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1.
Ann Surg Oncol ; 2021 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-34796431

RESUMO

BACKGROUND: Mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) status serves as a predictor of a poor response to adjuvant chemotherapy among stage 2 colon cancer patients. This study aimed to investigate the efficacy of adjuvant chemotherapy in dMMR/MSI-H gastric cancer (GC). METHODS: Clinical studies comparing adjuvant chemotherapy and surgery alone in dMMR/MSI-H GCs through June 2021 were retrieved to assess the survival of patients managed with both treatments. Two approaches were used to pool the hazard ratio (HR) of survival: (1) if Kaplan-Meier curves and number of patients at risk were provided, individual patient data were extracted. Cox models were used to calculate the HR with its 95% confidence interval (CI); (2) for study-level data, pooled HR was estimated using fixed/random-effects models. RESULTS: Seven clinical studies were assessed. For dMMR/MSI-H versus mismatch repair-proficient (pMMR)/microsatellite stable (MSS)/microsatellite instability-low (MSI-L) status, the estimated 5-year disease-free survival (DFS) rate was 74.2% versus 51.5% (HR, 0.44; 95% CI, 0.32-0.62; P < 0.001) and the estimated 5-year OS rate was 60.5% versus 49.1% (HR, 0.71; 95% CI, 0.60-0.85; P < 0.001). The study-level data showed pooled HRs of 0.42 for DFS (95% CI, 0.31-0.57; P < 0.001) and 0.65 for OS (95% CI, 0.38-1.11; P = 0.114). For adjuvant chemotherapy versus observation of dMMR/MSI-H, the estimated 5-year DFS rate was 76.1% versus 73.3% (HR, 0.72; 95% CI, 0.45-1.15; P = 0.171) and the estimated 5-year OS rate was 73.5% versus 59.7% (HR, 0.62; 95% CI, 0.46-0.83; P = 0.001). Significant survival differences also were observed at study level. CONCLUSIONS: The study findings confirm the benefit of adjuvant chemotherapy for dMMR/MSI-H GC patients.

2.
Am J Cancer Res ; 11(10): 5006-5015, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34765307

RESUMO

Gastric cancer (GC) patients with Epstein-Barr virus (EBV) positivity have demonstrated promising response with immunotherapy. We assessed the efficacy and safety of camrelizumab as salvage treatment in EBV-positive mGC. In this single-arm, phase 2 prospective clinical trial (NCT03755440), stage IV EBV-positive GC patients who failed/could not tolerate previous lines of chemotherapy were given intravenous camrelizumab 200 mg every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was objective response rate. Secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response, and toxicity. Exploratory analysis included the associations between treatment response and tumor mutation burden (TMB), programmed cell death ligand-1 (PD-L1) expression. Six eligible patients were enrolled in the first stage of the study. No patient achieved an objective response; thus, the study did not proceed to the second stage. The DCR was 67% (4/6). The median PFS rate was 2.2 months (95% CI: 1.5-not reached [NR]) and median OS was 6.8 months (95% CI: 1.7-NR). All treatment-related adverse events were grade 1-2, with reactive cutaneous capillary endothelial proliferation (n=4 [67%]) being the most commonly observed event. The only patient with PD-L1 combined positive score >1 had disease progression. Two stable disease and one disease progression were observed in three patients with TMB >10 Mut/Mb. EBV positivity may not be a good predictor for response to camrelizumab in mGC. Newer biomarkers are needed to identify EBV-positive mGC respondents who might benefit from immunotherapy.

