , Imunidade Vegetal , Solanum tuberosum/genética , Doenças das PlantasRESUMO
BACKGROUND: Due to individual differences in tumors and immune systems, the response rate to immunotherapy is low in lung adenocarcinoma (LUAD) patients. Combinations with other therapeutic strategies improve the efficacy of immunotherapy in LUAD patients. Although radioimmunotherapy has been demonstrated to effectively suppress tumors, the underlying mechanisms still need to be investigated. METHODS: Total RNA from LUAD cells was sequenced before and after radiotherapy to identify differentially expressed radiation-associated genes. The similarity network fusion (SNF) algorithm was applied for molecular classification based on radiation-related genes, immune-related genes, methylation data, and somatic mutation data. The changes in gene expression, prognosis, immune cell infiltration, radiosensitivity, chemosensitivity, and sensitivity to immunotherapy were assessed for each subtype. RESULTS: We used the SNF algorithm and multi-omics data to divide TCGA-LUAD patients into three subtypes. Patients with the CS3 subtype had the best prognosis, while those with the CS1 and CS2 subtypes had poorer prognoses. Among the strains tested, CS2 exhibited the most elevated immune cell infiltration and expression of immune checkpoint genes, while CS1 exhibited the least. Patients in the CS2 subgroup were more likely to respond to PD-1 immunotherapy. The CS2 patients were most sensitive to docetaxel and cisplatin, while the CS1 patients were most sensitive to paclitaxel. Experimental validation of signature genes in the CS2 subtype showed that inhibiting the expression of RHCG and TRPA1 could enhance the sensitivity of lung cancer cells to radiation. CONCLUSIONS: In summary, this study identified a risk classifier based on multi-omics data that can guide treatment selection for LUAD patients.
Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Multiômica , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/terapia , Imunoterapia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Análise por Conglomerados , PrognósticoRESUMO
Tumour-associated macrophages (TAMs) are one of the primary sources of PD-L1 expression in the tumour microenvironment (TME). Ionizing radiation (IR) promotes PD-L1 expression in tumour cells. However, the effect of IR on macrophage PD-L1 expression and the underlying mechanisms remain unclear. ATM kinase, as the key kinase for initiating DNA damage repair (DDR) process, is associated with innate immune STING axis activation. Here, we explored the molecular mechanism implicated in macrophage PD-L1 expression regulated by IR as well as the role of ATM kinase in this process. IR-regulated PD-L1 expression in macrophages and associated signalling pathways were explored by in vitro studies using murine and human macrophage cell lines. A colorectal xenograft murine model was employed to demonstrate the impact of targeting ATM and PD-L1 expression in TAMs following IR on growth of tumour in vivo. IR up-regulated PD-L1 expression in macrophages, which was further augmented by ATM kinase inhibition. ATM inhibition increased IR-induced DNA damage, which activated STING/interferon regulatory factor 3 (IRF3) signalling pathway and up-regulated type I interferon (IFN-I) expression in macrophages. IFN-I bound to the IFN α receptor 1 on macrophages, activated the downstream JAK1 and STAT1/3 signalling and eventually led to PD-L1 up-expression. ATM inhibition augmented IR-induced PD-L1 expression in macrophages and CD8+ T cell infiltration, and promoted anti-tumour efficacy in vivo. These results suggested that ATM inhibition promoted IR-induced PD-L1 expression through the activation of innate immunity in TAMs, which provided a novel approach to enhance the anti-tumour efficacy of RT.
