Induction Chemotherapy Followed by Radiotherapy vs Chemoradiotherapy in Nasopharyngeal Carcinoma: A Randomized Clinical Trial.

Importance: Induction chemotherapy plus concurrent chemoradiotherapy is recommended for locoregionally advanced nasopharyngeal carcinoma but is associated with higher rates of acute toxic effects and low compliance. Evidence on de-escalating treatment intensity after induction chemotherapy is limited. Objective: To assess if radiotherapy was noninferior to chemoradiotherapy after induction chemotherapy for locoregionally advanced nasopharyngeal carcinoma. Design, Setting, and Participants: From April 2015 to March 2018, a multicenter, open-label, randomized, noninferiority, phase 3 trial was conducted at 5 Chinese hospitals. A total of 383 patients aged 18 to 70 years with an untreated histologically confirmed nonkeratinizing tumor, Karnofsky performance status score not worse than 70, proper organ function, and stage III to IVB nasopharyngeal cancer were enrolled. Data were analyzed from April 2023 to June 2023. Interventions: Patients were assigned randomly. Both groups received 3 cycles of induction chemotherapy consisting of intravenous administration (on day 1) of cisplatin at 60 mg/m2 and docetaxel at 60 mg/m2 and continuous intravenous infusion (from day 1 to day 5) of daily fluorouracil (600 mg/m2), repeated every 21 days. Subsequently, the patients received radiotherapy alone (induction chemotherapy in combination with radiotherapy [IC-RT] group) or concomitant cisplatin (30 mg/m2/week) with radiotherapy for 6 to 7 weeks (induction chemotherapy combined with chemoradiotherapy [IC-CCRT] group). Main Outcomes and Measures: The primary end point was 3-year progression-free survival (time from the initiation of therapy until the first indication of disease progression or death), with a noninferiority margin of 10%. The secondary end points included overall survival, locoregional failure-free survival, distant metastasis-free survival, response rate, and toxic effects. Results: A total of 383 patients (median [range] age, 48 [19-70] years; 100 women [26%]). Median follow-up time was 76 months (IQR, 70-89 months). The 3-year progression-free survival was 76.2% and 76.8% in the IC-RT (n = 193) and IC-CCRT groups (n = 190), respectively, in the intention-to-treat population, showing a difference of 0.6% (95% CI, -7.9% to 9.1%; P = .01 for noninferiority). Identical outcomes were reported in the per-protocol population. The incidence of grade 3 to 4 short-term toxic effects in the IC-RT group was less than the IC-CCRT group. No differences were observed in late toxic effects. Conclusions and Relevance: The results of this randomized clinical trial suggest that after induction chemotherapy for locoregionally advanced nasopharyngeal carcinoma, radiotherapy alone was noninferior to chemoradiotherapy in terms of 3-year progression-free survival. Trial Registration: ClinicalTrials.gov Identifier: NCT02434614.

Intensity-modulated radiotherapy alone compared with intensity-modulated radiotherapy plus concurrent chemotherapy in intermediate-risk nasopharyngeal carcinoma : A prospective multicenter phase II trial.

BACKGROUND: This study aimed to investigate the clinical benefit of adding concurrent chemotherapy to intensity-modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC) patients with an intermediate risk (stage II and T3N0M0). METHODS: A multicenter phase II randomized trial was conducted in intermediate-risk NPC patients. Enrolled patients were previously untreated and aged ranged from 18 to 70 years without severe coexisting diseases. Patients were randomly assigned to receive IMRT alone or IMRT+concurrent chemotherapy (CC; three cycles of 80 mg/m2 cisplatin every 3 weeks). Primary endpoint was defined as 3­year progression-free survival (PFS). The secondary endpoints were distant metastasis-free survival (DMFS), locoregional relapse-free survival (LRRFS), overall survival (OS), and treatment-associated toxicity. We registered this study with Chinese Clinical Trial Registry (CliCTR1800017132; registered July 13, 2018, study start July 13, 2018). RESULTS: From November 2015 to July 2019, 42 patients with stage II and T3N0M0 NPC were enrolled; 20 patients received IMRT alone while 22 patients received IMRT+CC. After a median of 58 months of follow-up, we estimated the 3­year PFS rates as 90% (IMRT group) and 86.4% (IMRT+CC group; hazard ratio 1.387, 95% confidence interval 0.240-8.014; P = 0.719). The 3­year PFS, OS, and cumulative DMFS and LRRFS showed no significant differences between the two groups (P > 0.05). However, the IMRT group displayed a lower incidence of nausea/vomiting, leucopenia, and dry mouth than the IMRT+CC group. CONCLUSION: Adding CC to IMRT provided no survival benefit but increased treatment-associated toxicities in patients with intermediate-risk NPC.