3.
Genome Biol ; 22(1): 304, 2021 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-34736486

RESUMO

BACKGROUND: Coconut is an important tropical oil and fruit crop whose evolutionary position renders it a fantastic species for the investigation of the evolution of monocot chromosomes and the subsequent differentiation of ancient plants. RESULTS: Here, we report the assembly and annotation of reference-grade genomes of Cn. tall and Cn. dwarf, whose genome sizes are 2.40 Gb and 2.39 Gb, respectively. The comparative analysis reveals that the two coconut subspecies diverge about 2-8 Mya while the conserved Arecaceae-specific whole-genome duplication (ω WGD) occurs approximately 47-53 Mya. It additionally allows us to reconstruct the ancestral karyotypes of the ten ancient monocot chromosomes and the evolutionary trajectories of the 16 modern coconut chromosomes. Fiber synthesis genes in Cn. tall, related to lignin and cellulose synthesis, are found at a higher copy number and expression level than dwarf coconuts. Integrated multi-omics analysis reveals that the difference in coconut plant height is the result of altered gibberellin metabolism, with both the GA20ox copy number and a single-nucleotide change in the promoter together leading to the difference in plant height between Cn. tall and Cn. dwarf. CONCLUSION: We provide high-quality coconut genomes and reveal the genetic basis of trait differences between two coconuts through multi-omics analysis. We also reveal that the selection of plant height has been targeted for the same gene for millions of years, not only in natural selection of ancient plant as illustrated in coconut, but also for artificial selection in cultivated crops such as rice and maize.

4.
J Exp Bot ; 2021 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-34727176

RESUMO

Vegetable oils are indispensable nutritional components of human diet as well as important raw materials for a variety of industrial applications such as pharmaceuticals, cosmetics, oleochemicals and biofuels. The oil plant genomes are highly diverse, and the genetic variation leads to the diversity in oil biosynthesis and accumulation along with agronomic traits. This review discusses the plant oil biosynthetic pathways, the current state of genome assembly, the polyploidy and asymmetric evolution genomes of oil plants and their wild relatives, and the research progress of pan-genomics in oil plants. The availability of complete high-resolution genomes and pangenomes has enabled the identification of structural variations in the genomes that are associated with the diversity of agronomic and environment fitness traits. These and more future genomes also provide powerful tools to understand crop evolution and to harvest the rich natural variations to improve oil crops for enhanced productivity, oil quality, and adaptability to changing environments.

5.
Nat Struct Mol Biol ; 28(10): 847-857, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34625747

RESUMO

The protein K-Ras functions as a molecular switch in signaling pathways regulating cell growth. In the human mitogen-activated protein kinase (MAPK) pathway, which is implicated in many cancers, multiple K-Ras proteins are thought to assemble at the cell membrane with Ras effector proteins from the Raf family. Here we propose an atomistic structural model for such an assembly. Our starting point was an asymmetric guanosine triphosphate-mediated K-Ras dimer model, which we generated using unbiased molecular dynamics simulations and verified with mutagenesis experiments. Adding further K-Ras monomers in a head-to-tail fashion led to a compact helical assembly, a model we validated using electron microscopy and cell-based experiments. This assembly stabilizes K-Ras in its active state and presents composite interfaces to facilitate Raf binding. Guided by existing experimental data, we then positioned C-Raf, the downstream kinase MEK1 and accessory proteins (Galectin-3 and 14-3-3σ) on and around the helical assembly. The resulting Ras-Raf signalosome model offers an explanation for a large body of data on MAPK signaling.


Assuntos
Proteínas Proto-Oncogênicas c-raf/química , Proteínas Proto-Oncogênicas c-raf/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/química , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteínas Sanguíneas/química , Proteínas Sanguíneas/metabolismo , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Transferência Ressonante de Energia de Fluorescência , Proteínas Ativadoras de GTPase/química , Proteínas Ativadoras de GTPase/metabolismo , Galectinas/química , Galectinas/metabolismo , Guanosina Trifosfato/química , Guanosina Trifosfato/metabolismo , Células HEK293 , Humanos , MAP Quinase Quinase 1/metabolismo , Microscopia Eletrônica , Microscopia Eletrônica de Transmissão , Simulação de Dinâmica Molecular , Complexos Multiproteicos/química , Complexos Multiproteicos/metabolismo , Mutagênese , Multimerização Proteica , Proteínas Proto-Oncogênicas c-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Reprodutibilidade dos Testes , Transdução de Sinais , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo
6.
Mol Ther ; 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34547468

