440 results on '"Haberman, Yael"'
Search Results
2. Lubricating gel influence on vaginal microbiome sampling
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Amitai Komem, Daphna, Hadar, Rotem, Paulson, Joseph Nathaniel, Mordechai, Yael, Eskandarian, Haig Alexander, Efroni, Gilat, Amir, Amnon, Haberman, Yael, and Tsur, Abraham
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- 2024
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3. Diet-omics in the Study of Urban and Rural Crohn disease Evolution (SOURCE) cohort
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Braun, Tzipi, Feng, Rui, Amir, Amnon, Levhar, Nina, Shacham, Hila, Mao, Ren, Hadar, Rotem, Toren, Itamar, Algavi, Yadid, Abu-Saad, Kathleen, Zhuo, Shuoyu, Efroni, Gilat, Malik, Alona, Picard, Orit, Yavzori, Miri, Agranovich, Bella, Liu, Ta-Chiang, Stappenbeck, Thaddeus S., Denson, Lee, Kalter-Leibovici, Ofra, Gottlieb, Eyal, Borenstein, Elhanan, Elinav, Eran, Chen, Minhu, Ben-Horin, Shomron, and Haberman, Yael
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- 2024
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4. Long-term metabolic effects of non-nutritive sweeteners
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Rathaus, Moran, Azem, Loziana, Livne, Rinat, Ron, Sophie, Ron, Idit, Hadar, Rotem, Efroni, Gilat, Amir, Amnon, Braun, Tzipi, Haberman, Yael, and Tirosh, Amir
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- 2024
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5. Machine-learning-based integrative –‘omics analyses reveal immunologic and metabolic dysregulation in environmental enteric dysfunction
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Zulqarnain, Fatima, Zhao, Xueheng, Setchell, Kenneth D.R., Sharma, Yash, Fernandes, Phillip, Srivastava, Sanjana, Shrivastava, Aman, Ehsan, Lubaina, Jain, Varun, Raghavan, Shyam, Moskaluk, Christopher, Haberman, Yael, Denson, Lee A., Mehta, Khyati, Iqbal, Najeeha T., Rahman, Najeeb, Sadiq, Kamran, Ahmad, Zubair, Idress, Romana, Iqbal, Junaid, Ahmed, Sheraz, Hotwani, Aneeta, Umrani, Fayyaz, Amadi, Beatrice, Kelly, Paul, Brown, Donald E., Moore, Sean R., Ali, Syed Asad, and Syed, Sana
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- 2024
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6. Reduced LHFPL3-AS2 lncRNA expression is linked to altered epithelial polarity and proliferation, and to ileal ulceration in Crohn disease
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Sosnovski, Katya E., Braun, Tzipi, Amir, Amnon, BenShoshan, Marina, Abbas-Egbariya, Haya, Ben-Yishay, Rakefet, Anafi, Liat, Avivi, Camilla, Barshack, Iris, Denson, Lee A., and Haberman, Yael
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- 2023
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7. Gut microbial signature in lung cancer patients highlights specific taxa as predictors for durable clinical benefit
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Haberman, Yael, Kamer, Iris, Amir, Amnon, Goldenberg, Sapir, Efroni, Gilat, Daniel-Meshulam, Inbal, Lobachov, Anastasiya, Daher, Sameh, Hadar, Rotem, Gantz-Sorotsky, Hadas, Urban, Damien, Braun, Tzipi, and Bar, Jair
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- 2023
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8. Association of Baseline Luminal Narrowing With Ileal Microbial Shifts and Gene Expression Programs and Subsequent Transmural Healing in Pediatric Crohn Disease
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Ta, Allison D, Ollberding, Nicholas J, Karns, Rebekah, Haberman, Yael, Alazraki, Adina L, Hercules, David, Baldassano, Robert, Markowitz, James, Heyman, Melvin B, Kim, Sandra, Kirschner, Barbara, Shapiro, Jason M, Noe, Joshua, Oliva-Hemker, Maria, Otley, Anthony, Pfefferkorn, Marian, Kellermayer, Richard, Snapper, Scott, Rabizadeh, Shervin, Xavier, Ramnik, Dubinsky, Marla, Hyams, Jeffrey, Kugathasan, Subra, Jegga, Anil G, Dillman, Jonathan R, and Denson, Lee A
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Pediatric ,Inflammatory Bowel Disease ,Digestive Diseases ,Genetics ,Autoimmune Disease ,Oral and gastrointestinal ,Child ,Cohort Studies ,Constriction ,Pathologic ,Crohn Disease ,Gene Expression ,Humans ,RNA ,Ribosomal ,16S ,Wound Healing ,microbiome ,gene expression ,luminal narrowing ,magnetic resonance enterography ,transmural healing ,Clinical Sciences ,Gastroenterology & Hepatology - Abstract
BackgroundTransmural healing (TH) is associated with better long-term outcomes in Crohn disease (CD), whereas pretreatment ileal gene signatures encoding myeloid inflammatory responses and extracellular matrix production are associated with stricturing. We aimed to develop a predictive model for ileal TH and to identify ileal genes and microbes associated with baseline luminal narrowing (LN), a precursor to strictures.Materials and methodsBaseline small bowel imaging obtained in the RISK pediatric CD cohort study was graded for LN. Ileal gene expression was determined by RNASeq, and the ileal microbial community composition was characterized using 16S rRNA amplicon sequencing. Clinical, demographic, radiologic, and genomic variables were tested for association with baseline LN and future TH.ResultsAfter controlling for ileal location, baseline ileal LN (odds ratio [OR], 0.3; 95% confidence interval [CI], 0.1-0.8), increasing serum albumin (OR, 4; 95% CI, 1.3-12.3), and anti-Saccharomyces cerevisiae antibodies IgG serology (OR, 0.97; 95% CI, 0.95-1) were associated with subsequent TH. A multivariable regression model including these factors had excellent discriminant power for TH (area under the curve, 0.86; positive predictive value, 80%; negative predictive value, 87%). Patients with baseline LN exhibited increased Enterobacteriaceae and inflammatory and extracellular matrix gene signatures, coupled with reduced levels of butyrate-producing commensals and a respiratory electron transport gene signature. Taxa including Lachnospiraceae and the genus Roseburia were associated with increased respiratory and decreased inflammatory gene signatures, and Aggregatibacter and Blautia bacteria were associated with reduced extracellular matrix gene expression.ConclusionsPediatric patients with CD with LN at diagnosis are less likely to achieve TH. The association between specific microbiota, wound healing gene programs, and LN may suggest future therapeutic targets.
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- 2021
9. Stratification of risk of progression to colectomy in ulcerative colitis via measured and predicted gene expression
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Mo, Angela, Nagpal, Sini, Gettler, Kyle, Haritunians, Talin, Giri, Mamta, Haberman, Yael, Karns, Rebekah, Prince, Jarod, Arafat, Dalia, Hsu, Nai-Yun, Chuang, Ling-Shiang, Argmann, Carmen, Kasarskis, Andrew, Suarez-Farinas, Mayte, Gotman, Nathan, Mengesha, Emebet, Venkateswaran, Suresh, Rufo, Paul A, Baker, Susan S, Sauer, Cary G, Markowitz, James, Pfefferkorn, Marian D, Rosh, Joel R, Boyle, Brendan M, Mack, David R, Baldassano, Robert N, Shah, Sapana, LeLeiko, Neal S, Heyman, Melvin B, Griffiths, Anne M, Patel, Ashish S, Noe, Joshua D, Davis Thomas, Sonia, Aronow, Bruce J, Walters, Thomas D, McGovern, Dermot PB, Hyams, Jeffrey S, Kugathasan, Subra, Cho, Judy H, Denson, Lee A, and Gibson, Greg
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Digestive Diseases ,Inflammatory Bowel Disease ,Human Genome ,Autoimmune Disease ,Clinical Research ,Genetics ,Patient Safety ,Biotechnology ,Prevention ,Generic health relevance ,Biological Specimen Banks ,Cohort Studies ,Colectomy ,Colitis ,Ulcerative ,Colon ,Crohn Disease ,Datasets as Topic ,Disease Progression ,Gene Expression Profiling ,Genome-Wide Association Study ,Humans ,Multifactorial Inheritance ,Prognosis ,Quantitative Trait Loci ,Risk Assessment ,Transcriptome ,United Kingdom ,cell-type-specific gene expression ,eQTLs ,predicted polygenic transcriptional risk scores ,prediction of disease progression ,transcriptional risk scores ,transcriptome-wide association studies ,Biological Sciences ,Medical and Health Sciences ,Genetics & Heredity - Abstract
An important goal of clinical genomics is to be able to estimate the risk of adverse disease outcomes. Between 5% and 10% of individuals with ulcerative colitis (UC) require colectomy within 5 years of diagnosis, but polygenic risk scores (PRSs) utilizing findings from genome-wide association studies (GWASs) are unable to provide meaningful prediction of this adverse status. By contrast, in Crohn disease, gene expression profiling of GWAS-significant genes does provide some stratification of risk of progression to complicated disease in the form of a transcriptional risk score (TRS). Here, we demonstrate that a measured TRS based on bulk rectal gene expression in the PROTECT inception cohort study has a positive predictive value approaching 50% for colectomy. Single-cell profiling demonstrates that the genes are active in multiple diverse cell types from both the epithelial and immune compartments. Expression quantitative trait locus (QTL) analysis identifies genes with differential effects at baseline and week 52 follow-up, but for the most part, differential expression associated with colectomy risk is independent of local genetic regulation. Nevertheless, a predicted polygenic transcriptional risk score (PPTRS) derived by summation of transcriptome-wide association study (TWAS) effects identifies UC-affected individuals at 5-fold elevated risk of colectomy with data from the UK Biobank population cohort studies, independently replicated in an NIDDK-IBDGC dataset. Prediction of gene expression from relatively small transcriptome datasets can thus be used in conjunction with TWASs for stratification of risk of disease complications.