Palmitoylation landscapes across human cancers reveal a role of palmitoylation in tumorigenesis.

BACKGROUND: Protein palmitoylation, which is catalyzed by palmitoyl-transferase and de-palmitoyl-transferase, plays a crucial role in various biological processes. However, the landscape and dynamics of protein palmitoylation in human cancers are not well understood. METHODS: We utilized 23 palmitoyl-acyltransferases and seven de-palmitoyl-acyltransferases as palmitoylation-related genes for protein palmitoylation analysis. Multiple publicly available datasets were employed to conduct pan-cancer analysis, examining the transcriptome, genomic alterations, clinical outcomes, and correlation with c-Myc (Myc) for palmitoylation-related genes. Real-time quantitative PCR and immunoblotting were performed to assess the expression of palmitoylation-related genes and global protein palmitoylation levels in cancer cells treated with Myc depletion or small molecule inhibitors. Protein docking and drug sensitivity analyses were employed to predict small molecules that target palmitoylation-related genes. RESULTS: We identified associations between palmitoylation and cancer subtype, stage, and patient survival. We discovered that abnormal DNA methylation and oncogenic Myc-driven transcriptional regulation synergistically contribute to the dysregulation of palmitoylation-related genes. This dysregulation of palmitoylation was closely correlated with immune infiltration in the tumor microenvironment and the response to immunotherapy. Importantly, dysregulated palmitoylation was found to modulate canonical cancer-related pathways, thus influencing tumorigenesis. To support our findings, we performed a proof-of-concept experiment showing that depletion of Myc led to reduced expression of most palmitoylation-related genes, resulting in decreased global protein palmitoylation levels. Through mass spectrometry and enrichment analyses, we also identified palmitoyl-acyltransferases ZDHHC7 and ZDHHC23 as significant contributors to mTOR signaling, DNA repair, and immune pathways, highlighting their potential roles in tumorigenesis. Additionally, our study explored the potential of three small molecular (BI-2531, etoposide, and piperlongumine) to modulate palmitoylation by targeting the expression or activity of palmitoylation-related genes or enzymes. CONCLUSIONS: Overall, our findings underscore the critical role of dysregulated palmitoylation in tumorigenesis and the response to immunotherapy, mediated through classical cancer-related pathways and immune cell infiltration. Additionally, we propose that the aforementioned three small molecule hold promise as potential therapeutics for modulating palmitoylation, thereby offering novel avenues for cancer therapy.

Featured interactome of homocysteine-inducible endoplasmic reticulum protein uncovers novel binding partners in response to ER stress.

Homocysteine-inducible endoplasmic reticulum protein (HERP) is an endoplasmic reticulum (ER)-resident protein and important for the adaptation of cellular protein homeostasis by ER-associated degradation (ERAD) system. HERP interactors are critical for cellular viability and the reaction to ER stress. To explore the exact mechanisms by which HERP performed the biological functions, we conducted an interaction analysis of HERP protein in HeLa cells by co-immunoprecipitation (Co-IP) and liquid chromatography-mass spectrometer (LC-MS)/MS coupled with label-free quantification (LFQ). Among the interactome results, 123 proteins significantly interacted with HERP, which leads to numerous biological processes including protein import into nucleus, ubiquitin-dependent ERAD pathway, negative regulation of apoptotic process, and protein transport from ER, along with multiple pathways including several diseases, protein processing in ER, fatty acid metabolism, and steroid biosynthesis. Furthermore, we selected several prey proteins from the interactome data and confirmed that HERP interacted with ancient ubiquitous protein 1 (AUP1), Fas-associated factor family member 2 (FAF2), tripartite motif containing 47 (TRIM47), acyl-CoA synthetase long-chain family member 3 (ACSL3), sequestosome 1 (SQSTM1), and poly(rC) binding protein 2 (PCBP2) by Co-IP and confocal microscopy experiments, respectively. Moreover, the expression and location of several interacted proteins were obviously altered in response to ER stress induced by Thapsigargin stimulation and Enterovirus 71 infection. In conclusion, our findings revealed that the vital proteins interacted with HERP to mediate signaling transduction, thus providing novel clues for the mechanisms of HERP associated with ERAD and metabolism in response to ER stress under physiological and pathological conditions.

