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Item Amelioration of Ductular Reaction by Stem Cell Derived Extracellular Vesicles in MDR2 Knockout Mice via Lethal-7 microRNA(Wiley, 2019-02-05) McDaniel, Kelly; Wu, Nan; Zhou, Tianhao; Huang, Li; Sato, Keisaku; Venter, Julie; Ceci, Ludovica; Chen, Demeng; Ramos‐Lorenzo, Sugeily; Invernizzi, Pietro; Bernuzzi, Francesca; Wu, Chaodong; Francis, Heather; Glaser, Shannon; Alpini, Gianfranco; Meng, Fanyin; Medicine, School of MedicineCholangiopathies are diseases that affect cholangiocytes, the cells lining the biliary tract. Liver stem cells (LSCs) are able to differentiate into all cells of the liver and possibly influence the surrounding liver tissue by secretion of signaling molecules. One way in which cells can interact is through secretion of extracellular vesicles (EVs), which are small membrane-bound vesicles that contain proteins, microRNAs (miRNAs), and cytokines. We evaluated the contents of liver stem cell–derived EVs (LSCEVs), compared their miRNA contents to those of EVs isolated from hepatocytes, and evaluated the downstream targets of these miRNAs. We finally evaluated the crosstalk among LSCs, cholangiocytes, and human hepatic stellate cells (HSCs). We showed that LSCEVs were able to reduce ductular reaction and biliary fibrosis in multidrug resistance protein 2 (MDR2)−/− mice. Additionally, we showed that cholangiocyte growth was reduced and HSCs were deactivated in LSCEV-treated mice. Evaluation of LSCEV contents compared with EVs derived from hepatocytes showed a large increase in the miRNA, lethal-7 (let-7). Further evaluation of let-7 in MDR2−/− mice and human primary sclerosing cholangitis samples showed reduced levels of let-7 compared with controls. In liver tissues and isolated cholangiocytes, downstream targets of let-7 (identified by ingenuity pathway analysis), Lin28a (Lin28 homolog A), Lin28b (Lin28 homolog B), IL-13 (interleukin 13), NR1H4 (nuclear receptor subfamily 1 group H member 4) and NF-κB (nuclear factor kappa B), are elevated in MDR2−/− mice, but treatment with LSCEVs reduced levels of these mediators of ductular reaction and biliary fibrosis through the inhibition of NF-κB and IL-13 signaling pathways. Evaluation of crosstalk using cholangiocyte supernatants from LSCEV-treated cells on cultured HSCs showed that HSCs had reduced levels of fibrosis and increased senescence. Conclusion: Our studies indicate that LSCEVs could be a possible treatment for cholangiopathies or could be used for target validation for future therapies.Item Author Correction: Hypoxia-mediated downregulation of miRNA biogenesis promotes tumour progression(Nature, 2020-06-03) Rupaimoole, Rajesha; Wu, Sherry Y.; Pradeep, Sunila; Ivan, Cristina; Pecot, Chad V.; Gharpure, Kshipra M.; Nagaraja, Archana S.; Armaiz-Pena, Guillermo N.; McGuire, Michael; Zand, Behrouz; Dalton, Heather J.; Filant, Justyna; Miller, Justin Bottsford; Lu, Chunhua; Sadaoui, Nouara C.; Mangala, Lingegowda S.; Taylor, Morgan; van den Beucken, Twan; Koch, Elizabeth; Rodriguez-Aguayo, Cristian; Huang, Li; Bar-Eli, Menashe; Wouters, Bradly G.; Radovich, Milan; Ivan, Mircea; Calin, George A.; Zhang, Wei; Lopez-Berestein, Gabriel; Sood, Anil K.; Medicine, School of MedicineThis Article contains an error in Fig. 4. During the preparation of Fig. 4d, the image representing showing E-CADHERIN expression under hypoxia conditions in A2780 cells was inadvertently taken from the image in Supplementary Fig. 15C showing E-CADHERIN expression under hypoxia conditions in SKOV3 cells. The correct version of Fig. 4 is shown below. The error has not been corrected in the PDF or HTML versions of the Article.Item Clinicopathologic