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Colorectal cancer (CRC) is one of the most common cancers. Almost 80% of CRC cases are colon adenocarcinomas (COADs). Several studies have indicated the role of immunotherapy in the treatment of various cancers. Our study aimed to identify immune-related long non-coding RNAs (lncRNAs) and to use them to construct a risk assessment model for evaluating COAD prognosis. Using differential expression, correlation, and Cox regression analyses, we identified three immune-related differentially expressed lncRNAs (IR-DELs) and used them to construct a risk assessment model. The area under the curve (AUC) for each receiver operating characteristic (ROC) curve at 3-, 5-, and 10-years were greater than 0.6. In addition, the risk assessment model was correlated with several immune cells and factors. The three IR-DELs (AC124067.4, LINC02604, and MIR4435-2HG) identified in this study can be used to predict outcomes for patients with COAD and might help in identifying those who can benefit from anti-tumor immunotherapy.

Chen Fu,1,2 Zhaojin Yu,1,2 Ying He,1,3 Jian Ding,1,4 Minjie Wei1,2,5 1Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, People’s Republic of China; 2Liaoning Key Laboratory of Molecular Targeted Anti-tumor Drug Development and Evaluation, Department of Pharmacology, China Medical University, Shenyang, 110122, People’s Republic of China; 3Department of Oncology, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110000, People’s Republic of China; 4Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People’s Republic of China; 5Liaoning Medical Diagnosis and Treatment Center, Shenyang, 110000, People’s Republic of ChinaCorrespondence: Jian DingDivision of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People’s Republic of ChinaEmail carl.2000@163.comMinjie WeiDepartment of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, People’s Republic of ChinaEmail weiminjiecmu@163.comBackground: The relapse and distant metastasis in colon adenocarcinoma (COAD) patients with a poor prognosis. Autophagy has gained increasing attention recently.Methods: This study utilized univariate Cox analysis from the TCGA database to obtain 10 prognostic autophagy-related genes (ARGs). GO and KEGG functional annotation analysis suggested that the ARGs were significantly enriched in tumor metabolic processes. We verified the autophagy-related genes screened by TCGA clinical data. Then, we compared the expression of SERPINA1 in primary and metastatic tumor cells in the GEO database, and finally verified the relationship between SERPINA1 protein expression and prognosis with the CPTAC database.Results: The ROC curves showed SERPINA1 had robust prediction capability in judging the prognosis and disease process compared with the other 4 ARGs and risk score in COAD. Clinical relationship analysis further indicated SERPINA1 was related to TMN stage, clinical-stage, OS, RFS, and DMFS in COAD. Besides, survival analysis presented that higher expression of SERPINA1 was significantly associated with the longer OS, RFS, or DMFS. Moreover, SERPINA1 protein was validated to be associated with OS, RFS, and DMFS through our own IHC and CPTAC database. Finally, we exploratoryly combined the SERPINA1 mRNA and SERPINA1 protein as a new index for prognostics.Conclusion: This new combined index showed the highest prognostic value for OS, RFS, and DMFS, and had the potential to become a practical biomarker for prognosis.Keywords: SERPINA1, autophagy, COAD, prognostic, relapse, distant metastasis

Background: Colorectal cancer (CRC) is the most common type of gastrointestinal malignant tumour. Colorectal adenocarcinoma (COAD) – the most common type of CRC – is particularly dangerous. The role of the immune system in the development of tumour-associated inflammation and cancer has received increasing attention recently. Methods: In the present study, we compiled the expression profiles of 262 patients with complete follow-up data from The Cancer Genome Atlas (TCGA) database as an experimental group and selected 65 samples from the Gene Expression Omnibus (GEO) dataset (of which 46 samples were with M0) as a verification group. First, we screened the immune T helper 17 (Th17) cells related to the prognosis of COAD. Subsequently, we identified Th17 cells-related hub genes by utilising Weighted Gene Co-expression Network Analysis (WGCNA) and Least Absolute Shrinkage and Selector Operation (LASSO) regression analysis. Six genes associated with the prognosis in patients with COAD were identified, including: KRT23, ULBP2, ASRGL1, SERPINA1, SCIN, and SLC28A2. We constructed a clinical prediction model and analysed its predictive power. Results: The identified hub genes are involved in developing many diseases and closely linked to digestive disorders. Our results suggested that the hub genes could influence the prognosis of COAD by regulating Th17 cells’ infiltration. Conclusions: These newly discovered hub genes contribute to clarifying the mechanisms of COAD development and metastasis. Given that they promote COAD development, they may become new therapeutic targets and biomarkers of COAD.