Optical time-stretch imaging flow cytometry in the compressed domain.

Imaging flow cytometry based on optical time-stretch (OTS) imaging combined with a microfluidic chip attracts much attention in the large-scale single-cell analysis due to its high throughput, high precision, and label-free operation. Compressive sensing has been integrated into OTS imaging to relieve the pressure on the sampling and transmission of massive data. However, image decompression brings an extra overhead of computing power to the system, but does not generate additional information. In this work, we propose and demonstrate OTS imaging flow cytometry in the compressed domain. Specifically, we constructed a machine-learning network to analyze the cells without decompressing the images. The results show that our system enables high-quality imaging and high-accurate cell classification with an accuracy of over 99% at a compression ratio of 10%. This work provides a viable solution to the big data problem in OTS imaging flow cytometry, boosting its application in practice.

Natural Oncolysis of Enterovirus 71 in Antitumor Therapy of Colorectal Cancer.

Colorectal cancer (CRC) is an intestinal malignant tumor with high morbidity and mortality worldwide. Inoperability or resistanance to radiation and chemotherapy occur in the conventional treatments against CRC. Oncolytic viruses (OVs) are one kind of virus that selectively infects and lyses cancer cells, which is considered to be a new anticancer therapy with biological and immune-based approaches. Enterovirus 71 (EV71), belonging to the enterovirus genus in the family Picornaviridae, is a single positive-stranded RNA virus. EV71 is transmitted in a fetal-oral route and infects gastrointestinal tract in infants. Here, EV71 is exploited to be a novel oncolytic virus in colorectal cancer. It is revealed that EV71 infection can selectively cause colorectal cancer cells cytotoxicity but not primary intestinal epithelial cells. Consistently, EV71 injection significantly inhibits tumor growth in nude mice xenografted colorectal cancer cells. In detail, EV71 infects colorectal cancer cells to repress the expression of Ki67 and B-cell leukemia 2 (Bcl-2) leading to the inhibition of cell proliferation, while activating the cleavage of poly-adenosine diphosphatase-ribose polymerase and Caspase-3 protein resulting in the promotion of cell apoptosis. The findings demonstrate the oncolytic feature of EV71 in CRC treatment and may provide a potential clue for clinical anticancer therapy.

Cell damage evaluation by intelligent imaging flow cytometry.

Essential thrombocythemia (ET) is an uncommon situation in which the body produces too many platelets. This can cause blood clots anywhere in the body and results in various symptoms and even strokes or heart attacks. Removing excessive platelets using acoustofluidic methods receives extensive attention due to their high efficiency and high yield. While the damage to the remaining cells, such as erythrocytes and leukocytes is yet evaluated. Existing cell damage evaluation methods usually require cell staining, which are time-consuming and labor-intensive. In this paper, we investigate cell damage by optical time-stretch (OTS) imaging flow cytometry with high throughput and in a label-free manner. Specifically, we first image the erythrocytes and leukocytes sorted by acoustofluidic sorting chip with different acoustic wave powers and flowing speed using OTS imaging flow cytometry at a flowing speed up to 1 m/s. Then, we employ machine learning algorithms to extract biophysical phenotypic features from the cellular images, as well as to cluster and identify images. The results show that both the errors of the biophysical phenotypic features and the proportion of abnormal cells are within 10% in the undamaged cell groups, while the errors are much greater than 10% in the damaged cell groups, indicating that acoustofluidic sorting causes little damage to the cells within the appropriate acoustic power, agreeing well with clinical assays. Our method provides a novel approach for high-throughput and label-free cell damage evaluation in scientific research and clinical settings.