predictors of outcomes in children with stage I testicular germ cell tumors: A pooled post hoc analysis of trials from the Children’s Oncology Group(Elsevier, 2022) Singla, Nirmish; Wong, Justin; Singla, Shyamli; Krailo, Mark; Huang, Li; Shaikh, Furqan; Billmire, Deborah; Rescorla, Frederick; Ross, Jonathon; Dicken, Bryan; Amatruda, James F.; Frazier, A. Lindsay; Bagrodia, Aditya; Surgery, School of MedicineBackground: Patients with clinical stage I (CS I: cN0M0) testicular germ cell tumors (TGCT) exhibit favorable oncologic outcomes. While prognostic features can help inform treatment in adults with CS I TGCT, we lack reliable means to predict relapse among pediatric and adolescent patients. Objective: We sought to identify predictors of relapse in children with CS I TGCT. Study design: We performed a pooled post hoc analysis on pediatric and adolescent AJCC CS I TGCT patients enrolled in 3 prospective trials: INT-0097 (phase II), INT-0106 (phase III), and AGCT0132 (phase III). Pathology was centrally reviewed. Patient demographics, pT stage, serum tumor markers, margin status, histology, relapse, and survival were compiled. Cox regression analyses were used to identify predictors of events, defined as relapse, secondary malignant neoplasm, or death. Results: 106 patients were identified with outcomes data available. Most patients were pT1-2 stage. Among patients with evaluable histopathology, yolk sac tumor elements were present in all patients and lymphovascular invasion in 51% of patients. Over a median follow-up of 56 months, no patients died, and 25 patients (24%) experienced an event (median event-free survival not reached). Independent predictors of events on multivariable analysis included age ≥12 years at diagnosis (HR 8.87, p < 0.001) and higher pT stage (pT2 HR 7.31, p = 0.0017; pT3 HR 13.5, p = 0.0043). Discussion: Although our study population reflects the largest pooled prospective cohort of CS I pediatric and adolescent TGCT to our knowledge, the relatively low event rate limits our multivariable analysis, and longer follow-up duration would help further characterize the natural history of these patients. Centralized pathologic review was also unable to be performed for several patients. Conclusion: Pediatric and adolescent CS I TGCT patients exhibit remarkable 5-year survival. Using combined data from multiple prospective trials, our study identifies clinicopathologic features that predict relapse and inform personalized treatment for these patients by potentially guiding surveillance versus adjuvant treatment strategies.Item The CYP3A5 genotypes of both liver transplant recipients and donors influence the time-dependent recovery of tacrolimus clearance during the early stage following transplantation(Wiley, 2021-10) Huang, Li; Assiri, Abdullah A.; Wen, Peihao; Zhang, Kun; Fan, Junwei; Xing, Tonghai; Liu, Yuan; Zhang, Jinyan; Wang, Zhaowen; Su, Zhaojie; Chen, Jiajia; Xiao, Yi; Wang, Rui; Na, Risi; Yuan, Liyun; Liu, Dehua; Xia, Junjie; Zhong, Lin; Liu, Wanqing; Guo, Wenzhi; Overholser, Brian R.; Peng, Zhihai; Medicine, School of MedicineItem Generation of mice carrying a knockout-first and conditional-ready allele of transforming growth factor beta2 gene(Wiley, 2014-09) Ahmed, A. S. Ishtiaq; Bose, Gracelyn C.; Huang, Li; Azhar, Mohamad; Department of Pediatrics, Indiana University School of MedicineTransforming growth factor beta2 (TGFβ2) is a multifunctional protein which is expressed in several embryonic and adult organs. TGFB2 mutations can cause Loeys Dietz syndrome, and its dysregulation is involved in cardiovascular, skeletal, ocular, and neuromuscular diseases, osteoarthritis, tissue fibrosis, and various forms of cancer. TGFβ2 