Wei Liu,1 Shan Li2 1Department of Gastrointestinal Surgery, Xiantao First People’s Hospital Affiliated to Yangtze University, Xiantao, 433000, People’s Republic of China; 2Department of Endocrinology, Xiantao First People’s Hospital Affiliated to Yangtze University, Xiantao, 433000, People’s Republic of ChinaCorrespondence: Shan LiXiantao First People’s Hospital Affiliated to Yangtze University, Xiantao, 433000, People’s Republic of ChinaEmail hbxtlishan2020@163.comIntroduction: Colon adenocarcinoma (COAD) is the third most common tumor of the digestive tract. Recent studies reported that lncRNA’s abnormal expression might play a vital role in the occurrence and development of COAD.Methods: In the present study, we investigated the expression of ILF3-AS1 in COAD cell lines, human normal colon epithelial cell line, patient tumor tissues and adjacent normal tissues by real-time quantitative PCR (RT-qPCR). Small interfering RNAs (siRNAs) were transfected into COAD cells to inhibit the expression of ILF3-AS1. The effects of ILF3-AS1 on cell proliferation, migration, invasion and apoptosis were measured by CCK-8 assay, transwell migration and invasion assay, and flow cytometry apoptosis assay, respectively. The direct binding of ILF3-AS1 and miR-619-5p/CAMK1D was validated by the luciferase reporter assay. The expression of CAMK1D and epithelial-mesenchymal transformation (EMT)-related proteins was detected by Western Blot analysis. Besides, in vivo experiments were conducted to demonstrate the oncogenic role of ILF3-AS1 in COAD.Results: The results showed that the expression of ILF3-AS1 was significantly higher in COAD tissue than in normal adjacent samples, and this conclusion was confirmed in the available public datasets. After ILF3-AS1 knockdown, the proliferation of COAD cell lines SW480 and HT29 was significantly inhibited. At the same time, the apoptosis was increased, and the invasion and migration abilities were decreased. After further exploring the mechanisms, we found that ILF3-AS1 serves as a competitive endogenous RNA of mir-619-5p. It can bind to mir-619-5p and reduce its expression, thus regulating the target gene CAMK1D. In addition, we found that high expression of ILF3-AS1 was significantly associated with tumor grade, tumor size, and distant metastasis in COAD samples. In vivo experiments confirmed that ILF3-AS1 promotes tumor growth in COAD models.Conclusion: The present study demonstrated that ILF3-AS1 plays an oncogenic role in COAD through regulating the miR-619-5p/CAMK1D axis, and inhibition of ILF3-AS1 may pave the way for COAD treatment.Keywords: lncRNA ILF3-AS1, miR-619-5p, CAMK1D, COAD

Yiping Lu, Si Wu, Changwan Cui, Miao Yu, Shuang Wang, Yuanyi Yue, Miao Liu, Zhengrong Sun BioBank, The Affiliated Shengjing Hospital, China Medical University, Shenyang, Liaoning 110004, People’s Republic of ChinaCorrespondence: Zhengrong SunBioBank, The Affiliated Shengjing Hospital, China Medical University, Shenyang, Liaoning 110004, People’s Republic of ChinaTel/ Fax +86-24-83283768Email sunzr_sj@163.comPurpose: This study aims to systematically analyze multi-omics data to explore new prognosis biomarkers in colon adenocarcinoma (COAD).Materials and Methods: Multi-omics data of COAD and clinical information were obtained from The Cancer Genome Atlas (TCGA). Univariate Cox analysis was used to select genes which significantly related to the overall survival. GISTIC 2.0 software was used to identify significant amplification or deletion. Mutsig 2.0 software was used to identify significant mutation genes. The 9-gene signature was screened by random forest algorithm and Cox regression analysis. GSE17538 dataset was used as an external dataset to verify the predictive ability of 9-gene signature. qPCR was used to detect the expression of 9 genes in clinical specimens.Results: A total of 71 candidate genes are obtained by integrating genomic variation, mutation and prognostic data. Then, 9-gene signature was established, which includes HOXD12, RNF25, CBLN3, DOCK3, DNAJB13, PYGO2, CTNNA1, PTPRK, and NAT1. The 9-gene signature is an independent prognostic risk factor for COAD patients. In addition, the signature shows good predicting performance and clinical practicality in training set, testing set and external verification set. The results of qPCR based on clinical samples showed that the expression of HOXD12, RNF25, CBLN3, DOCK3, DNAJB13, and PYGO2 was increased in colon cancer tissues and the expression of CTNNA1, PTPRK, NAT1 was decreased in colon cancer tissues.Conclusion: In this study, 9-gene signature is constructed as a new prognostic marker to predict the survival of COAD patients.Keywords: COAD, multi-omics, 9-gene signature, prognosis biomarkers