Typing of acute leukemia by intelligent optical time-stretch imaging flow cytometry on a chip.

Acute leukemia (AL) is one of the top life-threatening diseases. Accurate typing of AL can significantly improve its prognosis. However, conventional methods for AL typing often require cell staining, which is time-consuming and labor-intensive. Furthermore, their performance is highly limited by the specificity and availability of fluorescent labels, which can hardly meet the requirements of AL typing in clinical settings. Here, we demonstrate AL typing by intelligent optical time-stretch (OTS) imaging flow cytometry on a microfluidic chip. Specifically, we employ OTS microscopy to capture the images of cells in clinical bone marrow samples with a spatial resolution of 780 nm at a high flowing speed of 1 m s-1 in a label-free manner. Then, to show the clinical utility of our method for which the features of clinical samples are diverse, we design and construct a deep convolutional neural network (CNN) to analyze the cellular images and determine the AL type of each sample. We measure 30 clinical samples composed of 7 acute lymphoblastic leukemia (ALL) samples, 17 acute myelogenous leukemia (AML) samples, and 6 samples from healthy donors, resulting in a total of 227 620 images acquired. Results show that our method can distinguish ALL and AML with an accuracy of 95.03%, which, to the best of our knowledge, is a record in label-free AL typing. In addition to AL typing, we believe that the high throughput, high accuracy, and label-free operation of our method make it a potential solution for cell analysis in scientific research and clinical settings.

Identification and Analysis of Senescence-Related Genes in Head and Neck Squamous Cell Carcinoma by a Comprehensive Bioinformatics Approach.

Head and neck cancer is the sixth most frequent cancer all over the world, with the majority of subtypes of head and neck squamous cell carcinoma (HNSCC). Cellular senescence-associated genes have been confirmed to play a critical role in cancer and have the potential to be prognostic biomarkers for cancer. Clinical information of HNSCC samples and expression data were acquired from public databases. Expression profiles of genes related to cellular senescence were used to identify molecular subtypes by consensus clustering. To screen differentially expressed genes (DEGs) between different subtypes, differential analysis was performed. We used the univariate Cox regression to identify prognostic DEGs and performed least absolute shrinkage and selection operator (LASSO) to optimize and construct a prognostic model. CIBERSORT, ESTIMATE, and TIDE tools were applied to estimate immune characteristics. Four molecular subtypes were established based on cellular senescence-associated genes. Differential prognosis was observed among different subtypes with C4 having the longest overall survival and C1 having the worst prognosis. C4 subtype also showed the highest immune infiltration. We screened a total of eight cellular senescence prognosis-related genes and established a cellular senescence-related signature score (CSRS.Score) that could stratify samples into high-CSRS.Score and low-CSRS.Score groups. The high-CSRS.Score group had worse prognosis, lower immune infiltration, and lower response to immunotherapy. We further improved the prognostic model and survival prediction by combining CSRS.Score with clinicopathological features using a decision tree model, which had high predictive accuracy and survival prediction. This study demonstrated an important role of cellular senescence in HNSCC. The identified eight cellular senescence-associated genes have the potential to provide ideas for adjuvant treatment and personalized treatment of HNSCC patients.

An integrated microfluidics platform with high-throughput single-cell cloning array and concentration gradient generator for efficient cancer drug effect screening.

BACKGROUND: Tumor cell heterogeneity mediated drug resistance has been recognized as the stumbling block of cancer treatment. Elucidating the cytotoxicity of anticancer drugs at single-cell level in a high-throughput way is thus of great value for developing precision therapy. However, current techniques suffer from limitations in dynamically characterizing the responses of thousands of single cells or cell clones presented to multiple drug conditions. METHODS: We developed a new microfluidics-based "SMART" platform that is Simple to operate, able to generate a Massive single-cell array and Multiplex drug concentrations, capable of keeping cells Alive, Retainable and Trackable in the microchambers. These features are achieved by integrating a Microfluidic chamber Array (4320 units) and a six-Concentration gradient generator (MAC), which enables highly efficient analysis of leukemia drug effects on single cells and cell clones in a high-throughput way. RESULTS: A simple procedure produces 6 on-chip drug gradients to treat more than 3000 single cells or single-cell derived clones and thus allows an efficient and precise analysis of cell heterogeneity. The statistic results reveal that Imatinib (Ima) and Resveratrol (Res) combination treatment on single cells or clones is much more efficient than Ima or Res single drug treatment, indicated by the markedly reduced half maximal inhibitory concentration (IC50). Additionally, single-cell derived clones demonstrate a higher IC50 in each drug treatment compared to single cells. Moreover, primary cells isolated from two leukemia patients are also found with apparent heterogeneity upon drug treatment on MAC. CONCLUSION: This microfluidics-based "SMART" platform allows high-throughput single-cell capture and culture, dynamic drug-gradient treatment and cell response monitoring, which represents a new approach to efficiently investigate anticancer drug effects and should benefit drug discovery for leukemia and other cancers.