RESUMO

Cancer cells evade immune detection via programmed cell death 1/programmed cell death-ligand 1 (PD-1/PD-L1) interactions that inactivate T cells. PD-1/PD-L1 blockade has become an important therapy in the anti-cancer armamentarium. However, some patients do not benefit from PD-1/PD-L1 blockade despite expressing PD-L1. Here, we screened 101 gastric cancer (GC) patients at diagnosis and 141 healthy control subjects and reported one such subpopulation of GC patients with rs17718883 polymorphism in PD-L1, resulting in a nonsense P146R mutation. We detected rs17718883 in 44% of healthy control subjects, and rs17718883 was associated with a low susceptibility to GC and better prognosis in GC patients. Structural analysis suggests that the mutation weakens the PD-1:PD-L1 interaction. This was supported by co-culture experiments of T cells, with GC cells showing that the P146R substitution results in interferon (IFN)-γ secretion by T cells and enables T cells to suppress GC cell growth. Similar results with animal gastric tumor models were obtained in vivo. PD-1 monoclonal antibody treatment did not enhance the inhibitory effect of T cells on GC cells expressing PD-L1P146Rin vitro or in vivo. This study suggests that rs17718883 is common and may be used as a biomarker for exclusion from PD-1/PD-L1 blockade therapy.

7.
Ann Surg ; 2021 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-34225299

RESUMO

OBJECTIVE: A large-scale multicenter retrospective cohort study was conducted to compare the short- and long-term outcomes of robotic gastrectomy (RG) and laparoscopic gastrectomy (LG) for gastric cancer. SUMMARY OF BACKGROUND DATA: RG is being increasingly used worldwide, but data from large-scale multicenter studies on the short- and long-term oncologic outcomes of RG versus LG are limited. The potential benefits of RG compared with LG for gastric cancer remain controversial. METHODS: Data from eligible patients who underwent RG or LG for gastric cancer of 11 experienced surgeons from 7 centers in China between March 2010 and October 2019 were collected. The RG group was matched 1:1 with the LG group by using propensity score matching (PSM). The primary outcome was postoperative complications. RESULTS: After PSM, a well-balanced cohort of 3552 patients was included for further analysis. The occurrence of overall complications (12.6% vs 15.2%, P = 0.023) was lower in the RG group than in the LG group. RG was associated with less blood loss (126.8 vs 142.5 mL, P < 0.001) and more retrieved lymph nodes in total (32.5 vs 30.7, P < 0.001) and in suprapancreatic areas (13.3 vs 11.6, P < 0.001). The long-term oncological outcomes were comparable between the two groups. CONCLUSIONS: The results of this multicenter study demonstrate that RG is a safe and effective treatment for gastric cancer when performed by experienced surgeons, although longer operation time and higher costs are still concerns about RG. This study provides evidence suggesting that RG may represent an alternative surgical treatment to LG.

8.
J Exp Clin Cancer Res ; 40(1): 220, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34210327

RESUMO

BACKGROUND: Metastasis is a major challenge in cervical cancer treatment. Previous studies have shown that the dual functional protein apurinic/apyrimidinic endonuclease 1 (APE1) promotes tumor metastasis and is overexpressed in cervical cancer. However, the biological role and mechanism of APE1 in cervical cancer metastasis have rarely been studied. METHODS: We used gene set enrichment analysis (GSEA) to determine the APE1-related signaling pathways in cervical cancer. To investigate the role and mechanism of APE1 in cervical cancer metastasis and invasion, immunohistochemistry, immunofluorescence, western blotting, secondary structure prediction, coimmunoprecipitation, luciferase reporter, and electrophoretic mobility shift assays were performed. The inhibitory effects of the APE1 redox function inhibitor APX3330 on cervical cancer metastasis were evaluated using animal models. RESULTS: Clinical data showed that high expression of APE1 was associated with lymph node metastasis in cervical cancer patients. GSEA results showed that APE1 was associated with epithelial to mesenchymal transition (EMT) in cervical cancer. Ectopic expression of APE1 promoted EMT and invasion of cervical cancer cells, whereas inhibition of APE1 suppressed EMT and invasion of cervical cancer cells in a redox function-dependent manner. Notably, APE1 redox function inhibitor APX3330 treatment dramatically suppressed cervical cancer cell lymph node and distant metastasis in vivo. Furthermore, we found that APE1 enhanced the interaction between ZEB1 and the E-cadherin promoter by binding to ZEB1, thereby suppressing the expression of E-cadherin, a negative regulator of EMT. CONCLUSION: Our findings help to elucidate the role played by APE1 in cervical cancer metastasis and targeting APE1 redox function may be a novel strategy for inhibiting cervical cancer metastasis.

