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Residents are actively involved in patient assessment and all aspects of patient care, and they are critical in providing nutritional support education and treatment for patients with cancer. This study aims to assess the nutritional knowledge and performance of resident physicians, providing insights into existing gaps in awareness and practices related to cancer nutrition. A total of 300 resident physicians undergoing standardized residency training in China participated in this study. An anonymous online questionnaire covering demographic characteristics, nutritional knowledge, clinical practice, and training requirements was designed and administered through the "Wenjuanxing" platform. Data were collected from June 1, 2023, to July 31, 2023. Among the participants, only 40.00% demonstrated adequate knowledge of cancer nutrition, and merely 32.00% exhibited proficient performance in nutritional care. Socio-demographic analysis revealed that residents without affiliations and those specializing in obstetrics and gynecology had superior knowledge, while surgery specialists showed significantly worse performance. Most participants expressed a lack of exposure to cancer nutrition education during academic and standardized residency training. The study highlights the demand for enhanced education and the preference for case-based teaching methods. The findings underscore an urgent need for comprehensive oncology nutrition education within China's standardized residency training. Targeted interventions and curriculum enhancements are essential to improve medical talent development and enhance patient care outcomes in oncology. The study emphasizes the critical role of practical, case-based teaching methods in addressing identified gaps in nutritional knowledge and practices among resident physicians.
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BACKGROUND AND AIM: The prognosis of early-onset adenocarcinoma of esophagogastric junction (AEG) remains unclear. This research aimed at comparing the prognosis between early-onset and late-onset AEGs. METHODS: We extracted eligible patients with surgically resected, pathologically confirmed, nonmetastatic AEG from the Surveillance, Epidemiology, and End Results database from 2004 to 2015. The cutoff age of early-onset AEG was set at ≤50 years old. Univariate and multivariate Cox analysis as well as competing risk model were adopted for comparing overall survival (OS) and cancer-specific survival (CSS) between early-onset and late-onset AEGs. In addition, multiple imputation and propensity score matching (PSM) were also carried out for sensitivity analysis. RESULTS: In total, 4610 eligible AEG patients were collected in this study, including 610 early-onset AEGs and 4000 late-onset AEGs. Kaplan-Meier curves revealed significantly better survival in early-onset AEGs than late-onset AEGs. After interpolating missing data by multiple imputation, multivariate Cox regression analysis similarly showed better OS and CSS in early-onset AEGs. By using PSM analysis at a ratio of 1:1, we matched 610 early-onset AEG patients with 610 late-onset AEG patients. After PSM, univariate Cox regression model still revealed favorable prognosis in early-onset AEGs. Similar results were confirmed by performing PSM analysis at a ratio of 1:2 and 1:3. In addition, competing risk model demonstrated significantly lower cancer-specific death in early-onset AEGs compared to late-onset AEGs before and after matching. CONCLUSION: By applying several effective sensitivity analyses, we reported significantly favorable OS and CSS in early-onset AEGs compared to late-onset AEGs.
Subject(s)
Adenocarcinoma , Esophageal Neoplasms , Esophagogastric Junction , Humans , Esophagogastric Junction/surgery , Esophagogastric Junction/pathology , Adenocarcinoma/mortality , Adenocarcinoma/surgery , Adenocarcinoma/pathology , Middle Aged , Esophageal Neoplasms/mortality , Esophageal Neoplasms/surgery , Esophageal Neoplasms/pathology , Male , Female , Prognosis , Stomach Neoplasms/mortality , Stomach Neoplasms/surgery , Stomach Neoplasms/pathology , Age of Onset , Survival Rate , Proportional Hazards Models , Aged , Time Factors , Adult , Age Factors , SEER Program , Kaplan-Meier EstimateABSTRACT
OBJECTIVE: It remains unclear whether primary tumor resection improves survival in patients with metastatic Siewert type II adenocarcinoma of the esophagogastric junction (AEG). Therefore, our study attempted to investigate the prognostic value of primary tumor resection on metastatic AEG. METHODS: In total, 4200 patients diagnosed with metastatic AEG were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2015. Patients were categorized into two groups according to the performance of primary tumor resection. Pearson's chi-square test, Kaplan-Meier survival curve, and Cox regression analysis were conducted in this study. In addition, propensity-score matching was conducted to match 323 patients who received primary tumor resection and another 323 patients without. RESULTS: Multivariate Cox regression analysis demonstrated that primary tumor resection was a significant prognostic factor in patients with metastatic AEG before matching. Moreover, in the matched cohort, metastatic AEG patients receiving primary tumor resection had significantly longer overall survival (hazard ratio [HR]: .54, 95% confidence interval [CI]: .46-.64, P < .001) and cancer-specific survival (HR: .53, 95% CI: .45-.63, P < .001). Subgroup analysis similarly revealed that primary tumor resection was significantly associated with better survival in most subgroups. CONCLUSION: The present population-based study identified that primary tumor resection led to significantly superior survival in patients with metastatic AEG. These findings are likely to contribute to the development of individualized therapy in metastatic AEG.
