Integrative Proteomic Characterization of Human Lung Adenocarcinoma.

Genomic studies of lung adenocarcinoma (LUAD) have advanced our understanding of the disease's biology and accelerated targeted therapy. However, the proteomic characteristics of LUAD remain poorly understood. We carried out a comprehensive proteomics analysis of 103 cases of LUAD in Chinese patients. Integrative analysis of proteome, phosphoproteome, transcriptome, and whole-exome sequencing data revealed cancer-associated characteristics, such as tumor-associated protein variants, distinct proteomics features, and clinical outcomes in patients at an early stage or with EGFR and TP53 mutations. Proteome-based stratification of LUAD revealed three subtypes (S-I, S-II, and S-III) related to different clinical and molecular features. Further, we nominated potential drug targets and validated the plasma protein level of HSP 90ß as a potential prognostic biomarker for LUAD in an independent cohort. Our integrative proteomics analysis enables a more comprehensive understanding of the molecular landscape of LUAD and offers an opportunity for more precise diagnosis and treatment.

Spatial distribution pattern of immune cells is associated with patient prognosis in colorectal cancer.

BACKGROUND: The spatial context of tumor-infiltrating immune cells (TIICs) is important in predicting colorectal cancer (CRC) patients' clinical outcomes. However, the prognostic value of the TIIC spatial distribution is unknown. Thus, we aimed to investigate the association between TIICs in situ and patient prognosis in a large CRC sample. METHODS: We implemented multiplex immunohistochemistry staining technology in 190 CRC samples to quantify 14 TIIC subgroups in situ. To delineate the spatial relationship of TIICs to tumor cells, tissue slides were segmented into tumor cell and microenvironment compartments based on image recognition technology, and the distance between immune and tumor cells was calculated by implementing the computational pipeline phenoptr. RESULTS: MPO+ neutrophils and CD68+IDO1+ tumor-associated macrophages (TAMs) were enriched in the epithelial compartment, and myeloid lineage cells were located nearest to tumor cells. Except for CD68+CD163+ TAMs, other cells were all positively associated with favorable prognosis. The prognostic predictive power of TIICs was highly related to their distance to tumor cells. Unsupervised clustering analysis divided colorectal cancer into three subtypes with distinct prognostic outcomes, and correlation analysis revealed the synergy among B cells, CD68+IDO1+TAMs, and T lineage cells in producing an effective immune response. CONCLUSIONS: Our study suggests that the integration of spatial localization with TIIC abundance is important for comprehensive prognostic assessment.

Anti-aging and rejuvenating effects and mechanism of Dead Sea water in skin.

OBJECTIVE: External environmental stressors and internal factors have a significant impact on the skin, causing inflammation, aging, reduced immunity and other adverse responses. Dead Sea Water (DSW) is well known for its dermatological benefits and has been widely used in dermatological therapy and skin care for conditions such as psoriasis, atopic dermatitis and photoaging. However, the anti-aging and rejuvenating effects of DSW and the related biological pathways involved, which have attracted increasing attention, are not fully understood. The aim of this study is to investigate the anti-aging and rejuvenating effects of DSW and to explore the related potential biological mechanisms of DSW under different environmental conditions. METHODS: The effects of DSW were investigated using in vitro human dermal cells and reconstructed skin models. Extracellular matrix (ECM) components and the morphological changes at the dermal-epidermal junction (DEJ) in a 3D human skin model were evaluated after DSW treatment. RNA sequencing (RNA-seq) analysis of human dermal fibroblast models after DSW treatment was performed to explore the potential mechanisms of action of DSW under normal and UV stress conditions. RESULTS: The novel findings in this work present the biological functions of DSW, including procollagen-1 and elastin secretion, hemidesmosome increase and the epidermal basal cell regeneration. In addition, GO, KEGG and Reactome analyses reveal the activation of pathways related to ion transmembrane transporter activity, ECM component biosynthesis, senescence-associated secretory phenotype (SASP), DNA repair and autophagy, which are associated with the anti-aging activities of DSW. CONCLUSION: Our work provides new perspectives for understanding the anti-aging and rejuvenating effects and mechanisms of DSW. The new findings also provide a theoretical basis for the further development of age-related strategies.

