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Targeted Assessment of Mucosal Immune gene expression Predicts Clinical Outcomes in Children with Ulcerative Colitis

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JOURNAL OF CROHNS & COLITIS 2022年第11期16卷 1735-1750页

作者： Clarkston, Kathryn Karns, Rebekah Jegga, Anil G. Sharma, Mihika Fox, Sejal Ojo, Babajide A. Minar, Phillip Walters, Thomas D. Griffiths, Anne M. Mack, David R. Boyle, Brendan LeLeiko, Neal S. Markowitz, James Rosh, Joel R. Patel, Ashish S. Shah, Sapana Baldassano, Robert N. Pfefferkorn, Marian Sauer, Cary Kugathasan, Subra Haberman, Yael Hyams, Jeffrey S. Denson, Lee A. Rosen, Michael J. Cincinnati Childrens Hosp Med Ctr Div Gastroenterol Hepatol & Nutr Cincinnati OH 45229 USA Cincinnati Childrens Hosp Med Ctr Div Biomed Informat Cincinnati OH 45229 USA Univ Cincinnati Coll Med Dept Pediat Cincinnati OH USA Univ Missouri Sch Med Div Pediat Gastroenterol Childrens Mercy Hosp Kansas City MO 64108 USA Stanford Univ Dept Pediat Div Pediat Gastroenterol Sch Med Stanford CA 94305 USA Hosp Sick Children Div Pediat Gastroenterol Toronto ON Canada Childrens Hosp Eastern Ontario Div Gastroenterol Hepatol & Nutr Ottawa ON Canada Univ Ottawa Ottawa ON Canada Nationwide Childrens Hosp Div Gastroenterol Hepatol & Nutr Columbus OH USA Columbia Univ Dept Pediat Vagelos Coll Phys & Surg New York NY 10027 USA NewYork Presbyterian Morgan Stanley Childrens Hos New York NY USA Cohen Childrens Med Ctr New York Div Gastroenterol Hepatol & Nutr New Hyde Pk NY USA Goryeb Childrens Hosp Div Gastroenterol Hepatol & Nutr Morristown NJ USA Phoenix Childrens Hosp Div Gastroenterol Phoenix AZ USA UPMC Childrens Hosp Pittsburgh Div Gastroenterol Hepatol & Nutr Pittsburgh PA USA Childrens Hosp Philadelphia Div Gastroenterol Hepatol & Nutr Philadelphia PA 19104 USA Riley Childrens Hosp Div Gastroenterol Hepatol & Nutr Indianapolis IN USA Emory Univ Dept Pediat Div Gastroenterol Hepatol & Nutr Atlanta GA 30322 USA Childrens Healthcare Atlanta Atlanta GA USA Sheba Med Ctr Tel Hashomer Israel Connecticut Childrens Med Ctr Div Digest Dis Hepatol & Nutr Hartford CT USA

Background and Aims: We aimed to determine whether a targeted gene expression panel could predict clinical outcomes in paediatric ulcerative colitis [UC] and investigated putative pathogenic roles of predictive genes. Methods: In total, 313 rectal RNA samples from a cohort of newly diagnosed paediatric UC patients (PROTECT) were analysed by a real-time PCR microfluidic array for expression of type 1, 2 and 17 inflammation genes. Associations between expression and clinical outcomes were assessed by logistic regression. Identified prognostic markers were further analysed using existing RNA sequencing (RNA-seq) data sets and tissue immunostaining. Results: IL13RA2 was associated with a lower likelihood of corticosteroid-free remission (CSFR) on mesalamine at week 52 (p = .002). A model including IL13RA2 and only baseline clinical parameters was as accurate as an established clinical model, which requires week 4 remission status. RORC was associated with a lower likelihood of colectomy by week 52. A model including RORC and PUCAI predicted colectomy by 52 weeks (area under the receiver operating characteristic curve 0.71). Bulk RNA-seq identified IL13RA2 and RORC as hub genes within UC outcome-associated expression networks related to extracellular matrix and innate immune response, and lipid metabolism and microvillus assembly, respectively. Adult UC single-cell RNA-seq data revealed IL13RA2 and RORC co-expressed genes were localized to inflammatory fibroblasts and undifferentiated epithelial cells, respectively, which was supported by protein immunostaining. Conclusion: Targeted assessment of rectal mucosal immune gene expression predicts 52-week CSFR in treatment-naive paediatric UC patients. Further exploration of IL-13R alpha 2 as a therapeutic target in UC and future studies of the epithelial-specific role of RORC in UC pathogenesis are warranted.