Subject(s)
Adenocarcinoma , Esophageal Neoplasms , Stomach Neoplasms , Humans , Retrospective Studies , Stomach Neoplasms/pathology , Prognosis , Adenocarcinoma/pathology , Esophagogastric Junction/surgery , Esophagogastric Junction/pathology , Esophageal Neoplasms/surgery , Esophageal Neoplasms/pathologyABSTRACT
IMPORTANCE: NA is a crucial surface antigen and drug target of influenza A virus. A comprehensive understanding of NA's mutational effect and drug resistance profiles in vivo is essential for comprehending the evolutionary constraints and making informed choices regarding drug selection to combat resistance in clinical settings. In the current study, we established an efficient deep mutational screening system in mouse lung tissues and systematically evaluated the fitness effect and drug resistance to three neuraminidase inhibitors of NA single-nucleotide mutations. The fitness of NA mutants is generally correlated with a natural mutation in the database. The fitness of NA mutants is influenced by biophysical factors such as protein stability, complex formation, and the immune response triggered by viral infection. In addition to confirming previously reported drug-resistant mutations, novel mutations were identified. Interestingly, we identified an allosteric drug-resistance mutation that is not located within the drug-binding pocket but potentially affects drug binding by interfering with NA tetramerization. The dual assessments performed in this study provide a more accurate assessment of the evolutionary potential of drug-resistant mutations and offer guidance for the rational selection of antiviral drugs.
Subject(s)
Drug Resistance, Viral , Influenza A virus , Neuraminidase , Animals , Mice , Antiviral Agents/pharmacology , Influenza A virus/genetics , Mutation/genetics , Neuraminidase/genetics , Oseltamivir/pharmacologyABSTRACT
Martynoside (MAR), a bioactive component in several well-known tonic traditional Chinese herbs, exhibits pro-hematopoietic activity during 5-fluorouracil (5-FU) treatment. However, the molecular target and the mechanism of MAR are poorly understood. Here, by adopting the mRNA display with a library of even-distribution (md-LED) method, we systematically examined MAR-protein interactions in vitro and identified the ribosomal protein L27a (RPL27A) as a key cellular target of MAR. Structural and mutational analysis confirmed the specific interaction between MAR and the exon 4,5-encoded region of RPL27A. MAR attenuated 5-FU-induced cytotoxicity in bone marrow nucleated cells, increased RPL27A protein stability, and reduced the ubiquitination of RPL27A at lys92 (K92) and lys94 (K94). Disruption of MAR binding at key residues of RPL27A completely abolished the MAR-induced stabilization. Furthermore, by integrating label-free quantitative ubiquitination proteomics, transcriptomics, and ribosome function assays, we revealed that MAR restored RPL27A protein levels and thus rescued ribosome biogenesis impaired by 5-FU. Specifically, MAR increased mature ribosomal RNA (rRNA) abundance, prevented ribosomal protein degradation, facilitated ribosome assembly, and maintained nucleolar integrity. Collectively, our findings characterize the target of a component of Chinese medicine, reveal the importance of ribosome biogenesis in hematopoiesis, and open up a new direction for improving hematopoiesis by targeting RPL27A.