OBJECTIF: Les facteurs de stress environnementaux externes et les facteurs internes ont un impact significatif sur la peau, provoquant une inflammation, le vieillissement, une baisse de l'immunité et d'autres réactions indésirables. L'eau de la mer Morte est bien connue pour ses bienfaits dermatologiques, et a été largement utilisée dans le traitement dermatologique et les soins de la peau pour des affections telles que le psoriasis, la dermatite atopique et le photovieillissement. Cependant, les effets antivieillissement et rajeunissants de l'eau de la mer Morte et les voies biologiques connexes impliquées, qui font l'objet d'une attention croissante, ne sont pas entièrement compris. L'objectif de cette étude est d'étudier les effets antivieillissement et rajeunissants de l'eau de la mer Morte, et d'étudier les mécanismes biologiques potentiels liés à l'eau de la mer Morte dans différentes conditions environnementales. MÉTHODES: Les effets de l'eau de la mer Morte ont été étudiés à l'aide de cellules dermiques humaines in vitro et de modèles cutanés reconstruits. Les composants de la matrice extracellulaire (MEC) et les changements morphologiques au niveau de la jonction dermo­épidermique (JDE) dans un modèle 3D de peau humaine ont été évalués après le traitement avec de l'eau de la mer Morte. Une analyse de séquençage de l'ARN (ARN­seq) de modèles de fibroblastes dermiques humains après un traitement avec de l'eau de la mer Morte a été réalisée pour étudier les mécanismes d'action potentiels de l'eau de la mer Morte dans des conditions de stress normales et par UV. RÉSULTATS: Les nouveaux résultats de ce travail présentent les fonctions biologiques de l'eau de la mer Morte, y compris la sécrétion de procollagène­1 et d'élastine, l'augmentation des hémidesmosomes et la régénération des cellules basales épidermiques. En outre, les analyses GO, KEGG et Réactome révèlent l'activation de voies liées à l'activité des transporteurs transmembranaires d'ions, à la biosynthèse des composants de la MEC, au phénotype sécrétoire associé à la sénescence (Senescence­Associated Secretory Phenotype, SASP), à la réparation de l'ADN et à l'autophagie, qui sont associés aux activités antivieillissement de l'eau de la mer Morte. CONCLUSION: Notre travail apporte de nouvelles perspectives pour comprendre les effets et les mécanismes antivieillissement et rajeunissants de l'eau de la mer Morte. Les nouveaux résultats fournissent également une base théorique pour le développement ultérieur de stratégies liées à l'âge.

SIRPα antibody combined with oncolytic virus OH2 protects against tumours by activating innate immunity and reprogramming the tumour immune microenvironment.

BACKGROUND: The combination of oncolytic viruses (OVs) with immune checkpoint blockades is a research hotspot and has shown good efficacy. Here, we present the first attempt to combine oncolytic herpes simplex virus 2 (OH2) with an anti-SIRPα antibody as an antitumour treatment. Our results provide unique insight into the combination of innate immunity with OV. METHODS: We verified the polarization and activation of OH2 in RAW264.7 cells in vitro. Subsequently, we evaluated the antitumour ability of OH2 and anti-SIRPα combined therapy in a tumour-bearing mouse model. RNA-seq and Single-cell RNA-seq were used to characterize the changes in the tumour microenvironment. RESULTS: The OH2 lysates effectively stimulated RAW264.7 cells to polarize towards the M1 but not the M2 phenotype and activated the function of the M1 phenotype in vitro. In the macrophage clearance experiment, OH2 therapy induced polarization of M1 macrophages and participated in the antitumour immune response in a tumour-bearing mouse model. Treatment with a combination of OH2 and anti-SIRPα effectively inhibited tumour growth and significantly prolonged the survival time of the mice, and this result was more obvious in the mouse model with a larger tumour volume at the beginning of the treatment. These results suggest that combination therapy can more profoundly reshape the TME and activate stronger innate and adaptive immune responses. CONCLUSIONS: Our data support the feasibility of oncolytic virus therapy in combination with anti-SIRPα antibodies and suggest a new strategy for oncolytic virus therapy.

Decoding the colorectal cancer ecosystem emphasizes the cooperative role of cancer cells, TAMs and CAFsin tumor progression.