Assuntos
Ataxia Telangiectasia , Neoplasias , Humanos , Animais , Camundongos , Interferons , Macrófagos Associados a Tumor , Antígeno B7-H1/metabolismo , Transdução de Sinais , Microambiente TumoralRESUMO
BACKGROUND: The purpose of this analysis was to investigate the effectiveness of afatinib compared to that of osimertinib in patients with non-small cell lung cancer (NSCLC) who harbored uncommon epidermal growth factor receptor (EGFR) mutations. METHODS: A PubMed database-based literature review was conducted to retrieve related studies. Patients harboring EGFR mutations besides the deletion in exon 19 (19del) and point mutation of L858R were included in this analysis. The primary outcome events were the objective response rate (ORR) and progression-free survival (PFS). Propensity score matching (PSM) at a ratio of 1:1 was used between afatinib and osimertinib groups to control the confounding factors. Uncommon EGFR mutations were categorized into 4 groups: insertion in exon 20 (ex20ins), non-ex20ins single uncommon EGFR mutations, compound EGFR mutations that with 19del or L858R, and compound EGFR mutations without 19del or L858R. RESULTS: After PSM, 71 patients in either the afatinib or osimertinib group were matched. The afatinib group had an ORR of 60.6%, slightly higher than the osimertinib group's (50.3%), the difference was not statistically significant (Pâ =â .610). However, the afatinib group showed a significantly superior PFS benefit than the osimertinib group (11.0 vs. 7.0 months, Pâ =â .044). In addition, patients harboring non-ex20ins single uncommon EGFR mutations yield the best ORR and PFS, following treatment of either afatinib (ORR: 76.7%, mPFS: 14.1 months) or osimertinib (ORR: 68.8%, mPFS: 15.1 months). Moreover, there was no significant difference in terms of ORR or PFS between the cohort of patients treated with afatinib or osimertinib, regardless of whether or not the patients had brain metastases. CONCLUSIONS: Both afatinib and osimertinib displayed favorable clinical activities toward uncommon EGFR mutations. Afatinib showed a more profound and durable PFS benefit than osimertinib, although no efficacy advantage was observed.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Afatinib/farmacologia , Afatinib/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Receptores ErbB/genética , Receptores ErbB/uso terapêutico , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
New coronavirus (SARS-CoV-2), which has caused the coronavirus disease 2019 (COVID-19) pandemic, has brought about a huge burden on global healthcare systems. Rapid and early detection is important to prevent the spread of the pandemic. Here, an assay based on CRISPR/Cas13a and catalytic hairpin assembly (CHA), termed as Cas-CHA, was developed for ultrasensitive and specific detection of SARS-CoV-2 RNA. Upon specific recognition of the target, the CRISPR/Cas13a collaterally cleaved a well-designed hairpin reporter and triggered the CHA reaction. Under optimized conditions, the assay detected the SARS-CoV-2 RNA with a wide range of 100 aM to 100 nM and realized a low detection limit of 84 aM. At the same time, the whole detecting process could be completed within 35 min. More importantly, the assay was able to distinguish SARS-CoV-2 RNA from common human coronaviruses and analyze in saliva samples. By the flexible design of crRNA, the assay was expanded to detect other viruses. The clinical sample analysis verified that the proposed assay held a great potential for practical testing.
Assuntos
COVID-19 , Humanos , COVID-19/diagnóstico , RNA Viral/genética , SARS-CoV-2/genética , Bioensaio , CatáliseRESUMO
DNA methylation (5-methylcytosine, 5mC) is the most important epigenetic modification in mammals. Deciphering the roles of 5mC relies on the quantitative detection of 5mC at the single-base resolution. Bisulfite sequencing (BS-seq) is the most often employed technique for mapping 5mC in DNA. However, bisulfite treatment may cause serious degradation of input DNA due to the harsh reaction conditions. Here, we engineered the human apolipoprotein B mRNA-editing catalytic polypeptide-like 3C (A3C) protein to endow the engineered A3C (eA3C) protein with differential deamination activity toward cytosine and 5mC. By the virtue of the unique property of eA3C, we proposed an engineered A3C sequencing (EAC-seq) method for the bisulfite-free and quantitative mapping of 5mC in DNA at the single-base resolution. In EAC-seq, the eA3C protein can deaminate C but not 5mC, which is employed to differentiate C and 5mC in sequencing. Using the EAC-seq method, we quantitatively detected 5mC in genomic DNA of lung cancer tissue. In contrast to the harsh reaction conditions of BS-seq, which could lead to significant degradation of DNA, the whole procedure of EAC-seq is carried out under mild conditions, thereby preventing DNA damage. Taken together, the EAC-seq approach is bisulfite-free and straightforward, making it an invaluable tool for the quantitative detection of 5mC in limited DNA at the single-base resolution.