9.
Cancer Commun (Lond) ; 41(8): 747-795, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34197702

RESUMO

There exist differences in the epidemiological characteristics, clinicopathological features, tumor biological characteristics, treatment patterns, and drug selections between gastric cancer patients from the Eastern and Western countries. The Chinese Society of Clinical Oncology (CSCO) has organized a panel of senior experts specializing in all sub-specialties of gastric cancer to compile a clinical guideline for the diagnosis and treatment of gastric cancer since 2016 and renews it annually. Taking into account regional differences, giving full consideration to the accessibility of diagnosis and treatment resources, these experts have conducted expert consensus judgment on relevant evidence and made various grades of recommendations for the clinical diagnosis and treatment of gastric cancer to reflect the value of cancer treatment and meeting health economic indexes in China. The 2021 CSCO Clinical Practice Guidelines for Gastric Cancer covers the diagnosis, treatment, follow-up, and screening of gastric cancer. Based on the 2020 version of the CSCO Chinese Gastric Cancer guidelines, this updated guideline integrates the results of major clinical studies from China and overseas for the past year, focused on the inclusion of research data from the Chinese population for more personalized and clinically relevant recommendations. For the comprehensive treatment of non-metastatic gastric cancer, attentions were paid to neoadjuvant treatment. The value of perioperative chemotherapy is gradually becoming clearer and its recommendation level has been updated. For the comprehensive treatment of metastatic gastric cancer, recommendations for immunotherapy were included, and immune checkpoint inhibitors from third-line to the first-line of treatment for different patient groups with detailed notes are provided.


Assuntos
Neoplasias Gástricas , China , Humanos , Oncologia , Sociedades Médicas , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/tratamento farmacológico
11.
World J Gastroenterol ; 27(21): 2895-2909, 2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34135560

RESUMO

BACKGROUND: Poorly differentiated gastric neuroendocrine neoplasms (PDGNENs) include gastric neuroendocrine carcinoma (NEC) and mixed adenoneuroendocrine carcinoma, which are highly malignant and rare tumors, and their incidence has increased over the past few decades. However, the clinicopathological features and outcomes of patients with PDGNENs have not been completely elucidated. AIM: To investigate the clinicopathological characteristics and prognostic factors of patients with PDGNENs. METHODS: The data from seven centers in China from March 2007 to November 2019 were analyzed retrospectively. RESULTS: Among the 232 patients with PDGNENs, 191 (82.3%) were male, with an average age of 62.83 ± 9.11 years. One hundred and thirteen (49.34%) of 229 patients had a stage III disease and 86 (37.55%) had stage IV disease. Three (1.58%) of 190 patients had no clinical symptoms, while 187 (98.42%) patients presented clinical symptoms. The tumors were mainly (89.17%) solitary and located in the upper third of the stomach (cardia and fundus of stomach: 115/215, 53.49%). Most lesions were ulcers (157/232, 67.67%), with an average diameter of 4.66 ± 2.77 cm. In terms of tumor invasion, the majority of tumors invaded the serosa (116/198, 58.58%). The median survival time of the 232 patients was 13.50 mo (7, 31 mo), and the overall 1-year, 3-year, and 5-year survival rates were 49%, 19%, and 5%, respectively. According to univariate analysis, tumor number, tumor diameter, gastric invasion status, American Joint Committee on Cancer (AJCC) stage, and distant metastasis status were prognostic factors for patients with PDGNENs. Multivariate analysis showed that tumor number, tumor diameter, AJCC stage, and distant metastasis status were independent prognostic factors for patients with PDGNENs. CONCLUSION: The overall prognosis of patients with PDGNENs is poor. The outcomes of patients with a tumor diameter > 5 cm, multiple tumors, and stage IV tumors are worse than those of other patients.