BACKGROUND: Single-cell transcription data provided unprecedented molecular information, enabling us to directly encode the ecosystem of colorectal cancer (CRC). Characterization of the diversity of epithelial cells and how they cooperate with tumor microenvironment cells (TME) to endow CRC with aggressive characteristics at single-cell resolution is critical for the understanding of tumor progression mechanism. METHODS: In this study, we comprehensively analyzed the single-cell transcription data, bulk-RNA sequencing data and pathological tissue data. In detail, cellular heterogeneity of TME and epithelial cells were analyzed by unsupervised classification and consensus nonnegative matrix factorization analysis, respectively. Functional status of epithelial clusters was annotated by CancerSEA and its crosstalk with TME cells was investigated using CellPhoneDB and correlation analysis. Findings from single-cell transcription data were further validated in bulk-RNA sequencing data and pathological tissue data. RESULTS: A distinct cellular composition was observed between tumor and normal tissues, and tumors exhibited immunosuppressive phenotypes. Regarding epithelial cells, we identified one highly invasiveQuery cluster, C4, that correlated closely with tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs). Further analysis emphasized the TAMs subclass TAM1 and CAFs subclass S5 are closely related with C4. CONCLUSIONS: In summary, our study elaborates on the cellular heterogeneity of CRC, revealing that TAMs and CAFs were critical for crosstalk network epithelial cells and TME cells. This in-depth understanding of cancer cell-TME network provided theoretical basis for the development of new drugs targeting this sophisticated network in CRC.

Identification of an ACK1/TNK2-based prognostic signature for colon cancer to predict survival and inflammatory landscapes.

Activated Cdc42-associated kinase 1 (ACK1), a kind of tyrosine kinase, is considered to be an oncogene in many cancers, and it is likely to become a potential target for cancer treatment. We found that the expression of the ACK1 gene in colon cancer was higher than that in normal tissues adjacent to cancer, and high expression of the ACK1 gene was associated with poor prognosis of patients. We assessed the prognosis of colon cancer based on ACK1-related genes and constructed a model that can predict the prognosis of colon cancer patients in colon cancer data from The Cancer Genome Atlas (TCGA) database. We then explored the relationship between ACK1 and the immune microenvironment of colon cancer. The overexpression of ACK1 might hinder the function of antigen-presenting cells. The colon cancer prognosis prediction model we constructed has certain significance for clinicians to judge the prognosis of patients with colon cancer. The expression of the ACK1 gene might affect the infiltration level of a variety of immune cells and immunomodulators in the immune microenvironment.

Mutagenic Characteristics of Six Heavy Metals in Escherichia coli: The Commonality and Specificity.

The history of long-term environmental exposure to heavy metals can be recorded in the genome as sporadic and specific mutations. Variable environments introduce diverse and adaptive mutations to organisms. To reveal the information hidden in genomes about environmental exposure to heavy metals, we performed long-term mutation accumulation (MA) experiments with Escherichia coli, analyzed genomes from 36 populations across 1650 generations with 6 heavy metal exposure regimes (arsenic, cadmium, chromium, copper, nickel, and lead), and inferred metal-specific evolution modes at the genomic level. All heavy metals induced genetic mutations with a mean rate of 3.459 × 10-9 per nucleotide per generation. The mutational spectrum exhibited distinct signatures; however, heavy metals also shared common mutation signatures prominently associated with all cancer types. The mutated genes showed an average similarity of 54.4% within the same exposure regime, whereas only 38.8% between exposure regimes. In terms of biological insights, mutated genes were enriched to fundamental cellular processes such as metabolism, motility, and transport. Our study elucidates the mutagenic commonality and specificity of environmental heavy metals, which are highly specific at mutational features and locus, but conserved at gene and functional levels, and may play crucial roles in the convergence of adaptation to heavy metals.

Multiomics Analysis Reveals Distinct Immunogenomic Features of Lung Cancer with Ground-Glass Opacity.