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- 2021
10. DUOX2 variants associate with preclinical disturbances in microbiota-immune homeostasis and increased inflammatory bowel disease risk.
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Grasberger, Helmut, Magis, Andrew, Sheng, Elisa, Conomos, Matthew, Zhang, Min, Garzotto, Lea, Hou, Guoqing, Bishu, Shrinivas, Nagao-Kitamoto, Hiroko, El-Zaatari, Mohamad, Kitamoto, Sho, Kamada, Nobuhiko, Stidham, Ryan, Akiba, Yasutada, Kaunitz, Jonathan, Haberman, Yael, Kugathasan, Subra, Denson, Lee, Omenn, Gilbert, and Kao, John
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Gastroenterology ,Genetic variation ,Inflammatory bowel disease ,Innate immunity ,Animals ,Dual Oxidases ,Female ,Gastrointestinal Microbiome ,Genetic Variation ,HEK293 Cells ,Homeostasis ,Humans ,Inflammatory Bowel Diseases ,Interleukin-17 ,Male ,Mice ,Mice ,Knockout - Abstract
A primordial gut-epithelial innate defense response is the release of hydrogen peroxide by dual NADPH oxidase (DUOX). In inflammatory bowel disease (IBD), a condition characterized by an imbalanced gut microbiota-immune homeostasis, DUOX2 isoenzyme is the highest induced gene. Performing multiomic analyses using 2872 human participants of a wellness program, we detected a substantial burden of rare protein-altering DUOX2 gene variants of unknown physiologic significance. We identified a significant association between these rare loss-of-function variants and increased plasma levels of interleukin-17C, which is induced also in mucosal biopsies of patients with IBD. DUOX2-deficient mice replicated increased IL-17C induction in the intestine, with outlier high Il17c expression linked to the mucosal expansion of specific Proteobacteria pathobionts. Integrated microbiota/host gene expression analyses in patients with IBD corroborated IL-17C as a marker for epithelial activation by gram-negative bacteria. Finally, the impact of DUOX2 variants on IL-17C induction provided a rationale for variant stratification in case control studies that substantiated DUOX2 as an IBD risk gene. Thus, our study identifies an association of deleterious DUOX2 variants with a preclinical hallmark of disturbed microbiota-immune homeostasis that appears to precede the manifestation of IBD.
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- 2021
11. Mucosal Inflammatory and Wound Healing Gene Programs Reveal Targets for Stricturing Behavior in Pediatric Crohn's Disease.
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Haberman, Yael, Minar, Phillip, Karns, Rebekah, Dexheimer, Phillip J, Ghandikota, Sudhir, Tegge, Samuel, Shapiro, Daniel, Shuler, Brianne, Venkateswaran, Suresh, Braun, Tzipi, Ta, Allison, Walters, Thomas D, Baldassano, Robert N, Noe, Joshua D, Rosh, Joel, Markowitz, James, Dotson, Jennifer L, Mack, David R, Kellermayer, Richard, Griffiths, Anne M, Heyman, Melvin B, Baker, Susan S, Moulton, Dedrick, Patel, Ashish S, Gulati, Ajay S, Steiner, Steven J, LeLeiko, Neal, Otley, Anthony, Oliva-Hemker, Maria, Ziring, David, Gokhale, Ranjana, Kim, Sandra, Guthery, Stephen L, Cohen, Stanley A, Snapper, Scott, Aronow, Bruce J, Stephens, Michael, Gibson, Greg, Dillman, Jonathan R, Dubinsky, Marla, Hyams, Jeffrey S, Kugathasan, Subra, Jegga, Anil G, and Denson, Lee A
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Crohn's Disease ,Pediatric ,Clinical Research ,Genetics ,Digestive Diseases ,Inflammatory Bowel Disease ,Paediatric Crohn disease ,ileum ,small molecule ,surgery ,transcriptome ,pediatric Crohn Disease ,Clinical Sciences ,Gastroenterology & Hepatology - Abstract
Ileal strictures are the major indication for resective surgery in Crohn's disease (CD). We aimed to define ileal gene programs present at diagnosis linked with future stricturing behavior during five year follow-up, and to identify potential small molecules to reverse these gene signatures. Antimicrobial serologies and pre-treatment ileal gene expression were assessed in a representative subset of 249 CD patients within the RISK multicenter pediatric CD inception cohort study, including 113 that are unique to this report. These data were used to define genes associated with stricturing behavior and for model testing to predict stricturing behavior. A bioinformatics approach to define small molecules which may reverse the stricturing gene signature was applied. 19 of the 249 patients developed isolated B2 stricturing behavior during follow-up, while 218 remained B1 inflammatory. Using deeper RNA sequencing than in our prior report, we have now defined an inflammatory gene signature including an oncostatin M co-expression signature, tightly associated with extra-cellular matrix (ECM) gene expression in those who developed stricturing complications. We further computationally prioritize small molecules targeting macrophage and fibroblast activation and angiogenesis which may reverse the stricturing gene signature. A model containing ASCA and CBir1 serologies and a refined eight ECM gene set was significantly associated with stricturing development by year five after diagnosis (AUC (95th CI) = 0.82 (0.7-0.94)). An ileal gene program for macrophage and fibroblast activation is linked to stricturing complications in treatment naïve pediatric CD, and may inform novel small molecule therapeutic approaches.
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- 2021
12. Baseline Peripheral Blood Mononuclear Cell Transcriptomics Before Ustekinumab Treatment Is Linked With Crohnʼs Disease Clinical Response at 1 Year
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Granot, Maya, Braun, Tzipi, Efroni, Gilat, Picard, Orit, Fudim, Ella, Yavzori, Miri, Haj, Ola, Weiss, Batia, Ben-Horin, Shomron, Kopylov, Uri, and Haberman, Yael
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- 2023
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13. Multicenter Cohort Study of Infliximab Pharmacokinetics and Therapy Response in Pediatric Acute Severe Ulcerative Colitis
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Whaley, Kaitlin G., Xiong, Ye, Karns, Rebekah, Hyams, Jeffrey S., Kugathasan, Subra, Boyle, Brendan M., Walters, Thomas D., Kelsen, Judith, LeLeiko, Neal, Shapiro, Jason, Waddell, Amanda, Fox, Sejal, Bezold, Ramona, Bruns, Stephanie, Widing, Robin, Haberman, Yael, Collins, Margaret H., Mizuno, Tomoyuki, Minar, Phillip, D’Haens, Geert R., Denson, Lee A., Vinks, Alexander A., and Rosen, Michael J.