Assuntos
5-Metilcitosina , Citidina Desaminase , Metilação de DNA , Humanos , 5-Metilcitosina/metabolismo , Citidina Desaminase/genética , Citidina Desaminase/metabolismo , Citosina , DNA/genética , DNA/metabolismo , Epigênese Genética , Análise de Sequência de DNA/métodos , Sulfitos/metabolismoRESUMO
N6-Methyladenosine (m6A) is one of the most abundant and prevalent natural modifications occurring in diverse RNA species. m6A plays a wide range of roles in physiological and pathological processes. Revealing the functions of m6A relies on the faithful detection of individual m6A sites in RNA. However, developing a simple method for the single-base resolution detection of m6A is still a challenging task. Herein, we report an adenosine deamination sequencing (AD-seq) technique for the facile detection of m6A in RNA at single-base resolution. The AD-seq approach capitalizes on the selective deamination of adenosine, but not m6A, by the evolved tRNA adenosine deaminase (TadA) variant of TadA8e or the dimer protein of TadA-TadA8e. In AD-seq, adenosine is deaminated by TadA8e or TadA-TadA8e to form inosine, which pairs with cytidine and is read as guanosine in sequencing. m6A resists deamination due to the interference of the methyl group at the N6 position of adenosine. Thus, the m6A base pairs with thymine and is still read as adenosine in sequencing. The differential readouts from A and m6A in sequencing can achieve the single-base resolution detection of m6A in RNA. Application of the proposed AD-seq successfully identified individual m6A sites in Escherichia coli 23S rRNA. Taken together, the proposed AD-seq allows simple and cost-effective detection of m6A at single-base resolution in RNA, which provides a valuable tool to decipher the functions of m6A in RNA.
Assuntos
RNA de Transferência , RNA , RNA/metabolismo , Desaminação , RNA de Transferência/metabolismo , Adenosina/metabolismo , Adenosina Desaminase/metabolismoRESUMO
BACKGROUND: Prophylactic irradiation of supraclavicular lymph node drainage areas can improve the regional control rate of lymph node-positive or lymph node-negative disease but a locally-advanced stage breast cancer, and it can reduce breast cancer-related mortality. However, many controversies exist in the clinical target volume delineation of supraclavicular lymph node drainage in patients with breast cancer. METHODS: We retrospectively analyzed 42 patients with breast cancer and supraclavicular lymph node metastasis at our hospital between January 2017 and December 2021. Among these cases, 32 were locally advanced and 10 were stage IV at initial treatment. A patient with breast cancer who did not undergo dissection of the supraclavicular and infraclavicular lymph nodes at our hospital was selected as a standard patient. A contrast-enhanced computed tomography (CT) scan for positioning was used as a template image, and blood vessels, muscles, and bony landmarks were used as references for positioning. The metastatic supraclavicular lymph nodes were identified in all enrolled patients and projected into the template CT images. RESULTS: The metastastic pattern of supraclavicular lymph node in breast cancer was proposed: distribution along the posterolateral border of the internal jugular vein (medial supraclavicular group) and along the transverse jugular vein (lateral supraclavicular group). We theorized that the lateral and posterior borders of the clinical target volume in the supraclavicular region should include the lymph nodes in the posterior triangle of the neck (level V) in high-risk individuals. If the metastatic axillary lymph node is extensive, then the superior border of the supraclavicular region should be moved upward appropriately. CONCLUSIONS: This study analyzed patients with breast cancer and supraclavicular lymph node metastasis at initial treatment, explored the metastastic pattern of supraclavicular lymph node, and applied anatomical knowledge to further optimize the target volume delineation of supraclavicular lymph node drainage area in high-risk breast cancer.
Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/patologia , Metástase Linfática/patologia , Estudos Retrospectivos , Linfonodos/diagnóstico por imagem , Linfonodos/patologia , Mama/patologia , Axila/patologia , Excisão de LinfonodoRESUMO
DNA methylation (5-methylcytosine, 5mC) is the most prevalent epigenetic modification that is predominantly found in CG dinucleotides in mammalian genomes. In-depth investigation of the functions of 5mC heavily relies on the quantitative measurement of 5mC at single-base resolution in genomes. Here, we proposed a methyltransferase-directed labeling with APOBEC3A (A3A) deamination sequencing (MLAD-seq) method for the single-base resolution and quantitative detection of 5mC in DNA. In MLAD-seq, a mutant of DNA methyltransferase, M.MpeI-N374K, is utilized to selectively transfer a carboxymethyl group to the 5 position of cytosine in the CG dinucleotide to form 5-carboxymethylcytosine (5camC) using carboxy-S-adenosyl-l-methionine (caSAM) as the cofactor. After A3A treatment, 5camC is resistant to the deamination and base pairs with guanine. Thus, the cytosines in CG sites are read as C in sequencing. On the contrary, the methyl group in 5mC inhibits its carboxymethylcytosine by M.MpeI-N374K and therefore is readily deaminated by A3A to produce thymine that pairs with adenine and is read as T in sequencing. The differential readouts from C and 5mC in the MLAD-seq enable the single-base resolution mapping of 5mC in CG sites in DNA. With the developed MLAD-seq method, we observed the hypermethylation in the promoter region of retinoic acid receptor ß (RARB) gene from human nonsmall cell lung tumor tissue. Compared to harsh reaction conditions in bisulfite sequencing that could lead to significant degradation of DNA, the whole procedure of MLAD-seq is carried out under mild conditions, which will avoid DNA damage. Thus, MLAD-seq is more suitable in the scenario where only limited input DNA is available. Taken together, the MLAD-seq offers a valuable tool for bisulfite-free, single-base resolution and quantitative detection of 5mC in limited DNA.
Assuntos
5-Metilcitosina , Metiltransferases , Animais , Humanos , Desaminação , Análise de Sequência de DNA/métodos , Sulfitos , Epigênese Genética , DNA/genética , Citosina , Metilação de DNA , MamíferosRESUMO
BACKGROUND: Sterile alpha motif domain and histidine-aspartate domain-containing protein 1 (SAMHD1) is a DNA end resection factor, which is involved in DNA damage repair and innate immunity. However, the role of SAMHD1 in anti-tumor immunity is still unknown. This study investigated the effects of SAMHD1 on stimulator of interferon genes (STING)-type I interferon (IFN) pathway and radiation-induced immune responses. METHODS: The roles of SAMHD1 in the activation of cytosolic DNA sensing STING pathway in lung adenocarcinoma (LUAD) cells were investigated with flow cytometry, immunofluorescence, immunoblotting and qPCR. The combined effects of SAMHD1 silencing and radiation on tumor cell growth and STING pathway activation were also evaluated with colony formation and CCK8 assay. The Lewis lung cancer mouse model was used to evaluate the combined efficiency of SAMHD1 silencing and radiotherapy in vivo. Macrophage M1 polarization and cytotoxic T cell infiltration were evaluated with flow cytometry. RESULTS: The single-stranded DNA (ssDNA) accumulated in the cytosol of SAMHD1-deficient lung adenocarcinoma (LUAD) cells, accompanied by upregulated DNA sensor IFN-γ-inducible protein 16 (IFI16) and activated STING pathway. The translocation of IFI16 from nucleus to cytosol was detected in SAMHD1-deficient cells. IFI16 and STING were acquired in the activation of STING-IFN-I pathway in SAMHD1-deficient cells. SAMHD1 silencing in LUAD cells promoted macrophage M1 polarization in vitro. SAMHD1 silencing synergized with radiation to activate ssDNA-STING-IFN-I pathway, inhibit proliferation, promote apoptosis and regulate cell cycle. SAMHD1 silencing cooperated with radiotherapy to inhibit tumor growth and increase CD86+MHC-IIhigh M1 proportion and CD8+ T cell infiltration in vivo. CONCLUSIONS: SAMHD1 deficiency induced IFN-I production through cytosolic IFI16-STING pathway in LUAD cells. Moreover, SAMHD1 downregulation and radiation cooperated to inhibit tumor growth and enhance anti-tumor immune responses through macrophage M1 polarization and CD8+ T cell infiltration. Combination of SAMHD1 inhibition and radiotherapy may be a potentially therapeutic strategy for LUAD patients.
Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Animais , Camundongos , Proteína 1 com Domínio SAM e Domínio HD , Imunidade Inata , DNA , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/radioterapiaRESUMO
BACKGROUND: Radiotherapy has been widely used to treat various cancers, but its efficacy depends on the individual involved. Traditional gene-based machine-learning models have been widely used to predict radiosensitivity. However, there is still a lack of emerging powerful models, artificial neural networks (ANN), in the practice of gene-based radiosensitivity prediction. In addition, ANN may overfit and learn biologically irrelevant features. METHODS: We developed a novel ANN with Selective Connection based on Gene Patterns (namely ANN-SCGP) to predict radiosensitivity and radiocurability. We creatively used gene patterns (gene similarity or gene interaction information) to control the "on-off" of the first layer of weights, enabling the low-dimensional features to learn the gene pattern information. ANN-SCGP was trained and tested in 82 cell lines and 1,101 patients from the 11 pan-cancer cohorts. RESULTS: For survival fraction at 2 Gy, the root mean squared errors (RMSE) of prediction in ANN-SCGP was the smallest among all algorithms (mean RMSE: 0.1587-0.1654). For radiocurability, ANN-SCGP achieved the first and second largest C-index in the 12/20 and 4/20 tests, respectively. The low dimensional output of ANN-SCGP reproduced the patterns of gene similarity. Moreover, the pan-cancer analysis indicated that immune signals and DNA damage responses were associated with radiocurability. CONCLUSIONS: As a model including gene pattern information, ANN-SCGP had superior prediction abilities than traditional models. Our work provided novel insights into radiosensitivity and radiocurability.
Assuntos
Redes Neurais de Computação , Tolerância a Radiação , Humanos , Tolerância a Radiação/genética , Algoritmos , Aprendizado de Máquina , Linhagem CelularRESUMO
Aim: To review the efficacy and safety of regimens containing anti-PD-1/PD-L1 and bevacizumab for patients with advanced nonsquamous, non-small-cell lung cancer. Methods: Sixteen eligible trials were assessed. Clinical outcomes and adverse events were integrated. Subgroup analysis was conducted according to PD-L1 expression and liver metastases. Results: For the PD-L1 high population, a PD-1 inhibitor plus platinum-doublet provided significant progression-free survival (PFS) benefit versus bevacizumab. While for patients harboring PD-L1 <50%, anti-PD-1/PD-L1-containing regimens performed comparably to bevacizumab. With regard to the liver metastatic population, there existed a trend that anti-PD-1 plus chemotherapy brought about PFS benefits. Conclusion: The preference for chemoimmunotherapy lacks sufficient evidence in patients harboring PD-L1 <50%. Direct head-to-head clinical trials are warranted to identify optimal therapeutic regimens for specific patients.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antígeno B7-H1/metabolismo , Bevacizumab/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Neoplasias Pulmonares/patologia , Metanálise em RedeRESUMO
PURPOSE: We have combined analysis of clinical and laboratory markers to try to find an optimal model to predict venous thromboembolism in isocitrate dehydrogenase 1 (IDH1) wild-type glioblastoma (GBM) by a prospective research. METHODS: Patients with newly histologically confirmed IDH1 wild-type (IDH1wt) GBM were recruited for this study. Status of IDH1, PTEN, P53, BRAF, MGMT promoter methylation (MGMTp), and TERT promoter (TERTp) was determined using genetic sequencing through polymerase chain reaction (PCR). Amplification of EGFR was established through fluorescence in situ hybridization (FISH). Competing risk regression model was performed to calculate the risk of VTE. Clinical and laboratory parameters that were independently predicted risk of VTE were used to develop a risk assessment model (RAM). RESULTS: One hundred thirty-one patients with IDH1wt GBM were included in the present