Rationale: Ground-glass opacity (GGO)-associated lung cancers are common and radiologically distinct clinical entities known to have an indolent clinical course and superior survival, implying a unique underlying biology. However, the molecular and immune characteristics of GGO-associated lung nodules have not been systemically studied. Objectives: To provide mechanistic insights for the treatment of these radiologically distinct clinical entities. Methods: We initiated a prospective cohort study to collect and characterize pulmonary nodules with GGO components (nonsolid and part-solid nodules) or without GGO components, as precisely quantified by using three-dimensional image reconstruction to delineate the molecular and immune features associated with GGO. Multiomics assessment conducted by using targeted gene panel sequencing, RNA sequencing, TCR (T-cell receptor) sequencing, and circulating tumor DNA detection was performed. Measurements and Main Results: GGO-associated lung cancers exhibited a lower tumor mutation burden than solid nodules. Transcriptomic analysis revealed a less active immune environment in GGO components and immune pathways, decreased expression of immune activation markers, and less infiltration of most immune-cell subsets, which was confirmed by using multiplex immunofluorescence. Furthermore, T-cell repertoire sequencing revealed lower T-cell expansion in GGO-associated lung cancers. HLA loss of heterozygosity was significantly less common in lung adenocarcinomas with GGO components than in those without. Circulating tumor DNA analysis suggested that the release of tumor DNA to the peripheral blood was correlated with the tumor size of non-GGO components. Conclusions: Compared with lung cancers presenting with solid lung nodules, GGO-associated lung cancers are characterized by a less active metabolism and a less active immune microenvironment, which may be the mechanisms underlying their indolent clinical course. Clinical trial registered with www.clinicaltrials.gov (NCT03320044).

Eco-risk management of tylosin fermentation residues using vermicomposting.

Tylosin fermentation residues (TFR) pose an ecotoxicological risk through antibiotic resistant bacteria (ARBs) and their corresponding genes (ARGs). This study evaluated the ecotoxicity of TFR to soil biological activity, and further explored the mechanisms of vermicomposting to reduce the toxicological risk. The results showed that tylosin (TYL) was moderately degradable with a half-life (t1/2) of 37.5 d, inducing 28-44% inhibition rate of nitrogen transformation in soil, and the EC50 of earthworm avoidance was 880 mg/kg. The 30-d vermicomposting reduced the pH and OM content, while increased the EC and TN content, accelerated compost maturation (C/N ratio up to 20), and enriched the microbial community. ARGs were reduced by earthworm through removal of TYL (>70% degradation, t1/2 of <20 d), inhibiting abundance of intI1 and ARBs. We conclude that vermicomposting is an efficient method for TFR treatment and its eco-risk management.

Peripheral blood transcriptome heterogeneity and prognostic potential in lung cancer revealed by RNA-Seq.

Understanding of the complex interaction between the peripheral immune system and lung cancer (LC) remains incomplete, limiting patient benefit. Here, we aimed to characterize the host peripheral immune response to LC and investigate its potential prognostic value. Bulk RNA-sequencing data of peripheral blood leucocytes (PBLs) from healthy volunteers and LC patients (n = 142) were analysed for characterization of host systemic immunity in LC. We observed broad blood transcriptome perturbations in LC patients that were heterogeneous, as two new subtypes were established independent of histology. Functionally, the heterogeneity between the two subtypes included dysregulation of diverse biological processes, such as the cell cycle, blood coagulation and inflammatory signalling pathways, together with the abundance and activity of blood cells, particularly lymphocytes and neutrophils, ultimately manifesting as differences in antitumour immune status. Based on these findings, a prognostic model composed of ten genes dysregulated in one LC subtype with relatively poor immune status was developed and validated in a Gene Expression Omnibus (GEO) data set (n = 108), helping to generate a prognostic nomogram. Collectively, our study provides novel and comprehensive insight into the heterogeneity of the host peripheral immune response to LC. The expression heterogeneity-based predictive model may help guide prognostic management for LC patients.

Telomerase-positive circulating tumor cells are associated with poor prognosis via a neutrophil-mediated inflammatory immune environment in glioma.

BACKGROUND: Gliomas are the most common aggressive cancer in the central nervous system. Considering the difficulty in monitoring glioma response and progression, an approach is needed to evaluate the progression or survival of patients with glioma. We propose an application to facilitate clinical detection and treatment monitoring in glioma patients by using telomerase-positive circulating tumor cells (CTCs) and to further evaluate the relationship between the immune microenvironment and CTCs in glioma patients. METHODS: From October 2014 to June 2017, 106 patients newly diagnosed with glioma were enrolled. We used the telomerase reverse transcriptase CTC detection method to detect and analyze the CTC statuses of glioma patients before and after surgery. FlowSight and FISH confirmed the CTCs detected by the telomerase-based method. To verify the correlation between CTCs and the immune response, peripheral white blood cell RNA sequencing was performed. RESULTS: CTCs were common in the peripheral blood of glioma patients and were not correlated with the pathological classification or grade of patients. The results showed that the presence of postoperative CTCs but not preoperative CTCs in glioma patients was a poor prognostic factor. The level of postoperative CTCs, which predicts a poor prognosis after surgery, may be associated with neutrophils. RNA sequencing suggested that postoperative CTCs were positively correlated with innate immune responses, especially the activation of neutrophils and the generation of neutrophil extracellular traps, but negatively correlated with the cytotoxic response. CONCLUSIONS: Our results showed that telomerase-positive CTCs can predict a poor prognosis of patients with glioma. Our results also showed a correlation between CTCs and the immune macroenvironment, which provides a new perspective for the treatment of glioma.