Subject(s)
Biological Assay , Fluorouracil , Fluorouracil/pharmacology , Bone Marrow Cells , CaffeineABSTRACT
Intestinal fibrosis is one of the most severe complications of inflammatory bowel disease (IBD) and frequently requires surgery due to intestinal obstruction. Integrin αvß6, which is mainly regulated by the integrin ß6 subunit gene (ITGB6), is a special integrin subtype expressed only in epithelial cells. In our previous study, we found integrin αvß6 can promote the development of IBD, but the role of integrin αvß6 in intestinal fibrosis remains unclear. In this study, we observed a gradual increase of ITGB6 mRNA expression from normal region to stenotic region of IBD patients' intestinal specimens. Next, we established a dextran sulfate sodium (DSS)-induced intestinal fibrosis model and a heterotopic intestinal transplant model, and found intestinal fibrosis was decreased in ITGB6-deficient mice compared to wild-type (WT) mice. Furthermore, we performed RNA-sequencing and KEGG pathway analysis on intestinal tissues from ITGB6-overexpressing transgenic mice and WT mice, and found multiple pathways containing ITGB6, are related to the activation of focal adhesion kinase (FAK); finding was confirmed by Western blot. At last, we generated a heterotopic intestinal transplant model found the FAK/AKT pathway was inhibited in ITGB6-deficient mice. In conclusion, our data demonstrate that integrin αvß6 promotes the pathogenesis of intestinal fibrosis by FAK/AKT pathway, making integrin αvß6 a potential therapeutic target to prevent this condition.
Subject(s)
Antigens, Neoplasm/metabolism , Inflammatory Bowel Diseases/metabolism , Integrins/metabolism , Animals , Crohn Disease/etiology , Crohn Disease/metabolism , Crohn Disease/pathology , Disease Models, Animal , Female , Fibrosis , Focal Adhesion Protein-Tyrosine Kinases/metabolism , Humans , Inflammatory Bowel Diseases/etiology , Inflammatory Bowel Diseases/pathology , Integrin beta Chains/genetics , Integrin beta Chains/metabolism , Integrins/deficiency , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Proto-Oncogene Proteins c-akt/metabolism , Signal TransductionABSTRACT
BACKGROUND: Marital status has been reported as an independent prognostic factor in various types of malignancies. However, the association between marital status and outcomes of patients with adenocarcinoma of the esophagogastric junction (AEG) has not been fully explored. To this end, we aimed to investigate the effect of marital status on survival of AGE patients. METHODS: The Surveillance Epidemiology and End Results (SEER) database (2010-2015) was used to extract eligible patients with Siewert type II AEG. Meanwhile, propensity score matching was performed to match 1576 unmarried patients with 1576 married patients. Kaplan-Meier method with log-rank test was used to plot survival curves, univariate and multivariate Cox regression analyses were adopted to investigate the association of marital status with overall survival (OS) and cancer-specific survival (CSS) in AEG patients before and after matching. RESULTS: Multivariate analysis in the unmatched cohort revealed that marital status was an independent prognostic factor in patients with Siewert type II AEG. Unmarried patients had poorer OS (hazard ratio [HR]: 1.22, 95% confidence interval [CI]: 1.12-1.29, P < .001) and poorer CSS (HR: 1.19, 95% CI: 1.10-1.29, P < .001) than married patients before matching. Additionally, widowed patients had the poorest OS (HR: 1.26, 95% CI: 1.11-1.44, P < .001) and CSS (HR: 1.29, 95% CI: 1.12-1.48, P < .001) compared with married patients. Furthermore, unmarried status remained as an independent prognostic for both OS (HR: 1.20, 95% CI: 1.10-1.31, P < .001) and CSS (HR: 1.18, 95% CI: 1.08-1.30, P < .001) in 1:1 propensity score-matched analysis. Subgroup analysis further revealed that OS and CSS rates were significantly higher in married patients than unmarried ones in most subgroups stratified by different variables. CONCLUSIONS: This population-based study identified that marital status was an independent prognostic indicator for AEG patients. Married AEG patients had better prognosis than their unmarried counterparts.