关键词： Paediatric inflammatory bowel disease gene expression array weighted gene co-expression network analysis

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Persistent pesticides: effects of endosulfan at the molecular level on the aquatic invertebrate Chironomus riparius

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ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH 2021年第24期28卷 31431-31446页

作者： Muniz-Gonzalez, Ana-Belen Novo, Marta Martinez-Guitarte, Jose-Luis Univ Nacl Educ Distancia Dept Math & Fluid Phys Environm Biol & Toxicol Grp UNED Senda Rey 9 Madrid 28040 Spain Univ Complutense Madrid Fac Biol Biodivers Ecol & Evolut Dept Madrid Spain

Although banned in multiple areas, due to its persistence in the environment, endosulfan constitutes a significant environmental concern. In this work, fourth instar Chironomus riparius larvae were exposed at environmentally relevant endosulfan concentrations of 0.1, 1, and 10 mu g/L for 24 h to analyze the possible effects of this acaricide on gene expression and enzymatic activity. Transcriptional changes were studied through the implementation of a real-time polymerase chain reaction array with 42 genes related to several metabolic pathways (endocrine system, detoxification response, stress response, DNA reparation, and immune system). Moreover, glutathione-S-transferase (GST), phenoloxidase (PO), and acetylcholinesterase (AChE) activities were assessed. The five pathways were differentially altered by endosulfan exposure with significant changes in the E93, Dis, MAPR, Met, InR, GSTd3, GSTt3, MRP1, hsp70, hsp40, hsp24, ATM, PARP, Proph, and Def genes. Besides, all of the measured enzymatic activities were modified, with increased activity of GST, followed by PO and AChE. In summary, the results reflected the effects provoked in C. riparius at molecular level despite the absence of lethality. These data raise concerns about the strong alteration on different metabolic routes despite the low concentrations used. Therefore, new risk assessment strategies should consider include the effects at the sub-organismal level as endpoints in addition to the classical ecologically relevant parameters (such as survival). This endeavor will facilitate a comprehensive evaluation of toxicants in the environment.

关键词： Invertebrates Aquatic toxicology Insecticide gene expression array

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The early-phase transcriptome and the clinical efficacy analysis in three modes of subcutaneous immunotherapy for allergic rhinitis

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WORLD ALLERGY ORGANIZATION JOURNAL 2023年第8期16卷 100811页

作者： Huang, Jingyu Zhang, Wei Xiang, Rong Tan, Lu Liu, Peiqiang Tao, Zezhang Deng, Yuqin Tong, Huan Xu, Yu Wuhan Univ Otolaryngol Head & Neck Surg Ctr Dept Rhinol & Allergy Renmin Hosp Wuhan Peoples R China Wuhan Univ Renmin Hosp 238 Jiefang Rd Wuhan 430060 Peoples R China Wuhan Univ Tongren Hosp 241 Peng Liuyang Rd Wuhan 430060 Peoples R China Hubei Prov Key Lab Allergy & Immunol Wuhan Peoples R China Wuhan Univ Wound Repair&Rehabilitat Ctr Dept Tongren Hosp Wuhan Hosp 3 Wuhan Peoples R China Wuhan Univ Res Inst Otolaryngol Head & Neck Surg Renmin Hosp Wuhan Peoples R China