Breast cancer prognosis signature: linking risk stratification to disease subtypes.

Breast cancer is a very complex and heterogeneous disease with variable molecular mechanisms of carcinogenesis and clinical behaviors. The identification of prognostic risk factors may enable effective diagnosis and treatment of breast cancer. In particular, numerous gene-expression-based prognostic signatures were developed and some of them have already been applied into clinical trials and practice. In this study, we summarized several representative gene-expression-based signatures with significant prognostic value and separately assessed their ability of prognosis prediction in their originally targeted populations of breast cancer. Notably, many of the collected signatures were originally designed to predict the outcomes of estrogen receptor positive (ER+) patients or the whole breast cancer cohort; there are no typical signatures used for the prognostic prediction in a specific population of patients with the intrinsic subtype. We thus attempted to identify subtype-specific prognostic signatures via a computational framework for analyzing multi-omics profiles and patient survival. For both the discovery and an independent data set, we confirmed that subtype-specific signature is a strong and significant independent prognostic factor in the corresponding cohort. These results indicate that the subtype-specific prognostic signature has a much higher resolution in the risk stratification, which may lead to improved therapies and precision medicine for patients with breast cancer.

Non-SMC Condensin I Complex Subunit D2 Is a Prognostic Factor in Triple-Negative Breast Cancer for the Ability to Promote Cell Cycle and Enhance Invasion.

Triple-negative breast cancer (TNBC) is a heterogeneous disease with an unfavorable prognosis and no specific targeted therapies. The role of non-SMC condensin I complex subunit D2 (NCAPD2), a regulatory subunit of the condensin I complex that mainly participates in chromosome condensation and segregation, has not been reported in cancer. We therefore evaluated the prognostic value and biological function of NCAPD2 in TNBC. The expression of NCAPD2 was studied in 179 TNBC tissues by immunohistochemistry, and associations among NCAPD2 expression, clinicopathologic features, and the prognosis information of patients with TNBC were analyzed. The mRNA expression profiles of 99 TNBC tissues were also studied, and cell biological behaviors were detected when NCAPD2 was altered in three TNBC cell lines. NCAPD2 expression was positively associated with lymph node metastasis (P = 3.84 × 10-06), poor overall survival (P = 0.0033), and worse disease-free survival (P = 0.0013) of patients with TNBC. Moreover, knockdown of NCAPD2 might cause G2/M arrest through the p53 signaling pathway, which led to proliferation inhibition, polyploid cell production, and cell apoptosis and inhibited the invasiveness of TNBC cells. For the first time, we report the close association between NCAPD2 and cancer and demonstrate that NCAPD2 plays an important role in TNBC progression and acts as an independent poor prognostic factor and a potential therapeutic target for TNBC.

Antibacterial Mechanism of Liangguoan against Staphylococcus aureus and Escherichia coli.

This study examined the antibacterial activity of the biological pesticide Liangguoan against Staphylococcus aureus and Escherichia coli as a potential replacement for chemical pesticide use in the fruit and vegetable industry. We measured the minimum inhibitory concentration and observed the changes in bacterial morphology, mortality, conductivity, nucleic acid content, and ATP content in response to the bactericide. The minimum inhibitory concentration of Liangguoan was 20 mg/mL for S. aureus and 40 mg/mL for E. coli. After treatment with Liangguoan, the mortality rates of S. aureus and E. coli reached 78.3% and 63.7%, respectively. We observed that the cells were scattered and that the cell morphology was altered in that the cells shortened. The interconnection effect and ATP content decreased, whereas cell conductivity and the nucleic acid content increased. In summary, Liangguoan inhibited S. aureus and E. coli by destroying their cell structure and disrupting their metabolism.

Dissecting expression profiles of gastric precancerous lesions and early gastric cancer to explore crucial molecules in intestinal-type gastric cancer tumorigenesis.