analysis. A total of 48/131 patients (36.6%) developed VTE. D-dimer, ECOG score, and EGFR amplification were suggested to be significantly associated with the VTE risk in multivariable analysis. High ECOG score (>2), high D-dimer (>1.6 µg/ml), and EGFR amplification were used as the strongest independent predictors of increased risk of VTE. The cumulative incidence of VTE was 17.2% for patients with score 0 (n =29), 23.6% for patients with score 1 (n =55), and 63.8% for patients with score 2 (n = 35) or score 3 (n = 12) by application of a RAM. CONCLUSIONS: In IDH1wt GBM patients, by applying a VTE risk assessment model, we could identify patients with a very high and low risk of VTE.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Tromboembolia Venosa , Biomarcadores , Neoplasias Encefálicas/patologia , Receptores ErbB/genética , Glioblastoma/patologia , Humanos , Hibridização in Situ Fluorescente , Isocitrato Desidrogenase/genética , Mutação , Estudos Prospectivos , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/genéticaRESUMO
BACKGROUND: Tumor microenvironment (TME) is associated with tumor progression and prognosis. Previous studies provided tools to estimate immune and stromal cell infiltration in TME. However, there is still a lack of single index to reflect both immune and stromal status associated with prognosis and immunotherapy responses. METHODS: A novel immune and stromal scoring system named ISTMEscore was developed. A total of 15 datasets were used to train and validate this system, containing 2965 samples from lung adenocarcinoma, skin cutaneous melanoma and head and neck squamous cell carcinoma. RESULTS: The patients with high immune and low stromal scores (HL) were associated with low ratio of T cell co-inhibitory/stimulatory molecules and low levels of angiogenesis markers, while the patients with low immune and high stromal scores (LH) had the opposite characteristics. The HL patients had immune-centered networks, while the patients with low immune and low stromal scores (LL) had desert-like networks. Moreover, copy number alteration burden was decreased in the HL patients. For the clinical characteristics, our TME classification was an independent prognostic factor. In the 5 cohorts with immunotherapy, the LH patients were linked to the lowest response rate. CONCLUSIONS: ISTMEscore system could reflect the TME status and predict the prognosis. Compared to previous TME scores, our ISTMEscore was superior in the prediction of prognosis and immunotherapy response.
Assuntos
Neoplasias de Cabeça e Pescoço , Neoplasias Pulmonares , Melanoma , Neoplasias Cutâneas , Biomarcadores Tumorais , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Melanoma/genética , Prognóstico , Microambiente TumoralRESUMO
Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) and agonistic antibodies against TRAIL death receptors (DR) can induce apoptosis preferentially in tumor cells while causing virtually no damage to normal cells. However, their therapeutic potential is limited by occurring resistance in tumor cells, including non-small cell lung cancer (NSCLC). Thus, elucidation of the molecular targets and signaling pathways responsible for TRAIL resistance is imperative for devising effective therapeutic strategies for TRAIL resistant cancers. In the present study, we demonstrated that inhibition of Bromodomain-containing protein 4 (BRD4) or genetic knock-down of BRD4, an epigenetic reader and master transcription coactivator, can sensitize lung cancer cells to TRAIL. This sensitization is in a caspase-dependent manner. Inhibition of BRD4 by small molecule inhibitor (+)-JQ-1 and genetic knock-down of BRD4 can both recruit the FADD and activate caspases. The sensitization did not regulate the death receptors DR4 and DR5. Moreover, BRD4 inhibition can block TRAIL-induced IKK activation by suppressing the transcriptional activity of NF-κB. These findings indicate that targeting combination therapy with TRAIL and BRD4 inhibitors can be a promising strategy to overcome TRAIL resistance in NSCLC.