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- 2023
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14. Clinical and biological predictors of response to standardised paediatric colitis therapy (PROTECT): a multicentre inception cohort study
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Hyams, Jeffrey S, Davis Thomas, Sonia, Gotman, Nathan, Haberman, Yael, Karns, Rebekah, Schirmer, Melanie, Mo, Angela, Mack, David R, Boyle, Brendan, Griffiths, Anne M, LeLeiko, Neal S, Sauer, Cary G, Keljo, David J, Markowitz, James, Baker, Susan S, Rosh, Joel, Baldassano, Robert N, Patel, Ashish, Pfefferkorn, Marian, Otley, Anthony, Heyman, Melvin, Noe, Joshua, Oliva-Hemker, Maria, Rufo, Paul A, Strople, Jennifer, Ziring, David, Guthery, Stephen L, Sudel, Boris, Benkov, Keith, Wali, Prateek, Moulton, Dedrick, Evans, Jonathan, Kappelman, Michael D, Marquis, M Alison, Sylvester, Francisco A, Collins, Margaret H, Venkateswaran, Suresh, Dubinsky, Marla, Tangpricha, Vin, Spada, Krista L, Saul, Bradley, Wang, Jessie, Serrano, Jose, Hommel, Kevin, Marigorta, Urko M, Gibson, Greg, Xavier, Ramnik J, Kugathasan, Subra, Walters, Thomas, and Denson, Lee A
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Cancer ,Clinical Research ,Inflammatory Bowel Disease ,Human Genome ,Autoimmune Disease ,Genetics ,Digestive Diseases ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Adolescent ,Adrenal Cortex Hormones ,Anti-Inflammatory Agents ,Non-Steroidal ,Biomarkers ,Child ,Child ,Preschool ,Cohort Studies ,Colitis ,Ulcerative ,Female ,Hospitalization ,Humans ,Male ,Mesalamine ,Treatment Outcome ,Medical and Health Sciences ,General & Internal Medicine - Abstract
BACKGROUND:Lack of evidence-based outcomes data leads to uncertainty in developing treatment regimens in children who are newly diagnosed with ulcerative colitis. We hypothesised that pretreatment clinical, transcriptomic, and microbial factors predict disease course. METHODS:In this inception cohort study, we recruited paediatric patients aged 4-17 years with newly diagnosed ulcerative colitis from 29 centres in the USA and Canada. Patients initially received standardised mesalazine or corticosteroids, with pre-established criteria for escalation to immunomodulators (ie, thiopurines) or anti-tumor necrosis factor-α (TNFα) therapy. We used RNA sequencing to define rectal gene expression before treatment, and 16S sequencing to characterise rectal and faecal microbiota. The primary outcome was week 52 corticosteroid-free remission with no therapy beyond mesalazine. We assessed factors associated with the primary outcome using logistic regression models of the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT01536535. FINDINGS:Between July 10, 2012, and April 21, 2015, of 467 patients recruited, 428 started medical therapy, of whom 400 (93%) were evaluable at 52 weeks and 386 (90%) completed the study period with no protocol violations. 150 (38%) of 400 participants achieved week 52 corticosteroid-free remission, of whom 147 (98%) were taking mesalazine and three (2%) were taking no medication. 74 (19%) of 400 were escalated to immunomodulators alone, 123 (31%) anti-TNFα therapy, and 25 (6%) colectomy. Low baseline clinical severity, high baseline haemoglobin, and week 4 clinical remission were associated with achieving week 52 corticosteroid-free remission (n=386, logistic model area under the curve [AUC] 0·70, 95% CI 0·65-0·75; specificity 77%, 95% CI 71-82). Baseline severity and remission by week 4 were validated in an independent cohort of 274 paediatric patients with newly diagnosed ulcerative colitis. After adjusting for clinical predictors, an antimicrobial peptide gene signature (odds ratio [OR] 0·57, 95% CI 0·39-0·81; p=0·002) and abundance of Ruminococcaceae (OR 1·43, 1·02-2·00; p=0·04), and Sutterella (OR 0·81, 0·65-1·00; p=0·05) were independently associated with week 52 corticosteroid-free remission. INTERPRETATION:Our findings support the utility of initial clinical activity and treatment response by 4 weeks to predict week 52 corticosteroid-free remission with mesalazine alone in children who are newly diagnosed with ulcerative colitis. The development of personalised clinical and biological signatures holds the promise of informing ulcerative colitis therapeutic decisions. FUNDING:US National Institutes of Health.
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- 2019
15. Age-of-diagnosis dependent ileal immune intensification and reduced alpha-defensin in older versus younger pediatric Crohn Disease patients despite already established dysbiosis
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Haberman, Yael, Schirmer, Melanie, Dexheimer, Phillip J, Karns, Rebekah, Braun, Tzipi, Kim, Mi-Ok, Walters, Thomas D, Baldassano, Robert N, Noe, Joshua D, Rosh, Joel, Markowitz, James, Crandall, Wallace V, Mack, David R, Griffiths, Anne M, Heyman, Melvin B, Baker, Susan S, Kellermayer, Richard, Moulton, Dedrick, Patel, Ashish S, Gulati, Ajay S, Steiner, Steven J, LeLeiko, Neal, Otley, Anthony, Oliva-Hemker, Maria, Ziring, David, Kirschner, Barbara S, Keljo, David J, Guthery, Stephen L, Cohen, Stanley A, Snapper, Scott, Evans, Jonathan, Dubinsky, Marla, Aronow, Bruce, Hyams, Jeffrey S, Kugathasan, Subra, Huttenhower, Curtis, Xavier, Ramnik J, and Denson, Lee A
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Biomedical and Clinical Sciences ,Immunology ,Prevention ,Genetics ,Inflammatory Bowel Disease ,Clinical Research ,Digestive Diseases ,Pediatric ,Aetiology ,2.1 Biological and endogenous factors ,Adolescent ,Age Factors ,Aging ,Child ,Child ,Preschool ,Cohort Studies ,Crohn Disease ,Dysbiosis ,Female ,Gene Expression Regulation ,Humans ,Ileum ,Male ,Peyer's Patches ,Puberty ,Risk ,Th1 Cells ,alpha-Defensins ,Biological Sciences ,Medical and Health Sciences - Abstract
Age-of-diagnosis associated variation in disease location and antimicrobial sero-reactivity has suggested fundamental differences in pediatric Crohn Disease (CD) pathogenesis. This variation may be related to pubertal peak incidence of ileal involvement and Peyer's patches maturation, represented by IFNγ-expressing Th1 cells. However, direct mucosal evidence is lacking. We characterize the global pattern of ileal gene expression and microbial communities in 525 treatment-naive pediatric CD patients and controls (Ctl), stratifying samples by their age-of-diagnosis. We show a robust ileal gene signature notable for higher expression of specific immune genes including GM-CSF and INFγ, and reduced expression of antimicrobial Paneth cell α-defensins, in older compared to younger patients. Reduced α-defensin expression in older patients was associated with higher IFNγ expression. By comparison, the CD-associated ileal dysbiosis, characterized by expansion of Enterobacteriaceae and contraction of Lachnospiraceae and Ruminococcaceae, was already established within the younger group and did not vary systematically with increasing age-of-diagnosis. Multivariate analysis considering individual taxa, however did demonstrate negative associations between Lachnospiraceae and IFNγ, and positive associations between Bacteroides and α-defensin expression. These data provide evidence for maturation of mucosal Th1 immune responses and loss of epithelial antimicrobial α-defensins which are associated with specific taxa with increasing age-of-diagnosis in pediatric CD.
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- 2019
16. Genetic and Transcriptomic Variation Linked to Neutrophil Granulocyte-Macrophage Colony-Stimulating Factor Signaling in Pediatric Crohn's Disease.
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Denson, Lee A, Jurickova, Ingrid, Karns, Rebekah, Shaw, Kelly A, Cutler, David J, Okou, David, Valencia, C Alexander, Dodd, Anne, Mondal, Kajari, Aronow, Bruce J, Haberman, Yael, Linn, Aaron, Price, Adam, Bezold, Ramona, Lake, Kathleen, Jackson, Kimberly, Walters, Thomas D, Griffiths, Anne, Baldassano, Robert N, Noe, Joshua D, Hyams, Jeffrey S, Crandall, Wallace V, Kirschner, Barbara S, Heyman, Melvin B, Snapper, Scott, Guthery, Stephen L, Dubinsky, Marla C, Leleiko, Neal S, Otley, Anthony R, Xavier, Ramnik J, Stevens, Christine, Daly, Mark J, Zwick, Michael E, and Kugathasan, Subra
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Genetics ,Autoimmune Disease ,Crohn's Disease ,Clinical Research ,Inflammatory Bowel Disease ,Digestive Diseases ,2.1 Biological and endogenous factors ,Aetiology ,Adolescent ,Adult ,Case-Control Studies ,Child ,Child ,Preschool ,Crohn Disease ,Cytokine Receptor Common beta Subunit ,Female ,Follow-Up Studies ,Granulocyte-Macrophage Colony-Stimulating Factor ,Humans ,Infant ,Male ,Mutation ,Missense ,Neutrophils ,Prognosis ,Receptors ,Granulocyte-Macrophage Colony-Stimulating Factor ,Transcriptome ,Young Adult ,GM-CSF ,neutrophil ,pediatric inflammatory bowel disease ,RNA sequencing ,STAT5 ,whole-exome sequencing ,Clinical Sciences ,Gastroenterology & Hepatology - Abstract
BACKGROUND:Granulocyte-macrophage colony-stimulating factor auto-antibodies (GMAbs) suppress neutrophil-extrinsic GM-CSF signaling and increase risk for stricturing behavior in Crohn's disease (CD). We aimed to define clinical, genomic, and functional associations with neutrophil-intrinsic GM-CSF signaling. METHODS:Missense mutations in CSF2RA, CSF2RB, JAK2, STAT5A, and STAT5B were identified using whole-exome sequencing in 543 pediatric inflammatory bowel disease (IBD) patients. Neutrophil-intrinsic GM-CSF signaling was defined using the GM-CSF-induced STAT5 stimulation index (GMSI) in 180 pediatric IBD patients and 26 non-IBD controls. Reduced GM-CSF signaling (GMSI-Lo) was defined as the 20th percentile within the control group. Variation in neutrophil phospho-protein abundance, bacterial killing, and the global pattern of gene expression with the GMSI was determined. RESULTS:We validated 18 potentially damaging missense mutations in CSF2RA and CSF2RB. CSF2RA A17G carriage increased from 10% in those with intact neutrophil GMSI to 32% in those with low GMSI (P = 0.02). The frequency of reduced Staphylococcus aureus killing increased from 17% in those with intact neutrophil GMSI to 35% in GMSI-Lo neutrophils (P = 0.043). Crohn's disease neutrophils with low GMSI exhibited specific alterations in phospho-protein networks and genes regulating cytokine production, wound healing, and cell survival and proliferation. Stricturing behavior increased from 7% in patients with both low GMAb and intact GMSI to 64% in patients with both elevated GMAb and low GMSI (P < 0.0001). CONCLUSIONS:Low/normal neutrophil-intrinsic GM-CSF signaling is associated with CSF2RA missense mutations, alterations in gene expression networks, and higher rates of disease complications in pediatric CD.