Intestinal-type gastric cancer (IGC) has a clear and multistep histological evolution. No studies have comprehensively explored gastric tumorigenesis from inflammation through low-grade intraepithelial neoplasia (LGIN) and high-grade intraepithelial neoplasia (HGIN) to early gastric cancer (EGC). We sought to investigate the characteristics participating in IGC tumorigenesis and identify related prognostic information within the process. RNA expression profiles of 94 gastroscopic biopsies from 47 patients, including gastric precancerous lesions (GPL: LGIN and HGIN), EGC, and paired controls, were detected by Agilent Microarray. During IGC tumorigenesis from LGIN through HGIN to EGC, the number of activity-changed tumor hallmarks increased. LGIN and HGIN had similar expression profiles when compared to EGC. We observed an increase in the stemness of gastric epithelial cells in LGIN, HGIN, and EGC, and we found 27 consistent genes that might contribute to dedifferentiation, including five driver genes. Remarkably, we perceived that the immune microenvironment was more active in EGC than in GPL, especially in the infiltration of lymphocytes and macrophages. We identified a five-gene signature from the gastric tumorigenesis process that could independently predict the overall survival and disease-free survival of GC patients (log-rank test: p < 0.0001), and the robustness was verified in an independent cohort (n > 300) and by comparing with two established prognostic signatures in GC. In conclusion, during IGC tumorigenesis, cancer-like changes occur in LGIN and accumulate in HGIN and EGC. The immune microenvironment is more active in EGC than in LGIN and HGIN. The identified signature from the tumorigenesis process has robust prognostic significance for GC patients. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Circulating miR-19a-3p and miR-483-5p as Novel Diagnostic Biomarkers for the Early Diagnosis of Gastric Cancer.

BACKGROUND MicroRNAs (miRNAs) are attracting substantial interest as promising noninvasive biomarkers for gastric cancer (GC). Our study aimed to identify circulating miRNAs that are potential noninvasive markers for precancerous lesions and early gastric cancers (EGCs). MATERIAL AND METHODS Plasma specimens were obtained from 58 gastritis subjects, 54 patients with precancerous lesions, and 38 EGC patients for study. RESULTS Significant differences in the plasma expression levels of miR-19a-3p, miR-22-3p, miR-146a-5p, and miR-483-5p (all P<0.05) were observed between EGC patients and gastritis subjects. Multivariable analysis showed that age (OR, 1.054; 95% CI, 1.006-1.104), miR-19a-3p expression (OR, 3.676; 95% CI, 1.914-7.061), and miR-483-5p expression (OR, 1.589; 95% CI, 1.242-2.033) were independently associated with EGCs and precancerous lesions. A combined diagnostic model incorporating these 3 variables for the prediction of EGCs and precancerous lesions was derived. The area under the receiver operating characteristic curve (AUC) of the model was 0.84; the sensitivity was 87.7% and the specificity was 62.8% at the cutoff value of -0.08. CONCLUSIONS Plasma miR-19a-3p and miR-483-5p are promising and powerful noninvasive markers for the early detection of GC. Patients are more willing to undergo noninvasive diagnostic procedures than gastroscopy for cancer screening, economizing limited medical resources.

Revealing clonality and subclonality of driver genes for clinical survival benefits in breast cancer.

PURPOSE: Genomic studies have revealed that genomic aberrations play important roles in the progression of this disease. The aim of this study was to evaluate the associations between clinical survival outcomes of the clonality and subclonality status of driver genes in breast cancer. METHODS: We performed an integrated analysis to infer the clonal status of 55 driver genes in breast cancer data from TCGA. We used the chi-squared test to assess the relations between clonality of driver gene mutations and clinicopathological factors. The Kaplan-Meier method was performed for the visualization and the differences between survival curves were calculated by log-rank test. Univariate and multivariate Cox proportional hazards regression models were used to adjust for clinicopathological factors. RESULTS: We identified a high proportion of clonal mutations in these driver genes. Among them, there were 17 genes showing significant associations between their clonality and multiple clinicopathologic factors. Performing survival analysis on BRCA patients with clonal or subclonal driver gene mutations, we found that clonal ERBB2, FOXA1, and KMT2C mutations and subclonal GATA3 and RB1 mutations predicted shorter overall survival compared with those with wild type. Furthermore, clonal ERBB2 and FOXA1 mutations and subclonal GATA3 and RB1 mutations independently predicted for shorter overall survival after adjusting for clinicopathological factors. By longitudinal analysis, the clonality of ERBB2, FOXA1, GATA3, and RB1 significantly predicted patients' outcome within some specific BRCA tumor stages and histological subtypes. CONCLUSIONS: In summary, these clonal or subclonal mutations of driver genes have implications for diagnosis, prognosis, and treatment with BRCA patients.