Assuntos
Tumores Neuroendócrinos , Neoplasias Gástricas , Idoso , China/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Tumores Neuroendócrinos/patologia , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/patologia
12.
Front Oncol ; 11: 538174, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33816215

RESUMO

Recent trials have shown a promising anti-tumor activity for advanced cancer patients treated with PD-1/PD-L1 inhibitors; however, little is known on the use of PD-1/PD-L1 inhibitors in adults over 75 years of age. Here, we performed a study-level meta-analysis to compare the efficacy of anti-PD-1/PD-L1 agents between elderly (≥ 75 years) and non-elderly (< 75 years) patients. In the present study, we systematically reviewed phase 2/3 trials of PD-1/PD-L1 inhibitors of advanced solid tumors that reported treatment effect (hazard ratio [HR]) in patients based on age (≥ 75 years vs. < 75 years) and set anti-PD-1/PD-L1 monotherapy or combinational therapy as experimental arm. The HRs of OS and progression-free survival (PFS) are based on random-effect models. Overall, a total of eight qualifying trials comprising 5,393 subjects were included for meta-analysis, and 472 patients (8.8%) were aged 75 years or older. The overall estimated HR for OS was 0.70 (0.62-0.79) in patients < 75 years vs. 0.94 (0.67-1.30) in patients ≥ 75 years. Anti-PD-1/PD-L1 agents improved OS of melanoma patients in both elderly (HR 0.25 [0.10-0.60]) and non-elderly (HR 0.49 [0.33-0.71]) group. The OS difference in the efficacy of PD-1/PD-L1 inhibitors between elderly and non-elderly patients was significant (P = 0.043 for interaction). The overall estimated HR for PFS was 0.77 (0.60-1.00) in patients < 75 years vs. 0.97 (0.60-1.58) in patients ≥ 75 years. Therefore, with the exception of melanoma, elderly patients (≥ 75 years) could not benefit from the anti-PD-1/PD-L1 agents in survival, and toxicity profile of anti-PD-1/PD-L1 drugs should be explored in this population.

13.
J Surg Oncol ; 123(8): 1699-1707, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33684249

RESUMO

BACKGROUND AND OBJECTIVES: Carbohydrate antigen 72-4 (CA72-4) is widely used and has been associated with poor prognosis in gastric cancer (GC), but the prognostic significance of elevated preoperative CA72-4 that normalizes after resection remains unknown. METHODS: This retrospective cohort analysis was conducted at the Sun Yat-Sen University Cancer Center (SYSUCC). Consecutive patients (n = 1179) with GC who had undergone curative resection for stage Ⅰto Ⅲ gastric adenocarcinoma. The patients were grouped into three cohorts: normal preoperative CA72-4 (C1), elevated preoperative but normalized postoperative CA72-4 (C2), and elevated preoperative and postoperative CA72-4 (C3). RESULTS: In total, 1179 patients were identified. Kaplan-Meier analysis showed that patients with normal preoperative CA72-4 had a longer overall survival (OS) (p < .001) and recurrence-free survival (RFS) (p < .001) than those with elevated preoperative CA72-4. Patients with C1 had a longer OS and RFS than those with C2 or C3. Moreover, patients with C3 had the lowest OS, but had similar RFS to patients with C2. Multivariate Cox regression analysis showed that elevated pre- or postoperative CA72-4 was independently associated with shorter OS (hazard ratio [HR] = 1.273; 95% confidence interval [CI], 1.026-1.580; p = .029) and RFS (HR = 1.333; 95% CI, 1.064-1.668; p = .012). CONCLUSIONS: Both elevated preoperative and postoperative CA72-4 can well predict the poor prognosis of patients with GC. Therefore, routine measurement of both postoperative and preoperative CA72-4 is warranted.


Assuntos
Adenocarcinoma/sangue , Adenocarcinoma/cirurgia , Antígenos Glicosídicos Associados a Tumores/sangue , Gastrectomia , Neoplasias Gástricas/sangue , Neoplasias Gástricas/cirurgia , Adenocarcinoma/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , China , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias Gástricas/mortalidade , Taxa de Sobrevida , Resultado do Tratamento , Adulto Jovem
14.
BMC Cancer ; 21(1): 188, 2021 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-33622258