Background: Allergen immunotherapy is the only etiological treatment for allergic ***: To analyze the efficacy, safety, and mechanism of subcutaneous immunotherapy (SCIT).Methods: The efficacy, safety, and serum immunological changes of 3 modes of subcutaneous immunotherapy were compared. Peripheral blood mononuclear cells (PBMC) transcriptome changes were obtained on the Illumina sequencing platforms. We confirmed differentially expressed genes (DEGs) by quantitative real-time polymerase chain reaction (PCR). The DEGs were analyzed by gene ontology (GO), Kyoto Encyclopedia of genes and Genomes (KEGG), and protein-protein interaction (PPI) networks. The correlation between the common DEGs and clinical indicators was analyzed by Origin ***: The 3 SCITs were all effective after 1 year. The Combined Symptom and Medication Score (CSMS) and Visual Analog Score (VAS) in rush immunotherapy (RIT) are lowest after 24 and 48 weeks of treatment among the 3 groups. After treatment, the levels of sIgE, sIgE/tIgE, Th2 cytokines, Th17 cytokines, and percentage of peripheral eosinophils (EOS%) decreased significantly (P<0.05), while the levels of Th1 type cytokines did not change significantly. Transcriptome analysis identified 24, 24, and 91 DEGs at W3 and 42, 52, 175 DEGs at W7 in conventional immunotherapy (CIT), cluster immunotherapy (CLIT), and RIT groups, respectively. The pathways and functions involved in SCIT include secretion of Th1/2 cytokines, immune cell differentiation. Unlike CIT and CLIT, DEGs are also involved in T cell tolerance induction, T cell anergy, and lymphocyte anergy in RIT. CXCR1, CXCR2, and IER3 had a specific effect on reflecting the improvement of symptoms in allergic rhinitis patients with ***: The clinical efficacy of RIT appeared earlier than CIT and CLIT. Clinicians can use the highly conserved gene expression profile to evaluate responses to immunotherapy.

关键词： Allergic rhinitis gene expression profiles gene expression array Subcutaneous immunotherapy

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STAT3/HIF1A and EMT specific transcription factors regulated genes: Novel predictors of breast cancer metastasis

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gene 2022年第0期818卷 146245-146245页

作者： Hegde, Mangala Daimary, Uzini Devi Kumar, Aviral Chinnathambi, Arunachalam Alharbi, Sulaiman Ali Shakibaei, Mehdi Kunnumakkara, Ajaikumar B. Indian Inst Technol Guwahati Dept Biosci & Bioengn Canc Biol Lab Gauhati 781039 Assam India Indian Inst Technol Guwahati DBT AIST Int Ctr Translat & Environm Res Gauhati 781039 Assam India King Saud Univ Coll Sci Dept Bot & Microbiol POB 2455 Riyadh 11451 Saudi Arabia Ludwig Maximilian Univ Munich Musculoskeletal Res Grp & Tumor Biol Chair Vegetat Anat Fac MedInst Anat Munich Germany

Metastasis, the fatal hallmark of breast cancer (BC), is a serious hurdle for therapy. Current prognostic approaches are not sufficient to predict the metastasis risk for BC patients. Therefore, in the present study, we analyzed gene expression data from GSE139038 and TCGA database to develop predictive markers for BC metastasis. Initially, the data from GSE139038 which contained 65 samples consisting of 41 breast tumor tissues, 18 paired morphologically normal tissues and 6 from non-malignant breast tissues were analyzed for differentially expressed genes (DEGs). DEGs were obtained from three different comparisons: paired morphologically normal (MN) versus tumor samples (C), apparently normal (AN) versus tumor samples (C), and paired morphologically normal (MN) versus apparently normal samples (AN). Multiple bioinformatic methods were employed to evaluate metastasis, EMT and triple negative breast cancer (TNBC) specific genes. Further, regulation of gene expression, clinicopathological factors and DNA methylation patterns of DEGs in BC were validated with TCGA datasets. Our bioinformatic analysis showed that 40 genes were upregulated and 294 were found to be downregulated between AN vs C;124 were upregulated and 760 genes were downregulated between MN vs C;4 were upregulated and 13 were downregulated between MN vs AN. Analysis using TCGA dataset revealed 18 genes were significantly altered in nodal positive BC patients compared to nodal negative BC patients. Our study showed novel candidate genes as predictive markers for BC metastasis which can also be used for therapeutic targets for BC treatment.