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- 2019
17. Genetic variants and pathways implicated in a pediatric inflammatory bowel disease cohort
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Shaw, Kelly A, Cutler, David J, Okou, David, Dodd, Anne, Aronow, Bruce J, Haberman, Yael, Stevens, Christine, Walters, Thomas D, Griffiths, Anne, Baldassano, Robert N, Noe, Joshua D, Hyams, Jeffrey S, Crandall, Wallace V, Kirschner, Barbara S, Heyman, Melvin B, Snapper, Scott, Guthery, Stephen, Dubinsky, Marla C, Shapiro, Jason M, Otley, Anthony R, Daly, Mark, Denson, Lee A, Kugathasan, Subra, and Zwick, Michael E
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Biological Sciences ,Genetics ,Clinical Research ,Biotechnology ,Autoimmune Disease ,Pediatric ,Inflammatory Bowel Disease ,Crohn's Disease ,Digestive Diseases ,Human Genome ,2.1 Biological and endogenous factors ,Aetiology ,Oral and gastrointestinal ,Inflammatory and immune system ,Adolescent ,Child ,Child ,Preschool ,Female ,Genome-Wide Association Study ,Humans ,Infant ,Inflammatory Bowel Diseases ,Male ,Polymorphism ,Genetic ,Exome Sequencing ,Immunology - Abstract
In the United States, approximately 5% of individuals with inflammatory bowel disease (IBD) are younger than 20 years old. Studies of pediatric cohorts can provide unique insights into genetic architecture of IBD, which includes Crohn's disease (CD) and ulcerative colitis (UC). Large genome-wide association studies have found more than 200 IBD-associated loci but explain a minority of disease variance for CD and UC. We sought to characterize the contribution of rare variants to disease development, comparing exome sequencing of 368 pediatric IBD patients to publicly available exome sequencing (dbGaP) and aggregate frequency data (ExAC). Using dbGaP data, we performed logistic regression for common variants and optimal unified association tests (SKAT-O) for rare, likely-deleterious variants. We further compared rare variants to ExAC counts with Fisher's exact tests. We did pathway enrichment analysis on the most significant genes from each comparison. Many variants overlapped with known IBD-associated genes (e.g. NOD2). Rare variants were enriched in CD-associated loci (p = 0.009) and showed suggestive enrichment in neutrophil function genes (p = 0.05). Pathway enrichment implicated immune-related pathways, especially cell killing and apoptosis. Variants in extracellular matrix genes also emerged as an important theme in our analysis.
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- 2019
18. Ulcerative colitis mucosal transcriptomes reveal mitochondriopathy and personalized mechanisms underlying disease severity and treatment response
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Haberman, Yael, Karns, Rebekah, Dexheimer, Phillip J, Schirmer, Melanie, Somekh, Judith, Jurickova, Ingrid, Braun, Tzipi, Novak, Elizabeth, Bauman, Laura, Collins, Margaret H, Mo, Angela, Rosen, Michael J, Bonkowski, Erin, Gotman, Nathan, Marquis, Alison, Nistel, Mason, Rufo, Paul A, Baker, Susan S, Sauer, Cary G, Markowitz, James, Pfefferkorn, Marian D, Rosh, Joel R, Boyle, Brendan M, Mack, David R, Baldassano, Robert N, Shah, Sapana, Leleiko, Neal S, Heyman, Melvin B, Grifiths, Anne M, Patel, Ashish S, Noe, Joshua D, Aronow, Bruce J, Kugathasan, Subra, Walters, Thomas D, Gibson, Greg, Thomas, Sonia Davis, Mollen, Kevin, Shen-Orr, Shai, Huttenhower, Curtis, Xavier, Ramnik J, Hyams, Jeffrey S, and Denson, Lee A
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Biological Sciences ,Biomedical and Clinical Sciences ,Immunology ,Nutrition ,Inflammatory Bowel Disease ,Clinical Research ,Autoimmune Disease ,Digestive Diseases ,Genetics ,Biotechnology ,4.1 Discovery and preclinical testing of markers and technologies ,Aetiology ,2.1 Biological and endogenous factors ,Detection ,screening and diagnosis ,Oral and gastrointestinal ,Good Health and Well Being ,Adolescent ,Adult ,Anti-Inflammatory Agents ,Non-Steroidal ,Child ,Colitis ,Ulcerative ,Feces ,Female ,Gene Expression Profiling ,Genes ,Mitochondrial ,Glucocorticoids ,Humans ,Integrins ,Intestinal Mucosa ,Male ,Mesalamine ,Microbiota ,Mitochondria ,Mitochondrial Diseases ,Precision Medicine ,Prospective Studies ,Rectum ,Remission Induction ,Sequence Analysis ,RNA ,Severity of Illness Index ,Transcriptome ,Treatment Outcome ,Tumor Necrosis Factor-alpha - Abstract
Molecular mechanisms driving disease course and response to therapy in ulcerative colitis (UC) are not well understood. Here, we use RNAseq to define pre-treatment rectal gene expression, and fecal microbiota profiles, in 206 pediatric UC patients receiving standardised therapy. We validate our key findings in adult and paediatric UC cohorts of 408 participants. We observe a marked suppression of mitochondrial genes and function across cohorts in active UC, and that increasing disease severity is notable for enrichment of adenoma/adenocarcinoma and innate immune genes. A subset of severity genes improves prediction of corticosteroid-induced remission in the discovery cohort; this gene signature is also associated with response to anti-TNFα and anti-α4β7 integrin in adults. The severity and therapeutic response gene signatures were in turn associated with shifts in microbes previously implicated in mucosal homeostasis. Our data provide insights into UC pathogenesis, and may prioritise future therapies for nonresponders to current approaches.