BM-Net: CNN-Based MobileNet-V3 and Bilinear Structure for Breast Cancer Detection in Whole Slide Images.

Breast cancer is one of the most common types of cancer and is the leading cause of cancer-related death. Diagnosis of breast cancer is based on the evaluation of pathology slides. In the era of digital pathology, these slides can be converted into digital whole slide images (WSIs) for further analysis. However, due to their sheer size, digital WSIs diagnoses are time consuming and challenging. In this study, we present a lightweight architecture that consists of a bilinear structure and MobileNet-V3 network, bilinear MobileNet-V3 (BM-Net), to analyze breast cancer WSIs. We utilized the WSI dataset from the ICIAR2018 Grand Challenge on Breast Cancer Histology Images (BACH) competition, which contains four classes: normal, benign, in situ carcinoma, and invasive carcinoma. We adopted data augmentation techniques to increase diversity and utilized focal loss to remove class imbalance. We achieved high performance, with 0.88 accuracy in patch classification and an average 0.71 score, which surpassed state-of-the-art models. Our BM-Net shows great potential in detecting cancer in WSIs and is a promising clinical tool.

Nomogram for distant metastasis-free survival in patients with locoregionally advanced nasopharyngeal carcinoma.

OBJECTIVE: To develop and validate a nomogram to predict distant metastasis-free survival of patients with locoregionally advanced nasopharyngeal carcinoma. METHODS: We collected the total clinical data of 820 nasopharyngeal carcinoma (NPC) patients, of whom 482 formed the training cohort from one hospital and 328 made up the validation cohort from another hospital. By analyzing the prognosis of all patients after intensity-modulated radiotherapy by univariate and multivariate Cox regression models, a nomogram related to DMFS was created in the training cohort. The discriminatory and calibration power of the nomogram was successively assessed in the training and validation cohorts by the C­index and calibration curve. The predictive ability for 3­year DMFS was compared between the nomogram and TNM stage using ROC curves. Patients were divided into different risk groups based on scores calculated from the nomogram. RESULTS: Age, lymph node gross tumor volume (GTVnd), and gross tumor volume of the nasopharynx (GTVnx) were the factors included in the nomogram. The C­index of the nomogram was 0.721 in the training cohort and 0.750 in the validation cohort. The calibration curves were satisfactory. Patients in the high-risk group were more likely to develop metastases. CONCLUSION: A nomogram incorporating age, GTVnd, and GTVnx showed good performance for predicting DMFS in patients with locoregionally advanced NPC.

Apatinib for the treatment of metastatic or locoregionally recurrent nasopharyngeal carcinoma after failure of chemotherapy: A multicenter, single-arm, prospective phase 2 study.