RESUMO

BACKGROUND: Gastric outlet obstruction (GOO) is a late complication of advanced gastric cancer, and it is controversial how to select the therapeutic strategies: gastrojejunostomy and palliative gastrectomy? Therefore, this study was to compare the surgical and survival outcomes of gastrojejunostomy and palliative gastrectomy. METHODS: In total, 199 gastric cancer patients with outlet obstruction treated by surgery between January 2000 and December 2015 at Sun Yat-sen University Cancer Center were retrospectively reviewed. Patients were divided into gastrojejunostomy group and palliative gastrectomy group. Propensity score matching (PSM) was performed to balance the selection bias. RESULTS: After 1:1 PSM, a total of 104 patients were included for final analysis. The median overall survival (OS) times in the gastrojejunostomy group and palliative gastrectomy group were 8.50 and 11.87 months, respectively (P = 0.243). The postoperative complication rates in the gastrojejunostomy group and palliative gastrectomy group were 19.23% (10/52) and 17.31% (9/52), respectively (P = 0.800), and no treatment-related death was observed. Multivariate analysis showed that periton0eal seeding (P = 0.014) and chemotherapy (P < 0.001) were independent prognostic factors. Among them, peritoneal seeding was a risk factor and postoperative chemotherapy was a protective factor. CONCLUSIONS: Our results indicated that although the surgical complications of palliative gastrectomy were manageable, it showed no survival benefit. Therefore, relieving obstruction symptom, improving patients' quality of life and creating better conditions for chemotherapy appear to be the main therapeutic strategies for advanced gastric cancer with GOO.


Assuntos
Gastrectomia/métodos , Derivação Gástrica/métodos , Obstrução da Saída Gástrica/cirurgia , Cuidados Paliativos , Pontuação de Propensão , Neoplasias Gástricas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Gastrectomia/efeitos adversos , Derivação Gástrica/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Neoplasias Gástricas/complicações , Neoplasias Gástricas/mortalidade
15.
Neuroendocrinology ; 111(8): 752-763, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32668427

RESUMO

OBJECTIVE: The efficacy of the capecitabine/temozolomide (CAPTEM) regimen has been demonstrated in metastatic neuroendocrine neoplasms (NENs), but because of varying response rates among the patients, biomarkers to predict its response are greatly needed. Here, we investigated the clinical utility of a Ki-67 index to predict the CAPTEM regimen objective responses and select patients who could benefit from this regimen. METHODS: Metastatic NENs patients treated with the CAPTEM regimen from 4 high-volume medical centers were selected and grouped in a training and validation cohort. The classification and regression tree (CART) was generated to identify the optimal threshold of Ki-67 for stratifying the patients into different Ki-67 range groups based on their response to the CAPTEM regimen. RESULTS AND CONCLUSIONS: The overall response rate (ORR) and disease control rate of the entire cohort (N = 151) were 26.5 and 76.2%, respectively, with a median progression-free survival (PFS) of 12.0 months. CART analysis showed that patients in the Ki-67 range group 10-40% demonstrated a significantly higher ORR than those in Ki-67 >40 and <10% groups (p < 0.001 in the training cohort and p = 0.036 in the validation cohort). Response to the CAPTEM regimen was not influenced by the expression of O6-methylguanine-DNA methyltransferase or primary tumor location. Multivariate analysis identified the Ki-67 index as the only independent prognostic factor for overall survival (p = 0.031) and PFS (p = 0.006). The proposed Ki-67 index was externally validated and could be used to clinically identify suitable metastatic NENs patients who could achieve an optimal cytoreduction using the CAPTEM regimen.

16.
Sci Total Environ ; 749: 141440, 2020 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-32829270

RESUMO

Eight disinfection methods were applied to control biofilm contamination in domestic hot water system. The inactivation efficiency, responses of high- (≥1%), mid- (0.1% ~ 1%) and low-abundant taxa (≤0.1%) to disinfection, and interactions within and across three sub-communities were investigated. Ultraviolet was the most effective disinfection method for total bacteria and Escherichia coli, and chlorine dioxide had the highest inactivation efficiency on heterotrophic bacteria, while silver ions exhibited poor performance on all of them. At the phylum level, the responses of microorganisms to eight disinfection methods were different, but Proteobacteria and Firmicutes dominated in most samples. Eight disinfection methods had a greater impact on the proportion of high- and mid-abundant taxa than that of low-abundant taxa, and led to dissimilar transformations of genera among high-, mid- and low-abundant taxa in each sample. High-, mid- and low-abundant taxa of different samples showed similar structures and were roughly clustered into three Groups. Moreover, high-abundant taxa had more complex internal interactions than mid- and low-abundant taxa, and mainly presented co-occurrence patterns. The associations between high- and low-abundant taxa were close, and some low-abundant genera were identified as hub bacteria, such as Paracoccus, Thioalkalispira and Flavitalea. Furthermore, a total of 23 potential pathogens were detected in this study, and they mainly showed positive interactions, with Mycobacteria and Streptococcus as keystone genera. These results highlight the dissimilar responses of high-, mid- and low-abundant taxa to disinfection, and the critical role of some low-abundant genera in the microbial network, as well as the co-occurrence patterns among potential pathogens.


