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Background High-risk neuroblastoma remains the most difficult pediatric solid tumor to treat and is associated with chemotherapy and radiation resistance that may be secondary to epigenetic modifications. We have previously found that α-N-catenin, a cell-adhesion protein encoded by the gene CTNNA2, plays a tumor suppressor role in neuroblastoma by inhibiting the NF-κB signaling pathway. A subset of neuroblastoma tumors that lack α-N-catenin are resistant to all-trans retinoic acid. However, the mechanism of CTNNA2 silencing in neuroblastoma remains unknown. Herein, we sought to determine the mechanism of α-N-catenin silencing in neuroblastoma. Methods Two human neuroblastoma cell lines, SK-N-AS and BE(2)-C, were stably transfected with a plasmid expressing CTNNA2. Both cell lines were treated with the histone deacetylase inhibitor Trichostatin A alone and in combination with retinoic acid. Cell survival and colony formation were measured. Cellular differentiation and expression of cell survival signaling pathways were analyzed. Immunoblotting and reverse transcription quantitative polymerase chain reaction were used to examine protein and messenger RNA expression. Results Retinoic acid treatment induced cellular differentiation and inhibited cellular proliferation in BE(2)-C cells but did not induce differentiation in SK-N-AS cells. Re-expression of α-N-catenin enhanced the sensitivity to retinoic acid-induced cell growth arrest and downregulated key cell survival pathways in both cell lines. Trichostatin A treatment induced CTNNA2 expression in SK-N-AS cells, and combination treatment with Trichostatin A induced retinoic acid sensitivity in retinoic acid-resistant cells. Conclusion Re-expression of α-N-catenin in retinoic acid-resistant cells induced sensitivity to retinoic acid treatment and is controlled epigenetically via histone deacetylase. α-N-catenin is a potential biomarker for retinoic acid sensitivity and combination treatment with Trichostatin A and retinoic acid may improve survival among children with high-risk, retinoic acid-resistant neuroblastoma.
Rachael A. Clark; Micah Newton; Jingbo Qiao; Sora Lee; Dai H. Chung. Reactivation of silenced α-N-catenin induces retinoic acid sensitivity in neuroblastoma cells. Surgery 2021, 1 .
AMA StyleRachael A. Clark, Micah Newton, Jingbo Qiao, Sora Lee, Dai H. Chung. Reactivation of silenced α-N-catenin induces retinoic acid sensitivity in neuroblastoma cells. Surgery. 2021; ():1.
Chicago/Turabian StyleRachael A. Clark; Micah Newton; Jingbo Qiao; Sora Lee; Dai H. Chung. 2021. "Reactivation of silenced α-N-catenin induces retinoic acid sensitivity in neuroblastoma cells." Surgery , no. : 1.
Subcutaneous abscesses occur frequently in the pediatric population, yet there is great variability in the approach to diagnosis and management, partly due to opposing recommendations in the current literature and the lack of a standardized protocol for diagnosis and management among pediatric medical centers. This has led to inconsistencies by the providers, as well as the hospital clinical pathways, with regards to the appropriate management of subcutaneous abscesses. We hypothesize that the current variability in diagnostic work-up and management contributes to the wide use of unnecessary imaging and therapeutics without altering the overall outcomes. We performed a retrospective chart review that compared 200 encounters for patients < 18 years of age with a diagnosis of subcutaneous abscess at a single large tertiary pediatric institution. Our results showed that only 13.6% of wound cultures obtained led to a change in the antibiotic regimen and that blood cultures were positive in only 2.1% of cases. There was no difference in the incision and drainage performed based on ultrasound findings in the presence of fluctuance on physical exam. Patients presenting with fever were more likely to be admitted to the hospital for further care than those without fever. Our results showed no difference in outcome after incision and drainage for abscesses packed with gauze versus those left to drain via a vessel loop drain. There was no difference in recurrence in patients discharged with oral antibiotics versus without oral antibiotic treatment. Our data indicate that many of the diagnostic studies used for the management of a subcutaneous abscess have little to no effect on the outcome. Subcutaneous abscesses are a common pediatric complaint, and this study could help healthcare providers utilize more effective and efficient management strategies for skin and soft tissue infections.
Isabel Garcia; Rachael Clark; Dai Chung; Nakia Gaines. Pediatric Subcutaneous Abscess: Still a Clinical Exam-Based Diagnosis and Treatment. Children 2021, 8, 392 .
AMA StyleIsabel Garcia, Rachael Clark, Dai Chung, Nakia Gaines. Pediatric Subcutaneous Abscess: Still a Clinical Exam-Based Diagnosis and Treatment. Children. 2021; 8 (5):392.
Chicago/Turabian StyleIsabel Garcia; Rachael Clark; Dai Chung; Nakia Gaines. 2021. "Pediatric Subcutaneous Abscess: Still a Clinical Exam-Based Diagnosis and Treatment." Children 8, no. 5: 392.