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- 2019
19. Glycogen Storage Disease type IA refractory to cornstarch: Can next generation sequencing offer a solution?
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Steg Saban, Or, Pode-Shakked, Ben, Abu-Libdeh, Bassam, Granot, Maya, Barkai, Galia, Haberman, Yael, Roterman, Inon, Lahad, Avishay, Shouval, Dror S., Weiss, Batia, Marek-Yagel, Dina, Barel, Ortal, Loberman-Nachum, Nurit, Abraham, Smadar, Somech, Raz, Weinstein, David A., and Anikster, Yair
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- 2022
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20. Evaluating Eosinophilic Colitis as a Unique Disease Using Colonic Molecular Profiles: A Multi-Site Study
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Pablo Abonia, J., Aceves, Seema, Almonte, Samuel, Andrews, Rachel, Anvari, Sara, Arrington, Ashley, Arva, Nicoleta, Atkins, Fred, Bailey, Dominique, Berry, Alexis, Besl, Bridget, Bolton, Scott, Bonis, Peter, Book, Wendy, Bray, Kimberly, Brown, Teresa, Burger, Cassandra, Burke, Deirdre, Cahoon, Jonathon, Capocelli, Kelley, Chehade, Mirna, Chiou, Eric, Collins, Margaret, Davis, Carla, Dellon, Evan, DeMarshall, Maureen, DiTommaso, Lauren, Dohil, Ranjan, Eby, Michael, Falk, Gary, Fleischer, David, Foote, Heather, Foss, Kelci, Friedlander, Joel, Fulkerson, Patricia, Furuta, Glenn, Geno, Debra, Gonsalves, Nirmala, Greuter, Thomas, Gupta, Sandeep, Hamilton, Frank, Harris, Kirk, Harris, Jennifer, Hirano, Ikuo, Hiremath, Girish, Holland-Thomas, Nicole, Jacinto, Lea, Kagalwalla, Amir, Kaseta, Timothy, Katzka, David, Keeley, Kaitlin, Khosh-Hemmat, Emad, Khoury, Paneez, King, Eileen, Kliewer, Kara, Klion, Amy, Knowles, Jennifer, Kocher, Kendra, Kodroff, Ellyn, Krischer, Jeffrey, Kyle, Shay, Leung, John, Levy, Meredith, Liacouras, Chris, Mack, Denise, Martin, Lisa, Martin, Ellen, McCright-Gill, Talaya, Menard-Katcher, Paul, Menard-Katcher, Calies, Mendoza, Gabriela, Mingler, Melissa, Minnicozzi, Mike, Muir, Amanda, Mukkada, Vincent, Murray-Petzold, Cristin, Newbury, Robert, Nhu, Quan, Olive, Anthony, Oyibo, Oghenekpaobor (Joel), Paliana, Allisa, Pan, Zhaoxing, Pesek, Robbie, Peterson, Kathryn, Poppendeck, Heidi, Putnam, Philip, Rivera, Fabian, Rothenberg, Marc, Spergel, Amanda Rudman, Sable, Kathleen, Schoepfer, Alain, Scott, Melissa, Sheridan, Rachel, Sinanovic, Selma, Spergel, Jonathan, Strobel, Mary Jo, Sun, Kiki, Tasco, Amy, Tholen, Crystal, Thompson, Katherine, Tomkinson, Tiffany, Tran, Daisy, Tylicki, Alexandra, Urv, Tiina, Wang, Mei-Lun, Wechsler, Joshua, Wershil, Barry, Wheatley, Lisa, Wilkey, Leah, Yang, Guang-Yu, Zalewski, Angelika, Zicarelli, Amy, Shoda, Tetsuo, Collins, Margaret H., Rochman, Mark, Wen, Ting, Caldwell, Julie M., Mack, Lydia E., Osswald, Garrett A., Besse, John A., Haberman, Yael, Aceves, Seema S., Arva, Nicoleta C., Capocelli, Kelley E., Davis, Carla M., Dellon, Evan S., Falk, Gary W., Gupta, Sandeep K., Mukkada, Vincent A., Putnam, Philip E., Spergel, Jonathan M., Wechsler, Joshua B., Furuta, Glenn T., Denson, Lee A., and Rothenberg, Marc E.
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- 2022
- Full Text
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21. Meta-analysis defines predominant shared microbial responses in various diseases and a specific inflammatory bowel disease signal
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Abbas-Egbariya, Haya, Haberman, Yael, Braun, Tzipi, Hadar, Rotem, Denson, Lee, Gal-Mor, Ohad, and Amir, Amnon
- Published
- 2022
- Full Text
- View/download PDF
22. Gut microbiome development in early childhood is affected by day care attendance
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Amir, Amnon, Erez-Granat, Ortal, Braun, Tzipi, Sosnovski, Katya, Hadar, Rotem, BenShoshan, Marina, Heiman, Sophia, Abbas-Egbariya, Haya, Glick Saar, Efrat, Efroni, Gilat, and Haberman, Yael
- Published
- 2022
- Full Text
- View/download PDF
23. Crohn's Disease–Associated Pathogenic Mutation in the Manganese Transporter ZIP8 Shifts the Ileal and Rectal Mucosal Microbiota Implicating Aberrant Bile Acid Metabolism.
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Briggs, Kristi, Tomar, Vartika, Ollberding, Nicholas, Haberman, Yael, Bourgonje, Arno R, Hu, Shixian, Chaaban, Lara, Sunuwar, Laxmi, Weersma, Rinse K, Denson, Lee A, and Melia, Joanna M P
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- 2024
- Full Text
- View/download PDF
24. Clinical and Genomic Correlates of Neutrophil Reactive Oxygen Species Production in Pediatric Patients With Crohn’s Disease
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Denson, Lee A, Jurickova, Ingrid, Karns, Rebekah, Shaw, Kelly A, Cutler, David J, Okou, David T, Dodd, Anne, Quinn, Kathryn, Mondal, Kajari, Aronow, Bruce J, Haberman, Yael, Linn, Aaron, Price, Adam, Bezold, Ramona, Lake, Kathleen, Jackson, Kimberly, Walters, Thomas D, Griffiths, Anne, Baldassano, Robert N, Noe, Joshua D, Hyams, Jeffrey S, Crandall, Wallace V, Kirschner, Barbara S, Heyman, Melvin B, Snapper, Scott, Guthery, Stephen L, Dubinsky, Marla C, Leleiko, Neal S, Otley, Anthony R, Xavier, Ramnik J, Stevens, Christine, Daly, Mark J, Zwick, Michael E, and Kugathasan, Subra
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Biomedical and Clinical Sciences ,Clinical Sciences ,Autoimmune Disease ,Pediatric ,Crohn's Disease ,Digestive Diseases ,Inflammatory Bowel Disease ,Clinical Research ,Genetics ,Aetiology ,2.1 Biological and endogenous factors ,Adolescent ,Alleles ,Child ,Child ,Preschool ,Cohort Studies ,Crohn Disease ,Down-Regulation ,Female ,Gene Expression Profiling ,Glucose ,Humans ,Infant ,Male ,Mutation ,Missense ,NADPH Oxidases ,Neutrophils ,Phenotype ,Reactive Oxygen Species ,Sequence Analysis ,RNA ,Up-Regulation ,Exome Sequencing ,WES ,IBD ,Neutrophil Oxidative Burst ,Genetic Variant ,Neurosciences ,Paediatrics and Reproductive Medicine ,Gastroenterology & Hepatology ,Clinical sciences ,Nutrition and dietetics - Abstract
Background & aimsIndividuals with monogenic disorders of phagocyte function develop chronic colitis that resembles Crohn's disease (CD). We tested for associations between mutations in genes encoding reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, neutrophil function, and phenotypes of CD in pediatric patients.MethodsWe performed whole-exome sequence analysis to identify mutations in genes encoding NADPH oxidases (such as CYBA, CYBB, NCF1, NCF2, NCF4, RAC1, and RAC2) using DNA from 543 pediatric patients with inflammatory bowel diseases. Blood samples were collected from an additional 129 pediatric patients with CD and 26 children without IBD (controls); we performed assays for neutrophil activation, reactive oxygen species (ROS) production, and bacteria uptake and killing. Whole-exome sequence analysis was performed using DNA from 46 of the children with CD to examine associations with NADPH gene mutations; RNA sequence analyses were performed using blood cells from 46 children with CD to test for variations in neutrophil gene expression associated with ROS production.ResultsWe identified 26 missense mutations in CYBA, CYBB, NCF1, NCF2, and NCF4. Patients with CD who carried mutations in these genes were 3-fold more likely to have perianal disease (P = .0008) and stricturing complications (P = .002) than children with CD without these mutations. Among patients with CD with none of these mutations, 9% had undergone abdominal surgery; among patients with mutations in these NADPH oxidase genes, 31% had undergone abdominal surgery (P = .0004). A higher proportion of neutrophils from children with CD had low ROS production (47%) than from controls (15%) among the 129 patients tested for ROS (P = .002). Minor alleles of the NADPH genes were detected in 7% of children with CD whose neutrophils produced normal levels of ROS vs 38% of children whose neutrophils produced low levels of ROS (P = .009). Neutrophils that produced low levels of ROS had specific alterations in genes that regulate glucose metabolism and antimicrobial responses.ConclusionsWe identified missense mutations in genes that encode NADPH oxidases in children with CD; these were associated with a more aggressive disease course and reduced ROS production by neutrophils from the patients.