is involved in cell growth, apoptosis, cell migration, cell differentiation, cell-matrix remodeling, epithelial-mesenchymal transition, and wound healing in a highly context-dependent and tissue-specific manner. Tgfb2(-/-) mice die perinatally from congenital heart disease, precluding functional studies in adults. Here, we have generated mice harboring Tgfb2(βgeo) (knockout-first lacZ-tagged insertion) gene-trap allele and Tgfb2(flox) conditional allele. Tgfb2(βgeo/βgeo) or Tgfb2(βgeo/-) mice died at perinatal stage from the same congenital heart defects as Tgfb2(-/-) mice. β-galactosidase staining successfully detected Tgfb2 expression in the heterozygous Tgfb2(βgeo) fetal tissue sections. Tgfb2(flox) mice were produced by crossing the Tgfb2(+/βgeo) mice with the FLPeR mice. Tgfb2(flox/-) mice were viable. Tgfb2 conditional knockout (Tgfb2(cko/-) ) fetuses were generated by crossing of Tgfb2(flox/-) mice with Tgfb2(+/-) ; EIIaCre mice. Systemic Tgfb2(cko/-) embryos developed cardiac defects which resembled the Tgfb2(βgeo/βgeo) , Tgfb2(βgeo/-) , and Tgfb2(-/-) fetuses. In conclusion, Tgfb2(βgeo) and Tgfb2(flox) mice are novel mouse strains which will be useful for investigating the tissue specific expression and function of TGFβ2 in embryonic development, adult organs, and disease pathogenesis and cancer. genesisItem Hypoxia Mediated Downregulation of miRNA Biogenesis Promotes Tumor Progression(Nature Publishing Group, 2014-10-29) Rupaimoole, Rajesha; Wu, Sherry Y.; Pradeep, Sunila; Ivan, Cristina; Pecot, Chad V.; Gharpure, Kshipra M.; Nagaraja, Archana S.; Armaiz-Pena, Guillermo N.; McGuire, Michael; Zand, Behrouz; Dalton, Heather J.; Filant, Justyna; Miller, Justin Bottsford; Lu, Chunhua; Sadaoui, Nouara C.; Mangala, Lingegowda S.; Taylor, Morgan; van den Beucken, Twan; Koch, Elizabeth; Rodriguez-Aguayo, Cristian; Huang, Li; Bar-Eli, Menashe; Wouters, Bradly G.; Radovich, Milan; Ivan, Mircea; Calin, George A.; Zhang, Wei; Lopez-Berestein, Gabriel; Sood, Anil K.; Department of Surgery, IU School of MedicineCancer-related deregulation of miRNA biogenesis has been suggested, but the underlying mechanisms remain elusive. Here, we report a previously unrecognized effect of hypoxia in the downregulation of Drosha and Dicer in cancer cells that leads to dysregulation of miRNA biogenesis and increased tumor progression. We show that hypoxia mediated downregulation of Drosha is dependent on ETS1/ELK1 transcription factors. Moreover, mature miRNA array and deep sequencing studies reveal altered miRNA maturation in cells under hypoxic conditions. At a functional level, this phenomenon results in increased cancer progression in vitro and in vivo, and data from patient samples are suggestive of miRNA biogenesis downregulation in hypoxic tumors. Rescue of Drosha by siRNAs targeting ETS1/ELK1 in vivo results in significant tumor regression. These findings provide a new link in the mechanistic understanding of global miRNA downregulation in the tumor microenvironment.Item Imaging Appearance of Nongerminoma Pediatric Ovarian Germ Cell Tumors Does Not Discriminate Benign from Malignant Histology(Elsevier, 2020) Billmire, Deborah; Dicken, Bryan; Rescorla, Frederick; Ross, Jonathan; Piao, Jin; Huang, Li; Krailo, Mark; Pashankar, Farzana; Frazier, Lindsay; Surgery, School of MedicineStudy Objective Pediatric ovarian neoplasms with imaging appearance suggestive of teratoma are often presumed to have low risk of malignancy. We assessed the pre-operative imaging appearance of pediatric malignant ovarian germ cell tumors (MOGCT) and the presence of associated teratoma in a series of MOGCT. Design Retrospective review of clinical and pathology data. Setting