BACKGROUND: The authors aimed to investigate the efficacy and safety of apatinib in patients with metastatic or locoregionally recurrent nasopharyngeal carcinoma (NPC). METHODS: A multicenter, single-arm, prospective phase 2 study was conducted on patients (18-70 years of age) with metastatic or recurrent NPC who had failed chemotherapy. Patients with recurrent disease involving vascular structure invasion were excluded. All enrolled patients received apatinib (500 mg daily) in continuous 4-week cycles until disease progression or development of unacceptable toxicity. The primary end point of this study was objective response rate (ORR), and the secondary end points were progression-free survival (PFS), overall survival (OS), and toxicity. This study was registered with ClinicalTrials.gov (NCT03130270). RESULTS: Between January 2017 and June 2018, 33 patients were enrolled. At the end of the data collection (May 20, 2020), the 33 patients had completed a total of 261.2 cycles of apatinib. Although 12 patients achieved a partial response, no patient achieved a complete response; thus, the ORR in the 33 patients was 36.4% (95% CI, 19.0%-53.7%). At the end of follow-up (median, 30 months; 95% CI, 24.9-35.1), median OS and median PFS were 16 months (95% CI, 14.6-17.4 months) and 5.0 months (95% CI, 3.6-6.4 months), respectively. The most common adverse events (grade 1/2) were hand-foot syndrome (18 [54.5%]), hypertension (14 [42.4%]), oral ulcer (8 [24.2%]), and proteinuria (4 [12.1%]). Two patients (1 with diabetes and 1 with hypertension) developed cerebral infarction. Grade 3/4 toxicities were uncommon. CONCLUSIONS: Apatinib shows promising activity, with manageable toxicities, in patients with metastatic or locoregionally recurrent NPC. Further evaluation of apatinib in large-scale studies is warranted. LAY SUMMARY: Clinical studies on vascular endothelial growth factor receptor (VEGFR)-targeted therapy for recurrent or metastatic nasopharyngeal carcinoma (NPC) are limited. A recent preclinical study that evaluated apatinib in models of NPC showed a high objective response rate and a favorable safety profile. Our data further confirmed good efficacy in patients with lung metastasis. Further studies of the efficacy and safety of apatinib combined with immune checkpoint inhibitors or chemotherapy in NPC is warranted.

Dysregulation of miR-138-5p/RPS6KA1-AP2M1 Is Associated With Poor Prognosis in AML.

Acute myeloid leukemia (AML) is a malignant disease of hematopoietic stem/progenitor cells, and most AML patients are in a severe state. Internal tandem duplication mutations in FLT3 gene (FLT3-ITD) detected in AML stem cells account for 20-30 percent of AML patients. In this study, we attempted to study the impact of the interaction of FLT3-ITD mutation and the CXCL12/CXCR4 axis in AML, and the possible mechanisms caused by the impact by bioinformatics. Gene set variation analysis (GSVA) revealed that the PI3K-Akt-mTOR pathway positively correlated with the status of FLT3-ITD mutation. Multiple survival analyses were performed on TCGA-AML to screen the prognostic-related genes, and RPS6KA1 and AP2M1 are powerful prognostic candidates for overall survival in AML. WGCNA, KEGG/GO analysis, and the functional roles of RPS6KA1 and AP2M1 in AML were clarified by correlation analysis. We found that the expression levels of RPS6KA1 and AP2M1 were significantly associated with chemoresistance of AML, and the CXCL12/CXCR4 axis would regulate RPS6KA1/AP2M1 expression. Besides, miR-138-5p, regulated by the CXCL12/CXCR4 axis, was the common miRNA target of RPS6KA1 and AP2M1. Taken together, the interaction of FLT3-ITD mutation and the CXCL12/CXCR4 axis activated the PI3K-Akt-mTOR pathway, and the increased expression of RPS6KA1 and AP2M1 caused by hsa-miR-138-5p downregulation regulates the multi-resistance gene expression leading to drug indications.

Feasibility and efficiency of double-agent versus single-agent concurrent chemoradiotherapy in patients with nasopharyngeal carcinoma.