关键词： Breast cancer Metastasis Epithelial-mesenchymal transition (EMT) gene expression array TCGA database

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gene X environment: the cellular environment governs the transcriptional response to environmental chemicals

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HUMAN GENOMICS 2020年第1期14卷 19-19页

作者： Burman, Andreanna Garcia-Milian, Rolando Whirledge, Shannon Yale Sch Med Dept Obstet Gynecol & Reprod Sci 310 Cedar StPOB 208063 New Haven CT 06520 USA Yale Sch Med Bioinformat Support Program Cushing Whitney Med Lib New Haven CT 06520 USA

Background An individual's response to environmental exposures varies depending on their genotype, which has been termed the gene-environment interaction. The phenotype of cell exposed can also be a key determinant in the response to physiological cues, indicating that a cell-gene-environment interaction may exist. We investigated whether the cellular environment could alter the transcriptional response to environmental chemicals. Publicly available gene expression array data permitted a targeted comparison of the transcriptional response to a unique subclass of environmental chemicals that alter the activity of the estrogen receptor, xenoestrogens. Results Thirty xenoestrogens were included in the analysis, for which 426 human gene expression studies were identified. Comparisons were made for studies that met the predefined criteria for exposure length, concentration, and experimental replicates. The cellular response to the phytoestrogen genistein resulted in remarkably unique transcriptional profiles in breast, liver, and uterine cell-types. Analysis of gene regulatory networks and molecular pathways revealed that the cellular context mediated the activation or repression of functions important to cellular organization and survival, including opposing effects by genistein in breast vs. liver and uterine cell-types. When controlling for cell-type, xenoestrogens regulate unique gene networks and biological functions, despite belonging to the same class of environmental chemicals. Interestingly, the genetic sex of the cell-type also strongly influenced the transcriptional response to xenoestrogens in the liver, with only 22% of the genes significantly regulated by genistein common between male and female cells. Conclusions Our results demonstrate that the transcriptional response to environmental chemicals depends on a variety of factors, including the cellular context, the genetic sex of a cell, and the individual chemical. These findings highlight the importance o

关键词： gene expression array gene ontology analysis Environmental chemical gene-environment interaction Xenoestrogen

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Reduced expression of the IL7Ra signaling pathway in Neuromyelitis optica

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JOURNAL OF NEUROIMMUNOLOGY 2018年 324卷 81-89页

作者： Brill, Livnat Lavon, Iris Valmin-Dembinsky, Adi Hebrew Univ Jerusalem Hadassah Med Ctr Agnes Ginges Ctr Neurogenet Fac MedDept Neurol Jerusalem Israel Hadassah Med Ctr Leslie & Michael Ctr Neurooncol Jerusalem Israel

Neuromyelitis optica (NMO) is a chronic inflammatory demyelinating autoimmune disease of the central nervous system that most commonly affects the optic nerves and spinal cord. To characterize the immunological pathways involved in NMO, whole blood RNA expression array was performed using Nanostring nCounter technology. Two major clusters of genes were found associated with NMO: T cell-associated genes and the TNF/NF-kB signaling pathway. Analysis of the genes within the first cluster confirmed significantly reduced expression of IL7Ra (CD127) in the peripheral blood of NMO patients vs that in healthy controls. IL7Ra upstream transcription factors and its downstream survival signaling pathway were also markedly reduced. In line with the essential role of IL7Ra in T cell maturation and survival, a significantly lower number of naive T cells, and reduced T cell survival signaling mediated by increased BID (BH3-interacting domain death agonist) expression and increased apoptosis was observed. Cumulatively, these findings indicate that the IL7Ra signaling pathway may play a role in the autoimmune process in NMO.

关键词： IL7 receptor alpha (IL7Ra) CD127 Neuromyelitis optica (NMO) gene expression array T cells NF-kB

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DNA methylation and gene expression profiles show novel regulatory pathways in hepatocellular carcinoma

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CLINICAL EPIgeneTICS 2015年第1期7卷 1-13页

作者： Udali, Silvia Guarini, Patrizia Ruzzenente, Andrea Ferrarini, Alberto Guglielmi, Alfredo Lotto, Valentina Tononi, Paola Pattini, Patrizia Moruzzi, Sara Campagnaro, Tommaso Conci, Simone Olivieri, Oliviero Corrocher, Roberto Delledonne, Massimo Choi, Sang-Woon Friso, Simonetta Univ Verona Sch Med Dept Med Policlin GB Rossi I-37134 Verona Italy Univ Verona Sch Med Dept Surg Policlin GB Rossi I-37134 Verona Italy Univ Verona Sch Agroind Biotechnol Dept Biotechnol Genet & Hered Sect I-37134 Verona Italy Tufts Univ Friedman Sch Nutr Sci & Policy Boston MA 02111 USA CHA Univ Chaum Life Ctr Seoul 135948 South Korea