Proliferation genes in lung development associated with the prognosis of lung adenocarcinoma but not squamous cell carcinoma.

There are many similarities between embryonic development and tumorigenesis, and gene expression profiles show that certain correlations exist between the gene signature during development and the clinical phenotypes of different cancers. Our group previously reported the gene expression profiles of human lung development, and the expression of one group of proliferation-related genes (PTN1 genes) steadily decreased during lung development. Here, we examined the prognostic value of PTN1 genes in 5 independent lung adenocarcinoma (ADC) and 5 lung independent squamous cell carcinoma (SCC) microarray datasets and found that the expression levels of PTN1 genes were associated with survival in lung ADC but not lung SCC. All of the lung ADC datasets contained a set of highly correlated genes from PTN1 genes, but the lung SCC datasets had no similar set of genes. We identified 63 unique core genes from the PTN1 genes in the 5 lung ADC datasets: 17 of these core genes appeared in at least 4 of the lung ADC datasets, and the 17 corresponding proteins clearly interacted more strongly with each other in lung ADC than in lung SCC. Moreover, 16 of the 17 core genes play major roles in the G2 /M phase of the cell cycle. These data indicate that proliferation-related genes in lung development have a significant prognostic value for lung ADC; the synergistic effects of the 17 core genes play an important role in lung ADC prognosis. These genes may have significant clinical implications for the treatment and prognosis of lung ADC.

RRS1 gene expression involved in the progression of papillary thyroid carcinoma.

BACKGROUND: Papillary thyroid carcinoma (PTC) is one of the most frequent malignancies of the endocrine system, whose mechanisms of pathogenesis, progression and prognosis are still far from being clearly elucidated. Despite an increasing body of evidences highlights ribosome biogenesis regulator homolog (RRS1) as a ribosome biogenesis protein in yeast and plants, little is known about human RRS1 function. METHODS: Proliferation, cell cycle and apoptosis of PTC cells were assessed following the knockdown of RRS1 expression though MTT, colony formation assay, and flow cytometry. Then, transcriptome profiling was conducted to explore pathway changes after RRS1 silencing in PTC cells. Receiver operating characteristic curve and Youden's index were performed in twenty-four thyroid carcinoma samples to assess their potential clinical diagnostic value. RESULTS: Firstly, we found that silencing RRS1 significantly reduced cell proliferation, inhibited cell cycle, and promoted apoptosis in PTC cell line. The result also showed that knock-down of RRS1 could up-regulate genes involving apoptosis and metabolism, while, down-regulate genes relative to cell proliferation and blood vessel development. Notably, the present study confirmed the diagnostic value of RRS1 for thyroid carcinoma in both children and adults. CONCLUSIONS: In conclusion, these data afford a comprehensive view of a novel function of human RRS1 by promoting cell proliferation and could be a potential indicator for papillary thyroid carcinoma.

Extensive ceRNA-ceRNA interaction networks mediated by miRNAs regulate development in multiple rhesus tissues.

Crosstalk between RNAs mediated by shared microRNAs (miRNAs) represents a novel layer of gene regulation, which plays important roles in development. In this study, we analyzed time series expression data for coding genes and long non-coding RNAs (lncRNAs) to identify thousands of interactions among competitive endogenous RNAs (ceRNAs) in four rhesus tissues. The ceRNAs exhibited dynamic expression and regulatory patterns during each tissue development process, which suggests that ceRNAs might work synergistically during different developmental stages or tissues to control specific functions. In addition, lncRNAs exhibit higher specificity as ceRNAs than coding-genes and their functions were predicted based on their competitive coding-gene partners to discover their important developmental roles. In addition to the specificity of tissue development, functional analyses demonstrated that the combined effects of multiple ceRNAs can have major impacts on general developmental and metabolic processes in multiple tissues, especially transcription-related functions where competitive interactions. Moreover, ceRNA interactions could sequentially and/or synergistically mediate the crosstalk among different signaling pathways during brain development. Analyzing ceRNA interactions during the development of multiple tissues will provideinsights in the regulation of normal development and the dysregulation of key mechanisms during pathogenesis.