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- 2018
25. Long ncRNA Landscape in the Ileum of Treatment-Naive Early-Onset Crohn Disease.
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Haberman, Yael, BenShoshan, Marina, Di Segni, Ayelet, Dexheimer, Phillip J, Braun, Tzipi, Weiss, Batia, Walters, Thomas D, Baldassano, Robert N, Noe, Joshua D, Markowitz, James, Rosh, Joel, Heyman, Melvin B, Griffiths, Anne M, Crandall, Wallace V, Mack, David R, Baker, Susan S, Kellermayer, Richard, Patel, Ashish, Otley, Anthony, Steiner, Steven J, Gulati, Ajay S, Guthery, Stephen L, LeLeiko, Neal, Moulton, Dedrick, Kirschner, Barbara S, Snapper, Scott, Avivi, Camila, Barshack, Iris, Oliva-Hemker, Maria, Cohen, Stanley A, Keljo, David J, Ziring, David, Anikster, Yair, Aronow, Bruce, Hyams, Jeffrey S, Kugathasan, Subra, and Denson, Lee A
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Biotechnology ,Autoimmune Disease ,Prevention ,Crohn's Disease ,Inflammatory Bowel Disease ,Digestive Diseases ,Genetics ,Human Genome ,2.1 Biological and endogenous factors ,Aetiology ,Adolescent ,Caco-2 Cells ,Child ,Crohn Disease ,Down-Regulation ,Female ,Gene Expression Profiling ,Gene Expression Regulation ,Neoplastic ,Gene Regulatory Networks ,Hepatocyte Nuclear Factor 4 ,Humans ,Ileum ,Male ,Oligonucleotide Array Sequence Analysis ,RNA ,Long Noncoding ,RNA ,Messenger ,Up-Regulation ,Crohn disease ,long ncRNA ,RNAseq ,RNA expression ,Clinical Sciences ,Gastroenterology & Hepatology - Abstract
BackgroundLong noncoding RNAs (lncRNA) are key regulators of gene transcription and many show tissue-specific expression. We previously defined a novel inflammatory and metabolic ileal gene signature in treatment-naive pediatric Crohn disease (CD). We now extend our analyses to include potential regulatory lncRNA.MethodsUsing RNAseq, we systematically profiled lncRNAs and protein-coding gene expression in 177 ileal biopsies. Co-expression analysis was used to identify functions and tissue-specific expression. RNA in situ hybridization was used to validate expression. Real-time polymerase chain reaction was used to test lncRNA regulation by IL-1β in Caco-2 enterocytes.ResultsWe characterize widespread dysregulation of 459 lncRNAs in the ileum of CD patients. Using only the lncRNA in discovery and independent validation cohorts showed patient classification as accurate as the protein-coding genes, linking lncRNA to CD pathogenesis. Co-expression and functional annotation enrichment analyses across several tissues and cell types 1showed that the upregulated LINC01272 is associated with a myeloid pro-inflammatory signature, whereas the downregulated HNF4A-AS1 exhibits association with an epithelial metabolic signature. We confirmed tissue-specific expression in biopsies using in situ hybridization, and validated regulation of prioritized lncRNA upon IL-1β exposure in differentiated Caco-2 cells. Finally, we identified significant correlations between LINC01272 and HNF4A-AS1 expression and more severe mucosal injury.ConclusionsWe systematically define differentially expressed lncRNA in the ileum of newly diagnosed pediatric CD. We show lncRNA utility to correctly classify disease or healthy states and demonstrate their regulation in response to an inflammatory signal. These lncRNAs, after mechanistic exploration, may serve as potential new tissue-specific targets for RNA-based interventions.
- Published
- 2018
26. Bile Acid Profiling Reveals Distinct Signatures in Undernourished Children with Environmental Enteric Dysfunction
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Zhao, Xueheng, Setchell, Kenneth DR, Huang, Rong, Mallawaarachchi, Indika, Ehsan, Lubaina, Dobrzykowski III, Edward, Zhao, Junfang, Syed, Sana, Ma, Jennie Z, Iqbal, Najeeha T, Iqbal, Junaid, Sadiq, Kamran, Ahmed, Sheraz, Haberman, Yael, Denson, Lee A, Asad Ali, Syed, and Moore, Sean R
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- 2021
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27. Lack of gut microbiome recovery with spinal cord injury rehabilitation
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Gur Arie, Ayelet, primary, Toren, Itamar, additional, Hadar, Rotem, additional, Braun, Tzipi, additional, Efroni, Gilat, additional, Glick Saar, Efrat, additional, Madar, Zecharia, additional, Amir, Amnon, additional, Zeilig, Gabriel, additional, and Haberman, Yael, additional
- Published
- 2024
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28. Practice variations in the management of infants with non-IgE mediated cow’s milk protein allergy
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Granot, Maya, Machnes Maayan, Diti, Weiss, Batia, Haberman, Yael, Agmon-Levin, Nancy, and Shouval, Dror S.
- Published
- 2022
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29. Trabecular Bone Score in Children and Adolescents With Inflammatory Bowel Diseases
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Levy-Shraga, Yael, Megnazi, Ophir, Modan-Moses, Dalit, Tripto-Shkolnik, Liana, Gruber, Noah, Haberman, Yael, Shouval, Dror S., and Weiss, Batia
- Published
- 2021
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30. Mucosal Expression of Type 2 and Type 17 Immune Response Genes Distinguishes Ulcerative Colitis From Colon-Only Crohn’s Disease in Treatment-Naive Pediatric Patients
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Rosen, Michael J, Karns, Rebekah, Vallance, Jefferson E, Bezold, Ramona, Waddell, Amanda, Collins, Margaret H, Haberman, Yael, Minar, Phillip, Baldassano, Robert N, Hyams, Jeffrey S, Baker, Susan S, Kellermayer, Richard, Noe, Joshua D, Griffiths, Anne M, Rosh, Joel R, Crandall, Wallace V, Heyman, Melvin B, Mack, David R, Kappelman, Michael D, Markowitz, James, Moulton, Dedrick E, Leleiko, Neal S, Walters, Thomas D, Kugathasan, Subra, Wilson, Keith T, Hogan, Simon P, and Denson, Lee A
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Biomedical and Clinical Sciences ,Clinical Sciences ,Pediatric ,Inflammatory Bowel Disease ,Autoimmune Disease ,Crohn's Disease ,Cancer ,Colo-Rectal Cancer ,Genetics ,Digestive Diseases ,Clinical Research ,Oral and gastrointestinal ,Adolescent ,Area Under Curve ,Case-Control Studies ,Child ,Colitis ,Ulcerative ,Colon ,Crohn Disease ,Female ,Gene Expression ,Humans ,Immunity ,Mucosal ,Interleukin-13 ,Interleukin-13 Receptor alpha2 Subunit ,Interleukin-17 ,Interleukin-23 ,Interleukin-5 ,Interleukins ,Intestinal Mucosa ,Male ,Predictive Value of Tests ,Prognosis ,Prospective Studies ,RNA ,Messenger ,ROC Curve ,Rectum ,Transcriptome ,Up-Regulation ,Immune Regulation ,Gene Expression Profile ,Prognostic Factor ,AUROC ,Neurosciences ,Paediatrics and Reproductive Medicine ,Gastroenterology & Hepatology ,Clinical sciences ,Nutrition and dietetics - Abstract
Background & aimsThere is controversy regarding the role of the type 2 immune response in the pathogenesis of ulcerative colitis (UC)-few data are available from treatment-naive patients. We investigated whether genes associated with a type 2 immune response in the intestinal mucosa are up-regulated in treatment-naive pediatric patients with UC compared with patients with Crohn's disease (CD)-associated colitis or without inflammatory bowel disease (IBD), and whether expression levels are associated with clinical outcomes.MethodsWe used a real-time reverse-transcription quantitative polymerase chain reaction array to analyze messenger RNA (mRNA) expression patterns in rectal mucosal samples from 138 treatment-naive pediatric patients with IBD and macroscopic rectal disease, as well as those from 49 children without IBD (controls), enrolled in a multicenter prospective observational study from 2008 to 2012. Results were validated in real-time reverse-transcription quantitative polymerase chain reaction analyses of rectal RNA from an independent cohort of 34 pediatric patients with IBD and macroscopic rectal disease and 17 controls from Cincinnati Children's Hospital Medical Center.ResultsWe measured significant increases in mRNAs associated with a type 2 immune response (interleukin [IL]5 gene, IL13, and IL13RA2) and a type 17 immune response (IL17A and IL23) in mucosal samples from patients with UC compared with patients with colon-only CD. In a regression model, increased expression of IL5 and IL17A mRNAs distinguished patients with UC from patients with colon-only CD (P = .001; area under the receiver operating characteristic curve, 0.72). We identified a gene expression pattern in rectal tissues of patients with UC, characterized by detection of IL13 mRNA, that predicted clinical response to therapy after 6 months (odds ratio [OR], 6.469; 95% confidence interval [CI], 1.553-26.94), clinical response after 12 months (OR, 6.125; 95% CI, 1.330-28.22), and remission after 12 months (OR, 5.333; 95% CI, 1.132-25.12).ConclusionsIn an analysis of rectal tissues from treatment-naive pediatric patients with IBD, we observed activation of a type 2 immune response during the early course of UC. We were able to distinguish patients with UC from those with colon-only CD based on increased mucosal expression of genes that mediate type 2 and type 17 immune responses. Increased expression at diagnosis of genes that mediate a type 2 immune response is associated with response to therapy and remission in pediatric patients with UC.