Background: Alcohol is a well-known risk factor for hepatocellular carcinoma (HCC), but the mechanisms underlying the alcohol-related hepatocarcinogenesis are still poorly understood. Alcohol alters the provision of methyl groups within the hepatic one-carbon metabolism, possibly inducing aberrant DNA methylation. Whether specific pathways are epigenetically regulated in alcohol-associated HCC is, however, unknown. The aim of the present study was to investigate the genome-wide promoter DNA methylation and gene expression profiles in non-viral, alcohol-associated HCC. From eight HCC patients undergoing curative surgery, array-based DNA methylation and gene expression data of all annotated genes were analyzed by comparing HCC tissue and homologous cancer-free liver tissue. Results: After merging the DNA methylation with gene expression data, we identified 159 hypermethylated-repressed, 30 hypomethylated-induced, 49 hypermethylated-induced, and 56 hypomethylated-repressed genes. Notably, promoter DNA methylation emerged as a novel regulatory mechanism for the transcriptional repression of genes controlling the retinol metabolism (ADH1A, ADH1B, ADH6, CYP3A43, CYP4A22, RDH16), iron homeostasis (HAMP), one-carbon metabolism (SHMT1), and genes with a putative, newly identified function as tumor suppressors (FAM107A, IGFALS, MT1G, MT1H, RNF180). Conclusions: A genome-wide DNA methylation approach merged with array-based gene expression profiles allowed identifying a number of novel, epigenetically regulated candidate tumor-suppressor genes in alcohol-associated hepatocarcinogenesis. Retinol metabolism genes and SHMT1 are also epigenetically regulated through promoter DNA methylation in alcohol-associated HCC. Due to the reversibility of epigenetic mechanisms by environmental/nutritional factors, these findings may open up to novel interventional strategies for hepatocarcinogenesis prevention in HCC related to alcohol, a modifiable dietary component.

关键词： Alcohol Candidate tumor-suppressor genes DNA methylation Epigenetics gene expression array Hepatocellular carcinoma MeDIP-chip One-carbon metabolism Retinol metabolism

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DATA MINING METHODS FOR gene SELECTION ON THE BASIS OF gene expression arrayS

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INTERNATIONAL JOURNAL OF APPLIED MATHEMATICS AND COMPUTER SCIENCE 2014年第3期24卷 657-668页

作者： Muszynski, Michal Osowski, Stanislaw Warsaw Univ Technol Fac Elect Engn PL-00661 Warsaw Poland Mil Univ Technol Fac Elect Engn PL-00908 Warsaw Poland

The paper presents data mining methods applied to gene selection for recognition of a particular type of prostate cancer on the basis of gene expression arrays. Several chosen methods of gene selection, including the Fisher method, correlation of gene with a class, application of the support vector machine and statistical hypotheses, are compared on the basis of clustering measures. The results of applying these individual selection methods are combined together to identify the most often selected genes forming the required pattern, best associated with the cancerous cases. This resulting pattern of selected gene lists is treated as the input data to the classifier, performing the task of the final recognition of the patterns. The numerical results of the recognition of prostate cancer from normal (reference) cases using the selected genes and the support vector machine confirm the good performance of the proposed gene selection approach.

关键词： gene expression array gene ranking feature selection clusterization measures fusion SVM classification

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MKL1/2 and ELK4 co-regulate distinct serum response factor (SRF) transcription programs in macrophages

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BMC GENOMICS 2014年第1期15卷 1-15页

作者： Xie, Lan Tsinghua Univ Sch Med Dept Biomed Engn Med Syst Biol Res Ctr Beijing 100084 Peoples R China Univ Calif San Diego Dept Cellular & Mol Med La Jolla CA 92093 USA Natl Engn Res Ctr Beijing Biochip Technol Beijing 102206 Peoples R China