Assuntos
Azepinas/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Proteínas de Ciclo Celular/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Ligante Indutor de Apoptose Relacionado a TNF/administração & dosagem , Fatores de Transcrição/antagonistas & inibidores , Triazóis/farmacologia , Células A549 , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Azepinas/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proteína de Domínio de Morte Associada a Fas/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , NF-kappa B/metabolismo , Proteínas Recombinantes/administração & dosagem , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Ativação Transcricional/efeitos dos fármacos , Triazóis/uso terapêuticoRESUMO
Potato virus A (PVA) and potato virus Y (PVY) are two members of genus Potyvirus infecting potato crops worldwide. Host resistance offers an economical and effective means for the control or management of these viruses. In this study, 20 potato clones were screened for their resistance against PVA and PVY by mechanical or graft inoculation assay, and were explored for the relationship between extreme resistance genes Ra and Ry by the detection of molecular markers linked to Ryadg, Rysto, and Rychc. Six clones, including Barbara, Jizhangshu 8, Longshu 7, Longshu 8, M6, and Solara, were found to be extremely resistant to both PVA and PVY; three clones (AC142, Eshu 3, and Shepody) were deemed to be extremely resistant to PVA but susceptible to PVY. To further reveal the inheritance of the extreme resistance (ER) against PVA, a tetraploid F1 population of Barbara × F58050 (susceptible to both PVY and PVA) and a tetraploid BC1 population of BF145 (a PVA-resistant but PVY-susceptible progeny of Barbara × F58050) × F58050 were obtained. Phenotyping of the F1 and BC1 populations by graft inoculation with PVA showed segregation ratios of 3:1 and 1:1 (resistant:susceptible), respectively. These results suggest that two independent loci control ER against PVA in Barbara: one confers ER to both PVA and PVY and the other confers ER to PVA only. The deduced genotype of Barbara is RyryryryRararara.
Assuntos
Potyvirus , Solanum tuberosum , Genótipo , Doenças das Plantas , Potyvirus/genética , Solanum tuberosum/genéticaRESUMO
The transition to tuberization contributes greatly to the adaptability of potato to a wide range of environments. Phytochromes are important light receptors for the growth and development of plants, but the detailed functions of phytochromes remain unclear in potato. In this study, we first confirmed that phytochrome F (StPHYF) played essential roles in photoperiodic tuberization in potato. By suppressing the StPHYF gene, the strict short-day potato genotype exhibited normal tuber formation under long-day (LD) conditions, together with the degradation of the CONSTANTS protein StCOL1 and modulation of two FLOWERING LOCUS T (FT) paralogs, as demonstrated by the repression of StSP5G and by the activation of StSP6A during the light period. The function of StPHYF was further confirmed through grafting the scion of StPHYF-silenced lines, which induced the tuberization of untransformed stock under LDs, suggesting that StPHYF was involved in the production of mobile signals for tuberization in potato. We also identified that StPHYF exhibited substantial interaction with StPHYB both in vitro and in vivo. Therefore, our results indicate that StPHYF plays a role in potato photoperiodic tuberization, possibly by forming a heterodimer with StPHYB.
Assuntos
Fitocromo/metabolismo , Solanum tuberosum/fisiologia , Genótipo , Fotoperíodo , Fitocromo/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Tubérculos/genética , Tubérculos/fisiologia , Tubérculos/efeitos da radiação , Solanum tuberosum/genética , Solanum tuberosum/efeitos da radiaçãoRESUMO
Breast cancer is a popularly diagnosed malignant tumor. Genomic profiling studies suggest that breast cancer is a disease with heterogeneity. Chemotherapy is one of the chief means to treat breast cancer, while its responses and clinical outcomes vary largely due to the conventional clinicopathological factors and inherent chemosensitivity of breast cancer. Using the least absolute shrinkage and selection operator (LASSO) Cox regression model, our study established a multi-mRNA-based signature model and constructed a relative nomogram in predicting distant-recurrence-free survival for patients receiving surgery and following chemotherapy. We constructed a signature of eight mRNAs (IPCEF1, SYNDIG1, TIGIT, SPESP1, C2CD4A, CLCA2, RLN2, and CCL19) with the LASSO model, which was employed to separate subjects into groups with high- and low-risk scores. Obvious differences of distant-recurrence-free survival were found between these two groups. This eight-mRNA-based signature was independently associated with the prognosis and had better prognostic value than classical clinicopathologic factors according to multivariate Cox regression results. Receiver operating characteristic results demonstrated excellent performance in diagnosing 3-year distant-recurrence by the eight-mRNA signature. A nomogram that combined both the eight-mRNA-based signature and clinicopathological risk factors was constructed. Comparing with an ideal model, the nomograms worked well both in the training and validation sets. Through the results that the eight-mRNA signature effectively classified patients into low- and high-risk of distant recurrence, we concluded that this eight-mRNA-based signature played a promising predictive role in prognosis and could be clinically applied in breast cancer patients receiving adjuvant chemotherapy.