Subject(s)
Adenocarcinoma/mortality , Esophageal Neoplasms/mortality , Marital Status/statistics & numerical data , Aged , Esophagogastric Junction , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Multivariate Analysis , Prognosis , Propensity Score , Proportional Hazards Models , Risk Factors , SEER Program , Survival RateABSTRACT
[This corrects the article DOI: 10.3389/fonc.2021.631943.].
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BACKGROUND: Endoscopic resection has been introduced as an alternative treatment for superficial adenocarcinoma of the esophagogastric junction (AEG), but is limited by positive nodal status. We aimed to investigate the predictors of lymph node metastasis (LNM) in patients with Siewert type II T1 AEG. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify eligible patients with Siewert type II T1 AEG. The prevalence of LNM was assessed. Logistic regression analysis with multivariable adjustment was used to determine predictors of LNM. We also performed Cox regression analysis to examine the prognostic value of LNM, which was further confirmed by competing risk analysis and cumulative incidence function (CIF). RESULTS: In total, 2651 patients with T1 AEG were included, with a median age of 69 years and a median follow-up of 28 months. The overall prevalence of LNM was 17.2% in T1 AEG. When stratified by tumor invasion depth, the prevalence of LNM was 8.5% for intramucosal tumors and 22.6% for submucosal tumors. Adjusted logistic regression analysis showed that age, sex, tumor grade, tumor size and tumor infiltration depth were independent predictors of LNM in T1 AEG. Multivariate Cox regression analysis revealed that positive nodal status was significantly associated with worse overall survival and cancer-specific survival (CSS). Subgroup analysis consistently demonstrated that patients with LNM had significantly poorer CSS than those without LNM in most subgroups. Finally, the CIF was calculated, showing that patients with LNM had a significantly higher cancer-specific death rate than those without LNM. CONCLUSIONS: This population-based study identified age, sex, tumor grade, tumor infiltration depth and tumor size as independent predictors of LNM in T1 AEG. Considering the high prevalence of LNM in T1 AEG, endoscopic resection for curative aims may only be introduced in patients without high risks of LNM.
Subject(s)
Adenocarcinoma/pathology , Esophagogastric Junction/pathology , Lymphatic Metastasis/pathology , Stomach Neoplasms/pathology , Adenocarcinoma/mortality , Age Factors , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Neoplasm Grading , Neoplasm Invasiveness , Neoplasm Staging , Prognosis , Regression Analysis , Retrospective Studies , Risk Factors , SEER Program , Sex Factors , Socioeconomic Factors , Stomach Neoplasms/mortality , Tumor Burden , United StatesABSTRACT
Localized nasopharyngeal cancer (NPC) is a highly curable disease, but the prognosis of certain cases is still poor. Distinguishing patients with a poor outcome is necessary when developing therapeutic strategies. The aim of this study was to investigate the characteristics of early death (ED) among patients with localized NPC, and to identify independent predictors of ED. Patients diagnosed with localized NPC were included from the Surveillance, Epidemiology, and End Results dataset, and univariate and multivariate logistic regression analyses were performed to identify ED predictors. A total of 752 patients with localized NPC were enrolled, including 198 cases of ED and 480 long-term survivors. Older age, unmarried status, and white race were risk factors for ED, whereas diagnosis in the recent period and undifferentiated non-keratinizing histology type were protective factors. In addition, for older patients, women and those without radiation treatment, there was less ED for married patients than unmarried patients. In conclusion, this population-based study provides an overview of the characteristics of ED patients with localized NPC. Age, race, marital status, year of diagnosis and histology type are risk factors for ED. Moreover, married patients are at a significantly lower risk of ED. This protective effect is especially pronounced in older people, women and those without radiation treatment.