- Published
- 2017
31. Eicosatetraynoic Acid and Butyrate Regulate Human Intestinal Organoid Mitochondrial and Extracellular Matrix Pathways Implicated in Crohn’s Disease Strictures
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Jurickova, Ingrid, Bonkowski, Erin, Angerman, Elizabeth, Novak, Elizabeth, Huron, Alex, Akers, Grayce, Iwasawa, Kentaro, Braun, Tzipi, Hadar, Rotem, Hooker, Maria, Han, Sarah, Cutler, David J, Okou, David T, Kugathasan, Subra, Jegga, Anil, Wells, James, Takebe, Takanori, Mollen, Kevin P, Haberman, Yael, and Denson, Lee A
- Published
- 2022
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32. Eicosatetraynoic Acid Regulates Pro-Fibrotic Pathways in an Induced Pluripotent Stem Cell Derived Macrophage:Human Intestinal Organoid Model of Crohns Disease
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Jurickova, Ingrid, primary, Dreskin, Benjamin W., additional, Angerman, Elizabeth, additional, Bonkowski, Erin, additional, Tominaga, Kentaro, additional, Iwasawa, Kentaro, additional, Braun, Tzipi, additional, Takebe, Takanori, additional, Helmrath, Michael A., additional, Haberman, Yael, additional, Wells, James M., additional, and Denson, Lee A., additional
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- 2024
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- View/download PDF
33. SARS-CoV-2 does not have a strong effect on the nasopharyngeal microbial composition
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Braun, Tzipi, Halevi, Shiraz, Hadar, Rotem, Efroni, Gilate, Glick Saar, Efrat, Keller, Natahan, Amir, Amnon, Amit, Sharon, and Haberman, Yael
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- 2021
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34. Profiling non-coding RNA levels with clinical classifiers in pediatric Crohn’s disease
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Pelia, Ranjit, Venkateswaran, Suresh, Matthews, Jason D., Haberman, Yael, Cutler, David J., Hyams, Jeffrey S., Denson, Lee A., and Kugathasan, Subra
- Published
- 2021
- Full Text
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35. Clinical and Host Biological Factors Predict Colectomy Risk in Children Newly Diagnosed With Ulcerative Colitis
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Hyams, Jeffrey S, Brimacombe, Michael, Haberman, Yael, Walters, Thomas, Gibson, Greg, Mo, Angela, Mack, David, Griffiths, Anne, Boyle, Brendan, LeLeiko, Neal, Markowitz, James, Rosh, Joel, Patel, Ashish, Shah, Sapana, Baldassano, Robert, Pfefferkorn, Marian, Sauer, Cary, Dailey, Joelynn, Venkateswaran, Suresh, Kugathasan, Subra, and Denson, Lee A
- Published
- 2022
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36. Assessment of small bowel mucosal healing by video capsule endoscopy for the prediction of short-term and long-term risk of Crohn's disease flare: a prospective cohort study
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Ben-Horin, Shomron, Lahat, Adi, Amitai, Marianne M, Klang, Eyal, Yablecovitch, Doron, Neuman, Sandra, Levhar, Nina, Selinger, Limor, Rozendorn, Noa, Turner, Dan, Chowers, Yehuda, Odes, Shmuel, Schwartz, Doron, Yanai, Henit, Dotan, Iris, Braun, Tzipi, Haberman, Yael, Kopylov, Uri, and Eliakim, Rami
- Published
- 2019
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37. Pediatric Crohn disease patients exhibit specific ileal transcriptome and microbiome signature
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Haberman, Yael, Tickle, Timothy L, Dexheimer, Phillip J, Kim, Mi-Ok, Tang, Dora, Karns, Rebekah, Baldassano, Robert N, Noe, Joshua D, Rosh, Joel, Markowitz, James, Heyman, Melvin B, Griffiths, Anne M, Crandall, Wallace V, Mack, David R, Baker, Susan S, Huttenhower, Curtis, Keljo, David J, Hyams, Jeffrey S, Kugathasan, Subra, Walters, Thomas D, Aronow, Bruce, Xavier, Ramnik J, Gevers, Dirk, and Denson, Lee A
- Subjects
Prevention ,Digestive Diseases ,Genetics ,Inflammatory Bowel Disease ,Crohn's Disease ,Autoimmune Disease ,Clinical Research ,Aetiology ,2.1 Biological and endogenous factors ,Oral and gastrointestinal ,Adolescent ,Apolipoprotein A-I ,Case-Control Studies ,Child ,Cohort Studies ,Colitis ,Ulcerative ,Crohn Disease ,Dual Oxidases ,Female ,Gene Expression Profiling ,Humans ,Ileum ,Male ,Microbiota ,NADPH Oxidases ,Proteobacteria ,Transcriptome ,Medical and Health Sciences ,Immunology - Abstract
Interactions between the host and gut microbial community likely contribute to Crohn disease (CD) pathogenesis; however, direct evidence for these interactions at the onset of disease is lacking. Here, we characterized the global pattern of ileal gene expression and the ileal microbial community in 359 treatment-naive pediatric patients with CD, patients with ulcerative colitis (UC), and control individuals. We identified core gene expression profiles and microbial communities in the affected CD ilea that are preserved in the unaffected ilea of patients with colon-only CD but not present in those with UC or control individuals; therefore, this signature is specific to CD and independent of clinical inflammation. An abnormal increase of antimicrobial dual oxidase (DUOX2) expression was detected in association with an expansion of Proteobacteria in both UC and CD, while expression of lipoprotein APOA1 gene was downregulated and associated with CD-specific alterations in Firmicutes. The increased DUOX2 and decreased APOA1 gene expression signature favored oxidative stress and Th1 polarization and was maximally altered in patients with more severe mucosal injury. A regression model that included APOA1 gene expression and microbial abundance more accurately predicted month 6 steroid-free remission than a model using clinical factors alone. These CD-specific host and microbe profiles identify the ileum as the primary inductive site for all forms of CD and may direct prognostic and therapeutic approaches.
- Published
- 2014
38. Utility of Neutrophil Fc&ggr; Receptor I (CD64) Index as a Biomarker for Mucosal Inflammation in Pediatric Crohn's Disease
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Minar, Phillip, Haberman, Yael, Jurickova, Ingrid, Wen, Ting, Rothenberg, Marc E, Kim, Mi-Ok, Saeed, Shehzad A, Baldassano, Robert N, Stephens, Michael, Markowitz, James, Rosh, Joel, Crandall, Wallace V, Heyman, Melvin B, Mack, David R, Griffiths, Anne M, Baker, Susan S, Hyams, Jeffrey S, Kugathasan, Subra, and Denson, Lee A
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Biomedical and Clinical Sciences ,Clinical Sciences ,Digestive Diseases ,Pediatric ,Crohn's Disease ,Inflammatory Bowel Disease ,Autoimmune Disease ,Clinical Research ,Prevention ,Oral and gastrointestinal ,Adolescent ,Biomarkers ,Calgranulin B ,Child ,Child ,Preschool ,Cohort Studies ,Crohn Disease ,Female ,Humans ,Ileum ,Intestinal Mucosa ,Male ,Neutrophils ,Receptors ,IgG ,Rectum ,Recurrence ,Remission Induction ,Risk Factors ,Sensitivity and Specificity ,innate immune system in IBD ,Fc gamma receptor ,CD64 index ,pediatric Crohn's disease ,biomarker ,Gastroenterology & Hepatology ,Clinical sciences - Abstract
BackgroundNeutrophil expression of the Fcγ receptor I (CD64) is upregulated in adult patients with clinically active inflammatory bowel disease (IBD). We tested the relationship of CD64 with mucosal inflammation and clinical relapse in pediatric Crohn's disease (CD).MethodsIn a cohort of 208 newly diagnosed CD and 43 non-IBD controls, ileal expression of FcγRI/S100A9 was determined by RNA sequencing from biopsies obtained at ileocolonoscopy. In a second cohort, we tested for the peripheral blood polymorphonuclear neutrophil (PMN) CD64 index from 26 newly diagnosed CD, 30 non-IBD controls, and 83 children with established CD.ResultsIleal FcγRIA mRNA expression was significantly elevated in CD at diagnosis compared with non-IBD controls (P < 0.001), and correlated with ileal S100A9 (calprotectin) expression (r = 0.83, P < 0.001). The median (range) PMN CD64 index for newly diagnosed CD was 2.3 (0.74-9.3) compared with 0.76 (0.39-1.2) for non-IBD controls (P < 0.001) with 96% sensitivity and 90% specificity at the cut point of 1.0. The PMN CD64 index significantly correlated with mucosal injury as measured by the simple endoscopic score for CD (r = 0.62, P < 0.001). Patients with CD in clinical remission receiving maintenance therapy with a PMN CD64 index 1.0 (P < 0.01).ConclusionsAn elevated PMN CD64 index is associated with both mucosal inflammation and an increased risk for clinical relapse in pediatric CD. The PMN CD64 index is a reliable marker for sustained remission in patients with CD receiving maintenance therapy.