PURPOSE: Concurrent chemoradiotherapy (CCRT) is the mainstay of treatment for nasopharyngeal carcinoma (NPC) patients. It remains unclear whether double-agent CCRT (d-CCRT) is more effective than single-agent CCRT (s-CCRT). In this study, we compared the treatment efficiency and toxicity of d-CCRT with s-CCRT in NPC patients. METHODS AND MATERIALS: Patients with stage II-IV NPC treated with d-CCRT or s-CCRT were retrospectively reviewed. The d-CCRT group patients were compared with s-CCRT group patients for overall survival (OS), locoregional relapse-free survival (LRRFS), disease-free survival (DFS), distant metastasis-free survival (DMFS) and toxicity. Differences in baseline characteristics were adjusted using the pair-matching method. RESULTS: In this study, 933 patients who received CCRT for NPC between 2011 and 2014 were pair-matched at a 1:2 ratio (n = 311 for d-CCRT; n = 622 for s-CCRT). The d-CCRT treated patients showed no significant advantages in terms of 4-year OS (87.2% vs. 85.5%), DFS (84.1% vs. 79.5%), LRRFS (94.6% vs. 91.8%), DMFS (87.5% vs. 85.5%) compared with s-CCRT treated patients (P = 0.450, 0.106, 0.203, 0.366, respectively). Multivariate analysis showed that CCRT regimen had no significant effects on survival. In the d-CCRT group, the incidence of grade 3-4 hematological toxicities was significantly higher. CONCLUSIONS: The d-CCRT regimen did not confer significant survival benefits compared with the s-CCRT regimen in the treatment of stage II-IV NPC patients. Furthermore, patients treated with the d-CCRT regimen experienced greater hematological toxicity.

Analysis of the Interaction Network of Hub miRNAs-Hub Genes, Being Involved in Idiopathic Pulmonary Fibers and Its Emerging Role in Non-small Cell Lung Cancer.

Idiopathic pulmonary fibrosis (IPF) is a fibrotic interstitial lung disease with lesions confined to the lungs. To identify meaningful microRNA (miRNA) and gene modules related to the IPF progression, GSE32537 (RNA-sequencing data) and GSE32538 (miRNA-sequencing data) were downloaded and processed, and then weighted gene co-expression network analysis (WGCNA) was applied to construct gene co-expression networks and miRNA co-expression networks. GSE10667, GSE70866, and GSE27430 were used to make a reasonable validation for the results and evaluate the clinical significance of the genes and the miRNAs. Six hub genes (COL3A1, COL1A2, OGN, COL15A1, ASPN, and MXRA5) and seven hub miRNAs (hsa-let-7b-5p, hsa-miR-26a-5p, hsa-miR-25-3p, hsa-miR-29c-3p, hsa-let-7c-5p, hsa-miR-29b-3p, and hsa-miR-26b-5p) were clarified and validated. Meanwhile, iteration network of hub miRNAs-hub genes was constructed, and the emerging role of the network being involved in non-small cell lung cancer (NSCLC) was also analyzed by several webtools. The expression levels of hub genes were different between normal lung tissues and NSCLC tissues. Six genes (COL3A1, COL1A2, OGN, COL15A1, ASPN, and MXRA5) and three miRNAs (hsa-miR-29c-3p, hsa-let-7c-5p, and hsa-miR-29b-3p) were related to the survival time of lung adenocarcinoma (LUAD). The interaction network of hub miRNAs-hub genes might provide common mechanisms involving in IPF and NSCLC. More importantly, useful clues were provided for clinical treatment of both diseases based on novel molecular advances.

Screening and Functional Analysis of Hub MicroRNAs Related to Tumor Development in Colon Cancer.

Various microRNAs (miRNAs) are of importance in the development of colon cancer, but most of the mechanisms of the miRNAs are still unclear. In order to clarify the hub miRNAs and their roles in colon cancer development, GSE98406 was used to screen hub miRNAs by bioinformatics analysis. 46 DE-miRNAs (14 were upregulated and 32 were downregulated) and 1738 target genes of DE-miRNAs were ascertained. miRNAs-gene-networks and miRNAs-GO-networks were built to get more knowledge about the function of candidate miRNAs. After validation, three miRNAs (miR-17-5p, miR-182-5p and miR-200a-3p) were recognized to be hub miRNAs associated with the progression of colon cancer. More importantly, the hub miRNAs and the putative targets genes might be new diagnostic and therapeutic targets for colon cancer in the future.