Assuntos
Desinfecção , Purificação da Água , Biofilmes , Água , Microbiologia da Água , Abastecimento de Água
17.
Eur J Surg Oncol ; 46(12): 2221-2228, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32859432

RESUMO

OBJECTIVE: To investigate a reasonable lymph node (N) staging system for gastric cancer patients with ≤15 retrieved lymph nodes (LNs). METHODS: The clinicopathological and follow-up data of patients with ≤15 LNs were obtained from the US Surveillance, Epidemiology, and End Results (SEER) database to analyze the impact of the number of retrieved LNs and metastatic status on the prognosis. In addition, external validation was achieved with data from two medical centers in China. RESULTS: A total of 18,139 gastric cancer patients with 1-15 retrieved LNs from the SEER database were enrolled and randomly divided into the training group and the internal validation group. A new LN staging system, mNr staging (mNr0-4; 5 stages), was established according to the number of retrieved LNs and the metastatic rate. Compared with the TNM and TNrM staging systems (established by Wang J; misclassification rates of 50.4% and 62.5%, respectively), the mTNrM staging system had a lower misclassification rate (23.4%). Furthermore, there was a significant difference in the 5-year overall survival (OS) rate between the mTNrM staging subgroups (p < 0.05); however, no significant difference was found in the 5-year OS rate of partial adjacent stages in the TNM (8th edition) and TNrM (p > 0.05) staging systems. Similar results were obtained in the external validation cohort. CONCLUSION: mNr and mTNrM staging systems can efficiently distinguish a survival difference in patients who undergo gastrectomy with ≤15 retrieved LNs, with more accurate predictions of the 5-year OS rate of patients compared with the TNM and TNrM staging systems.


Assuntos
Carcinoma/patologia , Excisão de Linfonodo/métodos , Linfonodos/patologia , Neoplasias Gástricas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/cirurgia , China , Feminino , Gastrectomia , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Reprodutibilidade dos Testes , Programa de SEER , Neoplasias Gástricas/cirurgia , Taxa de Sobrevida , Carga Tumoral , Estados Unidos , Adulto Jovem
18.
Cancer Res ; 80(17): 3719-3731, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32605999

RESUMO

Assembly of RAS molecules into complexes at the cell membrane is critical for RAS signaling. We previously showed that oncogenic KRAS codon 61 mutations increase its affinity for RAF, raising the possibility that KRASQ61H, the most common KRAS mutation at codon 61, upregulates RAS signaling through mechanisms at the level of RAS assemblies. We show here that KRASQ61H exhibits preferential binding to RAF relative to PI3K in cells, leading to enhanced MAPK signaling in in vitro models and human NSCLC tumors. X-ray crystallography of KRASQ61H:GTP revealed that a hyperdynamic switch 2 allows for a more stable interaction with switch 1, suggesting that enhanced RAF activity arises from a combination of absent intrinsic GTP hydrolysis activity and increased affinity for RAF. Disruption of KRASQ61H assemblies by the RAS oligomer-disrupting D154Q mutation impaired RAF dimerization and altered MAPK signaling but had little effect on PI3K signaling. However, KRASQ61H oligomers but not KRASG12D oligomers were disrupted by RAF mutations that disrupt RAF-RAF interactions. KRASQ61H cells show enhanced sensitivity to RAF and MEK inhibitors individually, whereas combined treatment elicited synergistic growth inhibition. Furthermore, KRASQ61H tumors in mice exhibited high vulnerability to MEK inhibitor, consistent with cooperativity between KRASQ61H and RAF oligomerization and dependence on MAPK signaling. These findings support the notion that KRASQ61H and functionally similar mutations may serve as predictive biomarkers for targeted therapies against the MAPK pathway. SIGNIFICANCE: These findings show that oncogenic KRASQ61H forms a cooperative RAS-RAF ternary complex, which renders RAS-driven tumors vulnerable to MEKi and RAFi, thus establishing a framework for evaluating RAS biomarker-driven targeted therapies.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Quinases raf/genética , Animais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Feminino , Células HEK293 , Xenoenxertos , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Mutação , Proteínas Proto-Oncogênicas p21(ras)/química , Proteínas Proto-Oncogênicas p21(ras)/metabolismo
19.
Clin Transl Med ; 10(1): 353-362, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32508039