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- 2014
39. The Treatment-Naive Microbiome in New-Onset Crohn’s Disease
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Gevers, Dirk, Kugathasan, Subra, Denson, Lee A, Vázquez-Baeza, Yoshiki, Van Treuren, Will, Ren, Boyu, Schwager, Emma, Knights, Dan, Song, Jin, Yassour, Moran, Morgan, Xochitl C, Kostic, Aleksandar D, Luo, Chengwei, González, Antonio, McDonald, Daniel, Haberman, Yael, Walters, Thomas, Baker, Susan, Rosh, Joel, Stephens, Michael, Heyman, Melvin, Markowitz, James, Baldassano, Robert, Griffiths, Anne, Sylvester, Francisco, Mack, David, Kim, Sandra, Crandall, Wallace, Hyams, Jeffrey, Huttenhower, Curtis, Knight, Rob, and Xavier, Ramnik J
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Pediatric ,Inflammatory Bowel Disease ,Prevention ,Digestive Diseases ,Autoimmune Disease ,Crohn's Disease ,Clinical Research ,Detection ,screening and diagnosis ,2.1 Biological and endogenous factors ,4.1 Discovery and preclinical testing of markers and technologies ,Aetiology ,Oral and gastrointestinal ,Adolescent ,Bacteria ,Child ,Child ,Preschool ,Cohort Studies ,Crohn Disease ,Dysbiosis ,Gastrointestinal Tract ,Humans ,Metagenome ,Microbiota ,Microbiology ,Medical Microbiology ,Immunology - Abstract
Inflammatory bowel diseases (IBDs), including Crohn's disease (CD), are genetically linked to host pathways that implicate an underlying role for aberrant immune responses to intestinal microbiota. However, patterns of gut microbiome dysbiosis in IBD patients are inconsistent among published studies. Using samples from multiple gastrointestinal locations collected prior to treatment in new-onset cases, we studied the microbiome in the largest pediatric CD cohort to date. An axis defined by an increased abundance in bacteria which include Enterobacteriaceae, Pasteurellacaea, Veillonellaceae, and Fusobacteriaceae, and decreased abundance in Erysipelotrichales, Bacteroidales, and Clostridiales, correlates strongly with disease status. Microbiome comparison between CD patients with and without antibiotic exposure indicates that antibiotic use amplifies the microbial dysbiosis associated with CD. Comparing the microbial signatures between the ileum, the rectum, and fecal samples indicates that at this early stage of disease, assessing the rectal mucosal-associated microbiome offers unique potential for convenient and early diagnosis of CD.
- Published
- 2014
40. Baseline peripheral blood mononuclear cell (PBMC) transcriptomics before ustekinumab treatment is linked with Crohn Disease clinical response at 1 year
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Granot, Maya, primary, Braun, Tzipi, additional, Efroni, Gilat, additional, Picard, Orit, additional, Fudim, Ella, additional, Yavzori, Miri, additional, Haj, Ola, additional, Weiss, Batia, additional, Ben-Horin, Shomron, additional, Kopylov, Uri, additional, and Haberman, Yael, additional
- Published
- 2023
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41. Disruption of Epithelial HDAC3 in Intestine Prevents Diet-Induced Obesity in Mice
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Whitt, Jordan, Woo, Vivienne, Lee, Patrick, Moncivaiz, Jessica, Haberman, Yael, Denson, Lee, Tso, Patrick, and Alenghat, Theresa
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- 2018
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42. Tissue-based Gene Expression as Potential Biomarkers for IBD Course
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Haberman, Yael
- Published
- 2020
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43. Mucosal transcriptomics highlight lncRNAs implicated in ulcerative colitis, Crohn’s disease, and celiac disease
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Braun, Tzipi, primary, Sosnovski, Katya E., additional, Amir, Amnon, additional, BenShoshan, Marina, additional, VanDussen, Kelli L., additional, Karns, Rebekah, additional, Levhar, Nina, additional, Abbas-Egbariya, Haya, additional, Hadar, Rotem, additional, Efroni, Gilat, additional, Castel, David, additional, Avivi, Camila, additional, Rosen, Michael J., additional, Grifiths, Anne M., additional, Walters, Thomas D., additional, Mack, David R., additional, Boyle, Brendan M., additional, Ali, Syed Asad, additional, Moore, Sean R., additional, Schirmer, Melanie, additional, Xavier, Ramnik J., additional, Kugathasan, Subra, additional, Jegga, Anil G., additional, Weiss, Batya, additional, Mayer, Chen, additional, Barshack, Iris, additional, Ben-Horin, Shomron, additional, Ulitsky, Igor, additional, Beucher, Anthony, additional, Ferrer, Jorge, additional, Hyams, Jeffrey S., additional, Denson, Lee A., additional, and Haberman, Yael, additional
- Published
- 2023
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44. Intrahepatic portosystemic shunts, from prenatal diagnosis to postnatal outcome: a retrospective study
- Author
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Steg Saban, Or, primary, Weissbach, Tal, additional, Achiron, Reuven, additional, Pekar Zlotin, Marina, additional, Haberman, Yael, additional, Anis Heusler, Adi, additional, Kassif, Eran, additional, and Weiss, Batia, additional
- Published
- 2023
- Full Text
- View/download PDF
45. Achieving pan-microbiome biological insights via the dbBact knowledge base
- Author
-
Amir, Amnon, primary, Ozel, Eitan, additional, Haberman, Yael, additional, and Shental, Noam, additional
- Published
- 2023
- Full Text
- View/download PDF
46. Defining the Celiac Disease Transcriptome using Clinical Pathology Specimens Reveals Biologic Pathways and Supports Diagnosis
- Author
-
Loberman-Nachum, Nurit, Sosnovski, Katya, Di Segni, Ayelet, Efroni, Gilat, Braun, Tzipi, BenShoshan, Marina, Anafi, Lait, Avivi, Camila, Barshack, Iris, Shouval, Dror S., Denson, Lee A., Amir, Amnon, Unger, Ron, Weiss, Batia, and Haberman, Yael
- Published
- 2019
- Full Text
- View/download PDF
47. Lack of gut microbiome recovery with spinal cord injury rehabilitation.
- Author
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Arie, Ayelet Gur, Toren, Itamar, Hadar, Rotem, Braun, Tzipi, Efroni, Gilat, Saar, Efrat Glick, Madar, Zecharia, Amir, Amnon, Zeilig, Gabriel, and Haberman, Yael
- Published
- 2024
- Full Text
- View/download PDF
48. Intrahepatic portosystemic shunts, from prenatal diagnosis to postnatal outcome: a retrospective study.
- Author
-
Saban, Or Steg, Weissbach, Tal, Achiron, Reuven, Zlotin, Marina Pekar, Haberman, Yael, Heusler, Adi Anis, Kassif, Eran, and Weiss, Batia
- Subjects
PRENATAL diagnosis ,FAILURE to thrive syndrome ,ESOPHAGEAL atresia ,HEPATIC portal system - Published
- 2023
- Full Text
- View/download PDF
49. Genetic and Structural Analysis of a SKIV2L Mutation Causing Tricho-hepato-enteric Syndrome
- Author
-
Vardi, Iddo, Barel, Ortal, Sperber, Michal, Schvimer, Michael, Nunberg, Moran, Field, Michael, Ouahed, Jodie, Marek-Yagel, Dina, Werner, Lael, Haberman, Yael, Lahad, Avishay, Anikster, Yair, Rechavi, Gideon, Barshack, Iris, McElwee, Joshua J., Maranville, Joseph, Somech, Raz, Snapper, Scott B., Weiss, Batia, and Shouval, Dror S.
- Published
- 2018
- Full Text
- View/download PDF
50. Transcriptome analysis in acute gastrointestinal graft-versus host disease reveals a unique signature in children and shared biology with pediatric inflammatory bowel disease
- Author
-
Khandelwal, Pooja, primary, Lounder, Dana T, additional, Bartlett, Allison, additional, Haberman, Yael, additional, Jegga, Anil G., additional, Ghandikota, Sudhir, additional, Koo, Jane, additional, Luebbering, Nathan, additional, Leino, Daniel, additional, Abdullah, Sheyar, additional, Loveless, Michaela, additional, Minar, Phillip, additional, Lake, Kelly, additional, Litts, Bridget, additional, Karns, Rebekah, additional, Nelson, Adam S., additional, Denson, Lee A., additional, and Davies, Stella M., additional
- Published
- 2023
- Full Text
- View/download PDF
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