Objective: The objective was to identify and validate C-X-C motif chemokine ligand 1(CXCL1) for diagnosis and prognosis in colon adenocarcinoma (COAD). Methods: Our current study had enrolled one The Cancer Genome Atlas (TCGA) cohort and two Guangxi cohorts to identify and verify the diagnostic and prognostic values of CXCL1 in COAD. Functional enrichment was performed by gene set enrichment analysis (GSEA). Results: In TCGA cohort, the expression of CXCL1 was significantly up-regulated in tumor tissues and decreased as the tumor stage developed. The receiver operating characteristic (ROC) curve showed that CXCL1 had a high diagnostic value for COAD. The result of Kaplan-Meier survival analysis showed that CXCL1 gene expression (P=0.045) was significantly correlated with overall survival (OS) of COAD. Results of Guangxi cohort also verified the diagnostic value of CXCL1 in COAD, and sub-group survival analyses also suggested that patients with high CXCL1 expression were related to a favorable OS (Corrected P=0.005). GSEA revealed that CXCL1 high expression phenotype was related to cytokine activity, cell apoptosis, P53 regulation pathway, and regulation of autophagy in COAD. Conclusions: In this study, we found that CXCL1 gene might be a potential diagnostic biomarker for COAD, and might serve as a prognostic biomarker for specific subgroup of COAD.

Abnormal DNA methylation is a major early contributor to colon cancer (COAD) development. We conducted a cohort-based systematic investigation of genome-wide DNA methylation using 299 COAD and 38 normal tissue samples from TCGA. Through conditional screening and machine learning with a training cohort, we identified one hypomethylated and nine hypermethylated differentially methylated CpG sites as potential diagnostic biomarkers, and used them to construct a COAD-specific diagnostic model. Unlike previous models, our model precisely distinguished COAD from nine other cancer types (e.g., breast cancer and liver cancer; error rate ≤ 0.05) and from normal tissues in the training cohort (AUC = 1). The diagnostic model was verified using a validation cohort from The Cancer Genome Atlas (AUC = 1) and five independent cohorts from the Gene Expression Omnibus (AUC ≥ 0.951). Using Cox regression analyses, we established a prognostic model based on six CpG sites in the training cohort, and verified the model in the validation cohort. The prognostic model sensitively predicted patients' survival (p ≤ 0.00011, AUC ≥ 0.792) independently of important clinicopathological characteristics of COAD (e.g., gender and age). Thus, our DNA methylation analysis provided precise biomarkers and models for the early diagnosis and prognostic evaluation of COAD.

Objective The long non‐coding RNA zinc finger E‐box‐binding homeobox 1 antisense 1 (ZEB1‐AS1) acts as an oncogenic regulator in many human tumours. In the present study, we identify the role and potential molecular biological mechanisms of ZEB1‐AS1 in colon adenocarcinoma (COAD). Methods QRT‐PCR was used to detect the expression of ZEB1‐AS1, miR‐455‐3p and p21‐activated kinases 2 (PAK2) in COAD tissues. CCK8 assay, EdU assay, transwell assay and scratch wound assay were used to explore the biological function of ZEB1‐AS1 in COAD cells. Bioinformatics, luciferase reporter assays and an RNA pull‐down assay were used to demonstrate the mechanism of ZEB1‐AS1. We further explore the role of ZEB1‐AS1 in vivo though xenograft tumour assay. Results We found that ZEB1‐AS1 expression was significantly up‐regulated in COAD tissues, and high ZEB1‐AS1 level was correlated with the poor prognosis of COAD patients. MiR‐455‐3p plays an anti‐cancer role in COAD by targeting PAK2. We confirmed that ZEB1‐AS1 promotes PAK2 expression by sponging miR‐455‐3p, thus facilitating COAD cell growth and metastasis. Conclusions To sum up, this result illustrates the novel molecular mechanism of ZEB1‐AS1 in COAD and provides a new target for the diagnosis and treatment of COAD patients.