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Martynoside (MAR) is a bioactive glycoside of Rehmannia glutinosa, a traditional Chinese herb frequently prescribed for treating chemotherapy-induced pancytopenia. Despite its clinical usage in China for thousands of years, the mechanism of MAR's hematopoietic activity and its impact on chemotherapy-induced antitumor activity are still unclear. Here, we showed that MAR protected ex vivo bone marrow cells from 5-fluorouracil (5-FU)-induced cell death and inflammation response by down-regulating the TNF signaling pathway, in which II1b was the most regulatory gene. Besides, using mouse models with melanoma and colon cancer, we further demonstrated that MAR had protective effects against 5-FU-induced myelosuppression in mice without compromising its antitumor activity. Our results showed that MAR increased the number of bone marrow nucleated cells (BMNCs) and the percentage of leukocyte and granulocytic populations in 5-FU-induced myelosuppressive mice, accompanied by an increase in numbers of circulating white blood cells and platelets. The transcriptome profile of BMNCs further showed that the mode of action of MAR might be associated with the increased survival of BMNCs and the improvement of the bone marrow microenvironment. In summary, we revealed the potential molecular mechanism of MAR to counteract 5-FU-induced bone marrow cytotoxicity both ex vivo and in vivo, and highlighted its potential clinical usage in cancer patients experiencing chemotherapy-induced multi-lineage myelosuppression.
Subject(s)
Antimetabolites, Antineoplastic/toxicity , Cytotoxins/toxicity , Fluorouracil/toxicity , Glucosides/pharmacology , Mesenchymal Stem Cells/drug effects , Animals , Dose-Response Relationship, Drug , Female , Gene Regulatory Networks/drug effects , Gene Regulatory Networks/physiology , Mesenchymal Stem Cells/metabolism , Mesenchymal Stem Cells/pathology , Mice , Mice, Inbred C57BLABSTRACT
Purpose: Colorectal liver metastasis (CRLM) is the major cause of death due to colorectal cancer. Although great efforts have been made in treatment of CRLM, about 60-70% of patients will develop hepatic recurrence. Hepatic steatosis was reported to provide fertile soil for metastasis. However, whether hepatic steatosis predicts higher incidence of CRLM recurrence is not clear. Therefore, we aimed to determine the role of hepatic steatosis in CRLM recurrence in the present study. Methods: Consecutive CRLM patients undergoing curative treatment were retrospectively enrolled and CT liver-spleen attenuation ratio was used to detect the presence of hepatic steatosis. In patients with hepatic steatosis, we also detected the presence of fibrosis. Besides, a systematic literature search was performed to do meta-analysis to further analyze the association between hepatic steatosis and CRLM recurrence. Results: A total of 195 eligible patients were included in our center. Patients with hepatic steatosis had a significantly worse overall (P = 0.0049) and hepatic recurrence-free survival (RFS) (P = 0.0012). Univariate and multivariate analysis confirmed its essential role in prediction of RFS. Besides, hepatic fibrosis is associated with worse overall RFS (P = 0.039) and hepatic RFS (P = 0.048). In meta-analysis, we included other four studies, with a total of 1,370 patients in the case group, and 3,735 patients in the control group. The odds ratio was 1.98 (95% CI: 1.25-3.14, P = 0.004), indicating that patients with steatosis had a significantly higher incidence of CRLM recurrence. Conclusion: In summary, patients with hepatic steatosis had a significantly worse overall and hepatic RFS and it's associated with higher incidence of CRLM recurrence.