RESUMO
BACKGROUND: Patients with cancer have a higher risk of coronavirus disease 2019 (COVID-19) than noncancer patients. The authors conducted a multicenter retrospective study to investigate the clinical manifestations and outcomes of patients with cancer who are diagnosed with COVID-19. METHODS: The authors reviewed the medical records of hospitalized patients who were treated at 5 hospitals in Wuhan City, China, between January 5 and March 18, 2020. Clinical parameters relating to cancer history (type and treatment) and COVID-19 were collected. The primary outcome was overall survival (OS). Secondary analyses were the association between clinical factors and severe COVID-19 and OS. RESULTS: A total of 107 patients with cancer were diagnosed with COVID-19, with a median age of 66 years (range, 37-98 years). Lung (21 patients; 19.6%), gastrointestinal (20 patients; 18.7%), and genitourinary (20 patients; 18.7%) cancers were the most common cancer diagnoses. A total of 37 patients (34.6%) were receiving active anticancer treatment when diagnosed with COVID-19, whereas 70 patients (65.4%) were on follow-up. Overall, 52.3% of patients (56 patients) developed severe COVID-19; this rate was found to be higher among patients receiving anticancer treatment than those on follow-up (64.9% vs 45.7%), which corresponded to an inferior OS in the former subgroup of patients (hazard ratio, 3.365; 95% CI, 1.455-7.782 [P = .005]). The detrimental effect of anticancer treatment on OS was found to be independent of exposure to systemic therapy (case fatality rate of 33.3% [systemic therapy] vs 43.8% [nonsystemic therapy]). CONCLUSIONS: The results of the current study demonstrated that >50.0% of infected patients with cancer are susceptible to severe COVID-19. This risk is aggravated by simultaneous anticancer treatment and portends for a worse survival, despite treatment for COVID-19.
Assuntos
Betacoronavirus/genética , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/mortalidade , Neoplasias/epidemiologia , Neoplasias/mortalidade , Pneumonia Viral/epidemiologia , Pneumonia Viral/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Antivirais/uso terapêutico , COVID-19 , China/epidemiologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Feminino , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Incidência , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Estudos Retrospectivos , Risco , SARS-CoV-2 , Índice de Gravidade de Doença , Esteroides/uso terapêutico , Taxa de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: To report the long-term outcomes of a phase III trial designed to test two hypotheses: (1) elective nodal irradiation (ENI) is superior to conventional field irradiation (CFI), and (2) chemoradiotherapy plus erlotinib is superior to chemoradiotherapy in locally advanced oesophageal squamous cell cancer (ESCC). METHODS: Patients with locally advanced ESCC were randomly assigned (1:1:1:1 ratio) to one of the four groups: A: radiotherapy adoption of ENI with two cycles of concurrent TP chemotherapy (paclitaxel and cisplatin) plus erlotinib; B: radiotherapy adoption of ENI with two cycles of concurrent TP; C: radiotherapy adoption of CFI with two cycles of concurrent TP plus erlotinib and D: radiotherapy adoption of CFI with two cycles of concurrent TP. A total of 60 Gy of radiation doses was delivered over 30 fractions. We explored the impact of epidermal growth factor receptor (EGFR) expression on the efficacy of erlotinib plus chemoradiotherapy. RESULTS: A total of 352 patients (88 assigned to each treatment group) were enrolled. The 5-year survival rates were 44.9%, 34.8%, 33.8% and 19.6% in groups A, B, C and D, respectively (P = 0.013). ENI significantly improved OS compared with standard CFI (median, 38.5 vs 22.6 months; HR, 0.74; P = 0.018). The addition of erlotinib significantly improved OS (median, 39.4 vs 27.4 months; HR, 0.75; P = 0.025). Patients with overexpressing EGFR treated with erlotinib had a better OS and PFS than those without erlotinib. CONCLUSIONS: Concurrent chemoradiotherapy with ENI and/or erlotinib improved long-term survival in locally advanced ESCC. CLINICAL TRIAL REGISTRATION: Trial registration: NCT00686114.