RESUMO

PURPOSE: To identify how Epstein-Barr virus (EBV) status combined with molecular profiling predicts the prognosis of gastric cancer patients and their associated clinical actionable biomarkers. EXPERIMENTAL DESIGN: A next-generation sequencing assay targeting 295 cancer-related genes was performed in 73 EBV-associated gastric cancer (EBVaGC) and 75 EBV-negative gastric cancer (EBVnGC) specimens and these results were compared with overall survival (OS). RESULTS: PIK3CA, ARID1A, SMAD4, and PIK3R1 mutated significantly more frequently in EBVaGC compared with their corresponding mutation rate in EBVnGC. As the most frequently mutated gene in EBVnGC (62.7%), TP53 also displayed a mutation rate of 15.1% in EBVaGC. PIK3R1 was revealed as a novel mutated gene (11.0%) associated almost exclusively with EBVaGC. PIK3CA, SMAD4, PIK3R1, and BCOR were revealed to be unique driver genes in EBVaGC. ARID1A displayed a significantly large proportion of inactivated variants in EBVaGC. A notable finding was that integrating the EBV status with tumor mutation burden (TMB) and large genomic instability (LGI) categorized the tumors into four distinct molecular subtypes and optimally predicted patient prognosis. The corresponding median OSs for the EBV+/TMB-high, EBV+/TMB-low, EBV-/LGI-, and EBV-/LGI+ subtypes were 96.2, 75.3, 44.4, and 20.2 months, respectively. The different subtypes were significantly segregated according to distinct mutational profiles and pathways. CONCLUSIONS: Novel mutations in PIK3R1 and TP53 genes, driver genes such as PIK3CA, SMAD4, PIK3R1, BCOR, and ARID1A, and distinguished genomic profiles from EBVnGC were identified in EBVaGC tumors. The classification of gastric cancer by EBV, TMB, and LGI could be a good prognostic indicator, and provides distinguishing, targetable markers for treatment.

20.
Ther Adv Med Oncol ; 12: 1758835920929583, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32595775

RESUMO

Background: We assessed the surrogacy of objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) for overall survival (OS) in anti-PD-1/PD-L1 trials of metastatic melanoma through a meta-analysis of randomized controlled trials (RCTs). Methods: PubMed and EMBASE were searched for phase II/III RCTs till June 2019 investigating anti-PD-1/PD-L1 agents. Treatment effect (hazard ratio or odds ratio) on potential surrogates (ORR/DCR/PFS) and OS were collected. At trial level, we assessed the correlation between treatment effect on potential surrogates and OS, weighted by sample size, fixed and random effect models, and calculated the surrogate threshold effect (STE). Sensitivity analyses and leave-one-out cross-validation approach were performed to evaluate the robustness of our findings. Results: We included 8 RCTs (4110 patients; 11 comparisons). We did not identify strong correlations between ORR [coefficient of determination (R 2): 0.09-0.25], DCR (0.41-0.57) and OS. However, we noted a strong correlation between PFS and OS, with R 2 of 0.82 in sample size, 0.75 in fixed effect and 0.72 in random effect model weighting, the robustness of which was further verified by leave-one-out cross-validation approach. Sensitivity analyses with restriction to trials with less than 50% crossover, phase III trials, large trials and first-line trials strengthened the correlation (0.78-0.94). The STE for PFS was 0.78. Conclusions: PFS may be the appropriate surrogate for OS in anti-PD-1/PD-L1 trials of metastatic melanoma. A future anti-PD-1/PD-L1 trial would need less than 0.78 for PFS of the upper limit of confidence interval to predict an OS benefit.

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