Background: Serum response factor (SRF) is a widely expressed transcription factor involved in multiple regulatory programs. It is believed that SRF can toggle between disparate programs of gene expression through association with different cofactors. However, the direct evidence as to how these factors function on a genome-wide level is still lacking. Results: In the present study, I explored the functions of SRF and its representative cofactors, megakaryoblastic leukemia 1/2 (MKL1/2) and ETS-domain protein 4 (ELK4), during fungal infection challenge in macrophages. The knockdown study, combined with gene expression array analysis, revealed that MKL1/2 regulated SRF-dependent genes were related to actin cytoskeleton organization, while ELK4 regulated SRF-dependent genes were related to external stimulus responses. Subsequent chromatin immunoprecipitation coupled with massively parallel sequencing (ChIP-seq) suggested that many of these regulations were mediated directly in cis. Conclusions: I conclude that SRF utilizes MKL1/2 to fulfill steady state cellular functions, including cytoskeletal organization, and utilizes ELK4 to facilitate acute responses to external infection. Together, these findings indicate that SRF, along with its two cofactors, are important players in both cellular homeostasis and stress responses in macrophages.

关键词： SRF MKL1 MKL2 ELK4 gene expression array ChIP-seq

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gene expression signatures of primary and metastatic uterine leiomyosarcoma

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HUMAN PATHOLOGY 2014年第4期45卷 691-700页

作者： Davidson, Ben Abeler, Vera Maria Forsund, Mette Holth, Arild Yang, Yanqin Kobayashi, Yusuke Chen, Lily Kristensen, Gunnar B. Shih, Ie-Ming Wang, Tian-Li Oslo Univ Hosp Norwegian Radium Hosp Dept Pathol N-0424 Oslo Norway Univ Oslo Fac Med N-0316 Oslo Norway NHLBI Genom Core Facil NIH Bethesda MD 20892 USA Johns Hopkins Med Inst Dept Gynecol Baltimore MD 21231 USA Johns Hopkins Med Inst Dept Obstet Baltimore MD 21231 USA Johns Hopkins Med Inst Dept Oncol Baltimore MD 21231 USA Oslo Univ Hosp Norwegian Radium Hosp Dept Gynecol Oncol N-0424 Oslo Norway Oslo Univ Hosp Norwegian Radium Hosp Inst Med Informat N-0424 Oslo Norway Johns Hopkins Med Inst Dept Pathol Baltimore MD 21231 USA

Leiomyosarcoma (LMS) is the most common uterine sarcoma. Although the disease is relatively rare, it is responsible for considerable mortality due to frequent metastasis and chemoresistance. The molecular events related to LMS metastasis are unknown to date. The present study compared the global gene expression patterns of primary uterine LMSs and LMS metastases. gene expression profiles of 13 primary and 15 metastatic uterine LMSs were analyzed using the HumanRef-8 BeadChip from Illumina. Differentially expressed candidate genes were validated using quantitative real-time polymerase chain reaction (PCR) and immunohistochemistry. To identify differently expressed genes between primary and metastatic tumors, we performed one-way analysis of variance with Benjamini-Hochberg correction. This led to identification of 203 unique probes that were significantly differentially expressed in the 2 tumor groups by greater than 1.58-fold with P < .01, of which 94 and 109 were overexpressed in primary and metastatic LMSs, respectively. genes overexpressed in primary uterine LMSs included OSTN, NLGN4X, NLGN1, SLITRK4, MASP1, XRN2, ASS1, RORB, HRASLS, and TSPAN7. genes overexpressed in LMS metastases included TNNT1, FOLR3, TDO2, CRYM, GJA1, TSPAN10, THBS1, SGK1, SHMT1, EGR2, and AGT. Quantitative real-time PCR confirmed significant anatomical site-related differences in FOLR3, OSTN, and NLGN4X levels;and immunohistochemistry showed significant differences in TDO2 expression. gene expression profiling differentiates primary uterine LMSs from LMS metastases. The molecular signatures unique to primary and metastatic LMSs may aid in understanding tumor progression in this cancer and in providing a molecular basis for prognostic studies and therapeutic target discovery. (C) 2014 Elsevier Inc. All rights reserved.

关键词： gene expression array Uterine leiomyosarcoma Metastasis

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