Aim This scoping review will gather existing evidence on specific interventions at presentation and discharge which aim to standardize care and/or reduce unnecessary admissions and/or readmissions to hospital for patients presenting with acute exacerbation of chronic obstructive pulmonary (airways) disease. Design Scoping review of relevant literature from January 2000–March 2019. Methods Database searches for primary evidence in peer‐reviewed journals will be conducted electronically using Web of Science, EMBASE (Elsevier) and PUBMED. Eligibility criteria will include hospital‐based interventions for presentations of acute exacerbation of chronic obstructive pulmonary disease with outcomes specific to standardizing care or reducing unnecessary admissions or readmissions. Abstract, full‐text screening and data extraction will be completed independently by a panel of expert reviewers. Results We aim to identify current interventions and improvement approaches in acute exacerbation of chronic obstructive pulmonary (airways) disease care that have an impact on admission and discharge processes or readmissions. Recommendations as a result of this review will aid the design and development of future improvement intervention.

Background The chronic obstructive pulmonary disease (COPD) and the bronchial asthma are widespread diseases. They need long-lasting and sustainable rehabilitation. Objectives The goal of this HTA is to describe the present supply and the economic relevance of out-patient pulmonary rehabilitation in conjunction with its social aspects. A further target is to derivate options for actions in the health-care system and possible research necessities. Methods Relevant publications are identified by means of a structured search in 37 database accessed through the German Institute of Medical Documentation and Information (DIMDI). In addition a manual search of identified reference lists has been done. The present report includes German and English literature published from 2004 to 2009. The methodological quality was assessed by two independent researchers according to pre-defined quality criteria of evidence based medicine. Results Among 860 publications 31 medical studies, four economic studies and 13 ethical studies meet the inclusion criteria. The studies cover rehabilitation programmes in 19 countries. The majority of them has a high level of evidence (1A to 2C). The pulmonary rehabilitation programmes differ by the setting (in-patient, out-patient, in-home, community-based), by the length of intervention (from two weeks to 36 months), by the way and the frequency of intervention and by the duration of the follow-up treatment. Overall out-patient rehabilitation programmes achieve the same positive effects for COPD patients as in-patient programmes do. This is especially true for physical performance and health related quality of life. There are only a few studies dealing with asthma. Therefore, valid statements cannot be given. The results for cost-effectiveness are not distinct enough. Discussion Goals of pulmonary rehabilitation like prevention and adequate treatment of acute exacerbations, the minimisation of hospitalisation and the reduction of mortality are attained in out-patient as well as in in-patient pulmonary rehabilitation. Regarding the best frequency of training units per week or the duration and the content of a unit further research is needed. Final results for the ideal length of an in-patient rehabilitation are still missing. None of the studies deals with the analysis of the different treatment forms of a COPD which are frequently defined by an alteration of in-patient and out-patient treatments and participation in sports clubs or self-help groups. There are some other limitations of the studies. The results concerning self-management programmes are not distinct. (Self-) Selection leads to high drop-out rates. Many studies have only small sample sizes. Confounder and long-time effects are seldom researched, relevant economic evaluations do not exist The improvement of health related quality of life is primarily obtained by an improved disease management than by an improvement of a medical parameter. Conclusion Out-patient pulmonary rehabilitation is as effective as in-patient pulmonary rehabilitation. But there is a critical shortage of out-patient pulmonary rehabilitation supply in Germany. Domains for further research are the evaluation of models for integrated care, the length, frequency and content of training programmes, psychiatric assessments and the cost-effectiveness of out-patient pulmonary rehabilitation., GMS Health Technology Assessment; 6:Doc11; ISSN 1861-8863