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BACKGROUND: Angiopoietin-like protein 1 (ANGPTL1) has been proved to suppress tumor metastasis in several cancers. However, its extracellular effects on the pre-metastatic niches (PMNs) are still unclear. ANGPTL1 has been identified in exosomes, while its function remains unknown. This study was designed to explore the role of exosomal ANGPTL1 on liver metastasis in colorectal cancer (CRC). METHODS: Exosomes were isolated by ultracentrifugation. The ANGPTL1 level was detected in exosomes derived from human CRC tissues. The effects of exosomal ANGPTL1 on CRC liver metastasis were explored by the intrasplenic injection mouse model. The liver PMN was examined by vascular permeability assays. Exosomal ANGPTL1 localization was validated by exosome labeling. The regulatory mechanisms of exosomal ANGPTL1 on Kupffer cells were determined by RNA sequencing. qRT-PCR, Western Blot, and ELISA analysis were conducted to examine gene expressions at mRNA and protein levels. RESULTS: ANGPTL1 protein level was significantly downregulated in the exosomes derived from CRC tumors compared with paired normal tissues. Besides, exosomal ANGPTL1 attenuated liver metastasis and impeded vascular leakiness in the liver PMN. Moreover, exosomal ANGPTL1 was mainly taken up by KCs and regulated the KCs secretion pattern, enormously decreasing the MMP9 expression, which finally prevented the liver vascular leakiness. In mechanism, exosomal ANGPTL1 downregulated MMP9 level in KCs by inhibiting the JAK2-STAT3 signaling pathway. CONCLUSIONS: Taken together, exosomal ANGPTL1 attenuated CRC liver metastasis and impeded vascular leakiness in the liver PMN by reprogramming the Kupffer cell and decreasing the MMP9 expression. This study suggests a suppression role of exosomal ANGPTL1 on CRC liver metastasis and expands the approach of ANGPTL1 functioning.
Subject(s)
Angiopoietin-like Proteins/metabolism , Colorectal Neoplasms/complications , Exosomes/metabolism , Kupffer Cells/metabolism , Liver Neoplasms/secondary , Matrix Metalloproteinase 9/metabolism , Angiopoietin-Like Protein 1 , Animals , Cell Line, Tumor , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Disease Models, Animal , Humans , Neoplasm Metastasis , TransfectionABSTRACT
Integrins, as a large family of cell adhesion molecules, play a crucial role in maintaining intestinal homeostasis. In inflammatory bowel disease (IBD), homeostasis is disrupted. Integrin αvß6, which is mainly regulated by the integrin ß6 subunit gene (ITGB6), is a cell adhesion molecule that mediates cell-cell and cell-matrix interactions. However, the role of ITGB6 in the pathogenesis of IBD remains elusive. In this study, we found that ITGB6 was markedly upregulated in inflamed intestinal tissues from patients with IBD. Then, we generated an intestinal epithelial cell-specific ITGB6 transgenic mouse model. Conditional ITGB6 transgene expression exacerbated experimental colitis in mouse models of acute and chronic dextran sulphate sodium (DSS)-induced colitis. Survival analyses revealed that ITGB6 transgene expression correlated with poor prognosis in DSS-induced colitis. Furthermore, our data indicated that ITGB6 transgene expression increased macrophages infiltration, pro-inflammatory cytokines secretion, integrin ligands expression and Stat1 signalling pathway activation. Collectively, our findings revealed a previously unknown role of ITGB6 in IBD and highlighted the possibility of ITGB6 as a diagnostic marker and therapeutic target for IBD.
Subject(s)
Colitis/etiology , Colitis/metabolism , Epithelial Cells/metabolism , Gene Expression , Integrin beta Chains/genetics , Intestinal Mucosa/metabolism , Animals , Biomarkers , Colitis/pathology , Cytokines/metabolism , Dextran Sulfate/adverse effects , Disease Models, Animal , Disease Susceptibility , Epithelial Cells/pathology , Gene Expression Profiling , Gene Targeting , Genetic Vectors/genetics , Humans , Inflammation Mediators/metabolism , Integrin beta Chains/metabolism , Intestinal Mucosa/pathology , Macrophages/immunology , Macrophages/metabolism , Macrophages/pathology , Mice , Mice, TransgenicABSTRACT
PURPOSE: The presence of microvascular invasion (MVI) is an unfavorable prognostic factor for hepatocellular carcinoma (HCC). This study aimed to construct a nomogram-based preoperative prediction model of MVI, thereby assisting to preoperatively select proper surgical procedures. METHODS: A total of 714 non-metastatic HCC patients undergoing radical hepatectomy were retrospectively selected from Zhongshan Hospital between 2010 and 2018, followed by random assignment into training (Nâ¯=â¯520) and validation cohorts (Nâ¯=â¯194). Nomogram-based prediction model for MVI risk was constructed by incorporating independent risk factors of MVI presence identified from multivariate backward logistic regression analysis in the training cohort. The performance of nomogram was evaluated by calibration curve and ROC curve. Finally, decision curve analysis (DCA) was used to determine the clinical utility of the nomogram. RESULTS: In total, 503 (70.4%) patients presented MVI. Multivariate analysis in the training cohort revealed that age (OR: 0.98), alpha-fetoprotein (≥400â¯ng/mL) (OR: 2.34), tumor size (>5â¯cm) (OR: 3.15), cirrhosis (OR: 2.03) and γ-glutamyl transpeptidase (OR: 1.61) were significantly associated with MVI presence. The incorporation of five risk factors into a nomogram-based preoperative estimation of MVI risk demonstrated satisfactory discriminative capacity, with C-index of 0.702 and 0.690 in training and validation cohorts, respectively. Calibration curve showed good agreement between actual and predicted MVI risks. Finally, DCA revealed the clinical utility of the nomogram. CONCLUSION: The nomogram showed a satisfactory discriminative capacity of MVI risk in HCC patients, and could be used to preoperatively estimate MVI risk, thereby establishing more rational therapeutic strategies.