Multicenter trial for extracranial malignant germ cell tumors in young female individuals by the Children's Oncology Group (COG study AGCT0132) that included yolk sac tumor, embryonal carcinoma and choriocarcinoma. Participants Female individuals 0-20 years of age at enrollment with ovarian primary nonseminomatous malignant germ cell tumors. Interventions Review of data forms, including prospectively collected surgical checklist documenting imaging characteristics of the tumor, and review of pathology reports. Main Outcome Measures Description of imaging appearance and frequency of mixed histology with benign teratoma elements. Results A total of 138 female individuals (11 months to 20 years of age) had primary ovarian tumors. Imaging appearance and pathology information were available for 133 patients. Among the 133 patients, tumor appearance was solid (10.5%), solid with calcification (3.0%), mixed cystic and solid (58.7%), mixed cystic and solid with calcification (24.8%), and unknown (3.0%). In all, 54% had elements of teratoma in addition to malignant histology. Conclusion Mixed cystic and solid appearance with or without calcification was seen in 83.5% of pediatric ovarian malignant germ cell tumors. Associated benign teratoma was common. The presence of a mixed cystic and solid appearance on preoperative imaging should not dissuade the surgeon from obtaining preoperative serum markers and undertaking complete surgical staging.Item Role of Transforming Growth Factor Beta2 in Congenital Heart Disease(Office of the Vice Chancellor for Research, 2014-04-11) Bose, Gracelyn C.; Ahmed, Abu; Huang, Li; Sarangdhar, Kirti; Azhar, MohamadCongenital heart disease (CHD) represents the largest class of birth defects in the US and affects about 0.8% of all babies born. As a result of remarkable advances in the medical and surgical management of CHD, more than 75% of children born with CHD now live into adulthood. As such, discovery of the causes for CHD is not only a fundamental research endeavor, but is vital to the health care of this growing community. Inherited genetic mutations in Transforming Growth Factor Beta (TGFB) gene are found in the patients of Loeys-Dietz syndrome. Several cardiac (endocardial, myocardial) and extra-cardiac (second heart field, neural crest) cell lineages that express Tgfb2 contribute to heart development. To study the role of Tgfb2 in different cell types involved in heart development, we have generated Tgfb2 conditional knockout mice. These mice harbor Tgfb2 LacZ-tagged conditional-ready allele (also called tm1a). By using long range PCR (LR-PCR) we have confirmed the germline transmission of Tgfb2tm1a allele. Histological examination shows that Tgfb2tm1a/tm1a embryos develop several congenital heart defects. This indicates that Tgfb2tm1a allele is a knockout-first allele, which is consistent with the original design of our conditional gene targeting scheme. Next, by crossing to Flp recombinase mice we can generate mice with a Tgfb2 conditional-ready allele (also called tm1c). The presence of Tgfb2tm1c allele in the mice is confirmed by genomic PCR. In the future, we plan to use Tgfb2tm1c mice to conditionally delete Tgfb2 in different cardiac or extra-cardiac cell types using well-characterized Cre recombinase transgenic mice. Collectively, we have produced, generated, and validated mice harboring the Tgfb2 LacZ tagged knockout-first and conditional-ready allele. Our results from embryos carrying homozygous Tgfb2tm1a allele indicate that TGFβ2 is required for heart development. Future research will be crucial in expanding knowledge of the unknown cellular etiology of cardiac malformations in patients with TGFB2 mutations.