Hintergrund Chronisch obstruktive Lungenerkrankungen (COPD) und Asthma bronchiale gehören zu den großen Volkskrankheiten. Sie bedürfen einer langfristigen bis dauerhaften Rehabilitation. Fragestellungen Ziel des HTA-Berichts (HTA = Health Technology Assessment) ist es, die derzeitigen Angebote sowie die gesundheitsökonomische Relevanz im Zusammenhang mit der sozialen Komponente der pneumologischen Rehabilitation (PR) darzustellen, Handlungsoptionen für die Akteure im System abzuleiten sowie Forschungsbedarf aufzuzeigen. Methodik Relevante Publikationen werden über eine strukturierte Datenbankrecherche in 37 Datenbanken sowie mittels Handrecherche identifiziert. Die Literaturrecherche erstreckt sich von 2004 bis 2009. Die methodische Qualität wird jeweils von zwei unabhängigen Gutachtern unter Beachtung von Kriterien der evidenzbasierten Medizin (EbM) systematisch geprüft. Ergebnisse Von insgesamt 860 Treffern erfüllen 31 medizinische, vier ökonomische und 13 ethische Studien die Einschlusskriterien. Die Studien decken Rehabilitationsprogramme in neunzehn Ländern ab. Sie weisen überwiegend einen hohen Evidenzgrad auf (1A bis 2C). Die Modelle der PR unterscheiden sich durch das Setting (in-patient, out-patient, in-home, community-based), durch die Länge der Intervention (zwei Wochen bis 36 Monate), durch die Art und Häufigkeit der Intervention sowie durch die Länge der nachfolgenden Betreuung. Insgesamt zeigt sich, dass sowohl stationäre als auch ambulante PR-Programme positive Wirkungen bei COPD-Patienten erzielen, vor allem können die körperliche Leistungsfähigkeit und die gesundheitsbezogene Lebensqualität gesteigert werden. Die Anzahl der Studien, die sich mit ambulanter Asthmarehabilitation befassen, ist zu gering, um gesicherte Aussagen zu treffen. Die Ergebnisse zur Kosten-Effektivität sind nicht eindeutig. Diskussion Die Ziele der PR wie die Vorbeugung und adäquate Behandlung akuter Exazerbationen, die Minimierung von Hospitalisationen sowie die Reduktion der Mortalität werden sowohl in stationären als auch in ambulanten Rehabilitationsprogrammen erreicht. Zur optimalen Häufigkeit der Schulungseinheiten pro Woche sowie zur Dauer und zu Schulungsinhalten pro Stunde gibt es weiteren Forschungsbedarf. Auch zur optimalen Länge der ambulanten Rehabilitationsprogramme liegen noch keine abschließenden Ergebnisse vor. Es fehlen Studien, die den realen Ablauf rehabilitativer Maßnahmen bei COPD-Patienten analysieren. Diese rehabilitativen Maßnahmen setzen sich häufig aus einer langfristigen Abfolge von stationären und ambulanten Maßnahmen zusammen. Sie bestehen beispielsweise in der Teilnahme an Sport- und Selbsthilfegruppen. Die Resultate zu Schulungsprogrammen sind nicht eindeutig. (Selbst-)Selektionseffekte führen zu hohen Drop-out-Raten. Viele Studien haben kleine Stichproben, Confounder und Langzeiteffekte werden selten untersucht, relevante ökonomische Evaluationen sind nicht vorhanden. Die Verbesserung der gesundheitsbezogenen Lebensqualität wird primär durch ein verbessertes Krankheitsmanagement und weniger durch eine Verbesserung der medizinischen Parameter erreicht. Schlussfolgerung Die ambulante Rehabilitation kann wie die stationäre Rehabilitation klinisch relevante und signifikante Verbesserungen für die Patienten erbringen. Es besteht jedoch eine deutliche Unterversorgung an ambulanten pneumologischen Rehabilitationsangeboten in Deutschland. Forschungsbedarf gibt es zur Evaluation von Modellen der integrierten Versorgung, zur Dauer, zur Frequenz und zu Inhalten von Trainingsprogrammen, zur psychiatrischen Betreuung und zur Kosten-Effektivität der ambulanten Versorgung., Schriftenreihe Health Technology Assessment (HTA) in der Bundesrepublik Deutschland; 106; ISSN 1864-9645