ABSTRACT
A comprehensive examination of protein-protein interactions (PPIs) is fundamental for the understanding of cellular machineries. However, limitations in current methodologies often prevent the detection of PPIs with low abundance proteins. To overcome this challenge, we develop a mRNA display with library of even-distribution (md-LED) method that facilitates the detection of low abundance binders with high specificity and sensitivity. As a proof-of-principle, we apply md-LED to IAV NS1 protein. Complementary to AP-MS, md-LED enables us to validate previously described PPIs as well as to identify novel NS1 interactors. We show that interacting with FASN allows NS1 to directly regulate the synthesis of cellular fatty acids. We also use md-LED to identify a mutant of NS1, D92Y, results in a loss of interaction with CPSF1. The use of high-throughput sequencing as the readout for md-LED enables sensitive quantification of interactions, ultimately enabling massively parallel experimentation for the investigation of PPIs.
Subject(s)
Gene Library , Influenza A virus/metabolism , Viral Nonstructural Proteins/metabolism , A549 Cells , Fatty Acid Synthase, Type I/metabolism , Gene Ontology , Humans , Influenza A virus/drug effects , Influenza A virus/physiology , Interferons/pharmacology , Lipid Metabolism/drug effects , Mutation/genetics , Protein Binding/drug effects , RNA, Messenger/genetics , RNA, Messenger/metabolism , Virus Replication/drug effects , Virus Replication/physiologyABSTRACT
Early identification of metastatic or recurrent colorectal cancer (CRC) patients who will be sensitive to FOLFOX (5-FU, leucovorin and oxaliplatin) therapy is very important. We performed microarray meta-analysis to identify differentially expressed genes (DEGs) between FOLFOX responders and nonresponders in metastatic or recurrent CRC patients, and found that the expression levels of WASHC4, HELZ, ERN1, RPS6KB1, and APPBP2 were downregulated, while the expression levels of IRF7, EML3, LYPLA2, DRAP1, RNH1, PKP3, TSPAN17, LSS, MLKL, PPP1R7, GCDH, C19ORF24, and CCDC124 were upregulated in FOLFOX responders compared with nonresponders. Subsequent functional annotation showed that DEGs were significantly enriched in autophagy, ErbB signaling pathway, mitophagy, endocytosis, FoxO signaling pathway, apoptosis, and antifolate resistance pathways. Based on those candidate genes, several machine learning algorithms were applied to the training set, then performances of models were assessed via the cross validation method. Candidate models with the best tuning parameters were applied to the test set and the final model showed satisfactory performance. In addition, we also reported that MLKL and CCDC124 gene expression were independent prognostic factors for metastatic CRC patients undergoing FOLFOX therapy.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/genetics , Colorectal Neoplasms/drug therapy , Machine Learning , Neoplasm Recurrence, Local/drug therapy , Cell Cycle Proteins/genetics , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Datasets as Topic , Fluorouracil/therapeutic use , Gene Expression Profiling/statistics & numerical data , Gene Expression Regulation, Neoplastic , Humans , Intracellular Signaling Peptides and Proteins/genetics , Leucovorin/therapeutic use , Neoplasm Recurrence, Local/genetics , Oligonucleotide Array Sequence Analysis/statistics & numerical data , Organoplatinum Compounds/therapeutic use , Prognosis , Protein Kinases/genetics , Response Evaluation Criteria in Solid TumorsABSTRACT
