Leina Alrabadi

All Publications

• Bile-Derived Organoids From Patients With Primary Sclerosing Cholangitis Recapitulate Their Inflammatory Immune Profile. Hepatology (Baltimore, Md.) Soroka, C. J., Assis, D. N., Alrabadi, L. S., Roberts, S., Cusack, L., Jaffe, A. B., Boyer, J. L. 2019; 70 (3): 871–82

  Abstract

  Primary sclerosing cholangitis (PSC) is a heterogeneous and progressive fibroinflammatory cholangiopathy with no known etiology or effective treatment. Studies of PSC are limited due to difficulty in accessing the cholangiocyte, the small percentage of these cells in the liver, instability of in vitro culture systems, and reliance on samples from end-stage disease. Here, we demonstrate that stem cells can be isolated from the bile of PSC patients undergoing endoscopic retrograde cholangiopancreatography earlier in their clinical course and maintained long term in vitro as three-dimensional (3D) organoids that express a biliary genetic phenotype. Additionally, bile-derived organoids (BDOs) can be biobanked and samples obtained longitudinally over the course of the disease. These BDOs express known cholangiocyte markers including gamma glutamyl transferase, cytokeratin 19, epithelial cellular adhesion molecule, cystic fibrosis transmembrane conductance regulator, and anion exchanger 2. RNA sequence analysis identified 39 genes whose expression differed in organoids from PSC patients compared to non-PSC controls, including human leukocyte antigen DM alpha chain and chemokine (C-C motif) ligand 20 (CCL20), immune-related genes previously described in genome-wide association studies of PSC. Incubation of these BDOs with interleukin 17A or tumor necrosis factor alpha led to an immune-reactive phenotype with a significant increase in secretion of proinflammatory mediators, including CCL20, a T-cell chemoattractant. Conclusion: This study demonstrates that bile can be used as a source of biliary-like cells that can be maintained long term in vitro as 3D organoids; these BDOs retain features of cholangiopathies, including the ability to react to inflammatory stimuli by secreting chemokines and propagating an immune-reactive phenotype reflective of the pathogenesis of these diseases; thus, BDOs represent a platform for the study of the pathogenesis and therapy of cholangiopathies, particularly PSC.

  View details for DOI 10.1002/hep.30470

  View details for PubMedID 30561836

• Refractory Infantile Chronic Diarrhea and Failure to Thrive in a 6-Month-Old Boy With a Complex Past Medical History CLINICAL PEDIATRICS Okafor, D., AlRabadi, L., Alper, A., Jeffries, L., McGrath, J., Porto, A. F. 2019; 58 (6): 707–10

  View details for DOI 10.1177/0009922819832034

  View details for Web of Science ID 000466124900017

  View details for PubMedID 30788983

• Bile-Derived Organoids from PSC Patients Recapitulate the Inflammatory Immune Profile Seen in Cholangiopathies, Providing an in Vitro Model to Test Candidate Therapeutic Agents. Soroka, C. J., Assis, D. N., Alrabadi, L., Roberts, S., Cusack, L., Silveira, M. G., Boyer, J. L. WILEY. 2018: 1080A

  View details for Web of Science ID 000446020503126

• Mindfulness-Based Stress Reduction Improves Stress, Disease Activity and Cytokine Levels in Patients with Autoimmune Hepatitis (AIH) Alrabadi, L., Dutton, A., Roberts, S., Deng, Y., Cusack, L., Rabiee, A., Silveira, M. G., Ciarleglio, M., Sinha, R., Assis, D. N., Boyer, J. L. WILEY. 2018: 1119A–1120A

  View details for Web of Science ID 000446020503191

• Assessment of Community Pediatric Providers' Approach to a Child With Celiac Disease and Available Serological Testing Associated With a Large Tertiary Care Center CLINICAL PEDIATRICS Alrabadi, L. S., Porto, A. F. 2018; 57 (10): 1199–1203

  Abstract

  An evidence-practice gap for use of celiac disease testing can lead to poor resource utilization. False positive tests may lead to unnecessary diet changes, gastroenterology consults, parental/patient concern, and additional testing and expenses complicated by varied available celiac bundles. An understanding of pediatric provider practices according to guideline recommendations further improves this gap.

  View details for DOI 10.1177/0009922818769453

  View details for Web of Science ID 000440685200009

  View details for PubMedID 29667919

• Biliary drainage as treatment for allograft steatosis following liver transplantation for PFIC-1 disease: A single-center experience PEDIATRIC TRANSPLANTATION Alrabadi, L. S., Morotti, R. A., Valentino, P. L., Rodriguez-Davalos, M. I., Ekong, U. D., Emre, S. H. 2018; 22 (4): e13184

  Abstract

  Development of macrovesicular steatosis post-LT in patients with PFIC-1 is increasingly being observed, with the etiology not fully understood. We highlight successful and effective EBD for reversal of allograft steatosis in 2 patients with PFIC-1 disease and discuss our experience with internal biliary diversion in this patient population.