Effects of hub genes on the clinicopathological and prognostic features of lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is a common malignancy; however, the majority of its underlying molecular mechanisms remain unknown. In the present study, weighted gene co-expression network analysis was applied to construct gene co-expression networks for the GSE19804 dataset, in order to screen hub genes associated with the pathogenesis of LUAD. In addition, with the aid of the Database for Annotation, Visualization and Integrated Discovery, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes, pathway enrichment analyses were performed on the genes in the selected module. Using the GSE40791 dataset and The Cancer Genome Atlas database, the hub genes were identified. It was discovered that the turquoise module was the most significant module associated with the tumor stage of LUAD. After performing functional enrichment analyses, it was indicated that the turquoise module was mainly enriched in signal transduction. Additionally, at the transcriptional and translational level, nine hub genes were identified and validated: Carbonic anhydrase 4 (CA4), platelet and endothelial cell adhesion molecule 1 (PECAM1), DnaJ member B4 (DNAJB4), advanced glycosylation end-product specific receptor (AGER), GTPase, IMAP family member 6 (GIMAP6), chromosome 10 open reading frame 54 (C10orf54), dedicator of cytokinesis 4 (DOCK4), Golgi membrane protein 1 (GOLM1) and platelet activating factor acetylhydrolase 1b catalytic subunit 3 (PAFAH1B3). CA4, PECAM1, DNAJB4, AGER, GIMAP6, C10orf54 and DOCK4 were expressed at lower levels in the tumor samples, whereas GOLM1 and PAFAH1B3 were highly expressed in tumor samples. In addition, all hub genes were associated with prognosis. In conclusion, one module and nine genes were recognized to be associated with the tumor stage of LUAD. These findings may enhance the understanding of the progression and prognosis of LUAD.

Comprehensive Analysis of Competitive Endogenous RNAs Network, Being Associated With Esophageal Squamous Cell Carcinoma and Its Emerging Role in Head and Neck Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a common malignancy with poor prognosis and survival rate. To identify meaningful long non-coding RNA (lncRNA), microRNA (miRNA), and messenger RNA (mRNA) modules related to the ESCC prognosis, The Cancer Genome Atlas-ESCC was downloaded and processed, and then, a weighted gene co-expression network analysis was applied to construct lncRNA co-expression networks, miRNA co-expression networks, and mRNA co-expression networks. Twenty-one hub lncRNAs, seven hub miRNAs, and eight hub mRNAs were clarified. Additionally, a competitive endogenous RNAs network was constructed, and the emerging role of the network involved in head and neck squamous cell carcinoma (HNSCC) was also analyzed using several webtools. The expression levels of eight hub genes (TBC1D2, ATP6V0E1, SPI1, RNASE6, C1QB, C1QC, CSF1R, and C1QA) were different between normal esophageal tissues and HNSCC tissues. The expression levels of TBC1D2 and ATP6V0E1 were related to the survival time of HNSCC. The competitive endogenous RNAs network might provide common mechanisms involving in ESCC and HNSCC. More importantly, useful clues were provided for clinical treatments of both diseases based on novel molecular advances.

Association Between TP53 Gene Codon 72 Polymorphism and Acute Myeloid Leukemia Susceptibility: Evidence Based on a Meta-Analysis.

BACKGROUND: Many studies have reported that the p53 codon 72 polymorphism is associated with acute myeloid leukemia (AML) susceptibility; however, the conclusions are inconsistent. Therefore, we performed this meta-analysis to obtain a more precise result. MATERIAL AND METHODS: We searched PubMed to identify relevant studies, and 6 published case-control studies were retrieved, including 924 AML patients and 3832 controls. Odds ratio (OR) with corresponding 95% confidence interval (95%CI) was applied to assess the association between p53 codon 72 polymorphism and AML susceptibility. The meta-analysis was performed with Comprehensive Meta-Analysis software, version 2.2. RESULTS: Overall, no significant association between p53 codon 72 polymorphism and AML susceptibility was found in this meta-analysis (Pro vs. Arg: OR=0.94, 95%CI=0.81-1.10; Pro/Pro vs. Arg/Arg: OR=0.93, 95%CI=0.71-1.22; Arg/Pro vs. Arg/Arg: OR=0.79, 95%CI=0.55-1.13; (Pro/Pro + Arg/Pro) vs. Arg/Arg: OR=0.84, 95%CI=0.62-1.13; Pro/Pro vs. (Arg/Arg + Arg/Pro): OR=1.06, 95%CI=0.83-1.35). Similar results were also found in stratified analysis according to ethnicity and source of controls. CONCLUSIONS: Our meta-analysis demonstrates that p53 codon 72 polymorphism may not be a risk factor for AML, which should be verified in future studies.