The incidence of colorectal cancer is increasing, and cancer metastasis is one of the major causes of poor outcomes. BEX2 has been reported to be involved in tumor development in several types of cancer, but its role in metastatic colorectal cancer remains largely undefined. Herein, we demonstrated that BEX2 knockout resulted in enhanced migratory and metastatic potential in colorectal cancer cells both in vitro and in vivo, and re-expression of BEX2 in knockout cells could reverse the enhanced migratory capacity. RNA-Seq results indicated that the hedgehog signaling pathway was activated after BEX2 knockout; moreover, the hedgehog signaling inhibitors, GANT61 and GDC-0449 could reverse the migratory enhancement of BEX2-/- colorectal cancer cells. We also demonstrated that the nuclear translocation of Zic2 after BEX2 silencing could activate the hedgehog signaling pathway, while Zic2 knockdown abrogated the migratory enhancement of BEX2-/- cells and inhibited the hedgehog signaling pathway. In summary, our findings suggest that BEX2 negatively modulates the hedgehog signaling pathway by retaining Zic2 in the cytoplasm in colorectal cancer cells, thereby inhibiting migration and metastasis of colorectal cancer cells.
Subject(s)
Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Hedgehog Proteins/metabolism , Nerve Tissue Proteins/metabolism , Animals , Blotting, Western , Cell Line, Tumor , Cell Proliferation/genetics , Cell Proliferation/physiology , Clustered Regularly Interspaced Short Palindromic Repeats/genetics , Colorectal Neoplasms/genetics , Gene Expression Regulation, Neoplastic/genetics , Gene Expression Regulation, Neoplastic/physiology , HEK293 Cells , Hedgehog Proteins/genetics , Humans , Mice , Mice, Nude , Microscopy, Confocal , Nerve Tissue Proteins/genetics , Plasmids , RNA Interference , Real-Time Polymerase Chain Reaction , Signal Transduction/genetics , Signal Transduction/physiologyABSTRACT
Background: Patients with rectal cancer who achieve pathologic complete response (pCR) after neoadjuvant chemoradiotherapy (nCRT) may have a better prognosis and may be eligible for non-operative management. The aim of this research was to identify variables for predicting pCR in rectal cancer patients after nCRT and to define clinical risk factors for poor outcome after pCR to nCRT and radical resection in rectal cancer patients. Methods: A retrospective review was performed using the Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2013. Non-metastatic rectal cancer patients who received radical resection after neoadjuvant chemoradiotherapy were included in this study. Multivariate analysis of the association between clinicopathological characteristics and pCR was performed, and a logistic regression model was used to identify independent predictors for pCR. A nomogram based on the multivariate logistics regression was built with decision curve analyses to evaluate the clinical usefulness. Results: A total of 6,555 patients were included in this study. The proportion of patients with pCR was 20.5% (n = 1,342). The nomogram based on multivariate logistic regression analysis showed that clinical T4 and N2 stages were the most significant independent clinical predictors for not achieving pCR, followed by mucinous adenocarcinoma and positive pre-treatment serum CEA results. The 3-year overall survival rate was 92.4% for those with pCR and 88.2% for those without pCR. Among all the pCR patients, mucinous adenocarcinoma patients had the worst survival, with a 3-year overall survival rate of 67.5%, whereas patients with common adenocarcinoma had an overall survival rate of 93.8% (P < 0.001). Univariate and multivariate analyses showed that histology and clinical N2 stage were independent risk factors. Conclusion: Mucinous adenocarcinoma, positive pre-treatment serum CEA results, and clinical T4 and N2 stages may impart difficulty for patients to achieve pCR. Mucinous adenocarcinoma and clinical N2 stage might be indicative of a prognostically unfavorable biological tumor profile with a greater propensity for local or distant recurrence and decreased survival.