  View details for DOI 10.1111/petr.13184

  View details for Web of Science ID 000433590800014

  View details for PubMedID 29654655

• Human bile contains stem cells which can be cultured in vitro as 3D organoids. Soroka, C. J., Alrabadi, L., Mennone, A., Assis, D. N., Rodriguez, R., Boyer, J. L. WILEY. 2017: 64A

  View details for Web of Science ID 000412089800110

• Diet-Induced Obesity Promotes Colon Tumor Development in Azoxymethane-Treated Mice PLOS ONE Tuominen, I., Al-Rabadi, L., Stavrakis, D., Karagiannides, I., Pothoulakis, C., Bugni, J. M. 2013; 8 (4): e60939

  Abstract

  Obesity is an important risk factor for colon cancer in humans, and numerous studies have shown that a high fat diet enhances colon cancer development. As both increased adiposity and high fat diet can promote tumorigenesis, we examined the effect of diet-induced obesity, without ongoing high fat diet, on colon tumor development. C57BL/6J male mice were fed regular chow or high fat diet for 8 weeks. Diets were either maintained or switched resulting in four experimental groups: regular chow (R), high fat diet (H), regular chow switched to high fat diet (RH), and high fat diet switched to regular chow (HR). Mice were then administered azoxymethane to induce colon tumors. Tumor incidence and multiplicity were dramatically smaller in the R group relative to all groups that received high fat diet at any point. The effect of obesity on colon tumors could not be explained by differences in aberrant crypt foci number. Moreover, diet did not alter colonic expression of pro-inflammatory cytokines tumor necrosis factor-α, interleukin-6, interleukin-1β, and interferon-γ, which were measured immediately after azoxymethane treatment. Crypt apoptosis and proliferation, which were measured at the same time, were increased in the HR relative to all other groups. Our results suggest that factors associated with obesity - independently of ongoing high fat diet and obesity - promote tumor development because HR group animals had significantly more tumors than R group, and these mice were fed the same regular chow throughout the entire carcinogenic period. Moreover, there was no difference in the number of aberrant crypt foci between these groups, and thus the effect of obesity appears to be on subsequent stages of tumor development when early preneoplastic lesions transition into adenomas.

  View details for DOI 10.1371/journal.pone.0060939

  View details for Web of Science ID 000318840100109

  View details for PubMedID 23560112

  View details for PubMedCentralID PMC3616169

• The neurotensin receptor-1 promotes tumor development in a sporadic but not an inflammation-associated mouse model of colon cancer INTERNATIONAL JOURNAL OF CANCER Bugni, J. M., Al-Rabadi, L., Jubbal, K., Karagiannides, I., Lawson, G., Pothoulakis, C. 2012; 130 (8): 1798–1805

  Abstract

  Neurotensin receptor-1 (NTR-1) is overexpressed in colon cancers and colon cancer cell lines. Signaling through this receptor stimulates proliferation of colonocyte-derived cell lines and promotes inflammation and mucosal healing in animal models of colitis. Given the causal role of this signaling pathway in mediating colitis and the importance of inflammation in cancer development, we tested the effects of NTR-1 in mouse models of inflammation-associated and sporadic colon cancer using NTR-1-deficient (Ntsr1(-) (/-)) and wild-type (Ntsr1(+/+)) mice. In mice treated with azoxymethane (AOM) to model sporadic cancer, NTR-1 had a significant effect on tumor development with Ntsr1(+/+) mice developing over twofold more tumors than Ntsr1(-) (/-) mice (p = 0.04). There was no effect of NTR-1 on the number of aberrant crypt foci or tumor size, suggesting that NT/NTR-1 signaling promotes the conversion of precancerous cells to adenomas. Interestingly, NTR-1 status did not affect tumor development in an inflammation-associated cancer model where mice were treated with AOM followed by two cycles of 5% dextran sulfate sodium (DSS). In addition, colonic molecular and histopathologic analyses were performed shortly after a single cycle of DSS. NTR-1 status did not affect colonic myeloperoxidase activity or histopathologic scores for damage and inflammation. However, Ntsr1(-) (/-) mice were more resistant to DSS-induced mortality (p = 0.01) and had over twofold higher colonic expression levels of Il6 and Cxcl2 (p < 0.04), cytokines known to promote tumor development. These results represent the first direct demonstration that targeted disruption of the Ntsr1 gene reduces susceptibility to colon tumorigenesis.

  View details for DOI 10.1002/ijc.26208

  View details for Web of Science ID 000300692300009

  View details for PubMedID 21630261

  View details for PubMedCentralID PMC3288327

• Obesity in the Absence of High Fat Diet Enhances Tumor Development in AOM-Treated Mice Bugni, J. M., Al Rabadi, L., Stavrakis, D. G., Jubbal, K., Karagiannidis, I., Pothoulakis, C. W B SAUNDERS CO-ELSEVIER INC. 2011: S818

  View details for Web of Science ID 000290167303612