// Rachael A. Clark 1 , * , Sora Lee 1 , * , Jingbo Qiao 1 and Dai H. Chung 1 1 Department of Surgery, Division of Pediatric Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA * These authors contributed equally to this work Correspondence to: Dai H. Chung, email: [email protected] Keywords: neuroblastoma; pralatrexate; N-myc; folate metabolism Received: February 14, 2020 Accepted: July 07, 2020 Published: August 11, 2020 ABSTRACT Introduction: Pralatrexate is a folate analogue inhibitor of dihydrofolate reductase exhibiting high affinity for reduced folate carrier-1 with antineoplastic and immunosuppressive activities, similar to methotrexate. Despite advances in multi-modality treatment strategies, the survival rates for children with high-risk neuroblastoma have failed to improve. Therefore, the intense research continues in order to identify the ideal novel agent or combination of chemotherapy drugs to treat high-risk neuroblastoma. Materials and Methods: Four human neuroblastoma cell lines were used to determine IC 50 values of select chemotherapy agents. Antiproliferative effects of pralatrexate were assessed by adherent and non-adherent colony formation assays. Cell cycle arrest and apoptosis were measured by flow cytometry and immunoblotting. PDX tissue culture was used to assess ex vivo efficacy. Results: Treatment with pralatrexate in all four neuroblastoma cell lines blocked cell growth in 2D and 3D culture conditions in a time-dependent manner. The potency of pralatrexate was ten-fold stronger than methotrexate, as measured by IC 50 . Pralatrexate-induced apoptosis was confirmed by caspase-3 activation and PARP cleavage. MYCN and SLC19A1 mRNA expressions were decreased with pralatrexate in MYCN -amplified neuroblastoma cells. Conclusions: Pralatrexate demonstrated effective inhibition of cell growth and viability. The higher potency of pralatrexate compared to methotrexate, a drug with high levels of toxicity, suggests pralatrexate may be a safer alternative to methotrexate as an effective chemotherapeutic agent in the treatment of patients with high-risk neuroblastoma.
Rachael A. Clark; Sora Lee; Jingbo Qiao; Dai H. Chung. Preclinical evaluation of the anti-tumor activity of pralatrexate in high-risk neuroblastoma cells. Oncotarget 2020, 11, 3069 -3077.
AMA StyleRachael A. Clark, Sora Lee, Jingbo Qiao, Dai H. Chung. Preclinical evaluation of the anti-tumor activity of pralatrexate in high-risk neuroblastoma cells. Oncotarget. 2020; 11 (32):3069-3077.
Chicago/Turabian StyleRachael A. Clark; Sora Lee; Jingbo Qiao; Dai H. Chung. 2020. "Preclinical evaluation of the anti-tumor activity of pralatrexate in high-risk neuroblastoma cells." Oncotarget 11, no. 32: 3069-3077.
MicroRNA-145 (miR-145) plays a suppressive role in the process of tumorigenesis and an important role in induction of autophagy. However, the exact role of miR-145 in therapeutically resistant neuroblastoma cells remain elusive. Herein, we sought to evaluate the effects of miR-145 overexpression in chemo‑ and radiation-resistant neuroblastoma cells. We hypothesized that miR-145 affects the aggressiveness of resistant cells by enhancing autophagy. We established Cisplatin-resistant (CDDP-R), Vincristine-resistant (Vin-R), and radiation-resistant (Rad-R) neuroblastoma cells and found that miR-145 expression was significantly decreased in the resistant cells compared to the parental cells. Exogenously expression of miR-145 inhibited oncogenic properties such as proliferation, clonogenicity, anchorage-independent growth, cell migration, and tubule formation in the resistant cells. In addition, we also found that an autophagy protein marker, LC3, was only minimally expressed in the resistant cells. In particular, when miR-145 was overexpressed in the resistant cells, LC3 I and II were expressed and an increased punctate fluorescence of LC3 protein was found indicating the induction of autophagy. Taken together, our data suggests that miR-145 inhibits tumorigenesis and aggressiveness via modulation of autophagy in neuroblastoma.
Kwang Woon Kim; Jingbo Qiao; Julia Y. Kim; Kyungho Park; Dai H. Chung. Overexpression of microRNA-145 inhibits tumorigenesis through autophagy in chemotherapy and radiation resistant neuroblastoma cells. Oncoscience 2020, 7, 1 -9.
AMA StyleKwang Woon Kim, Jingbo Qiao, Julia Y. Kim, Kyungho Park, Dai H. Chung. Overexpression of microRNA-145 inhibits tumorigenesis through autophagy in chemotherapy and radiation resistant neuroblastoma cells. Oncoscience. 2020; 7 (1-2):1-9.
Chicago/Turabian StyleKwang Woon Kim; Jingbo Qiao; Julia Y. Kim; Kyungho Park; Dai H. Chung. 2020. "Overexpression of microRNA-145 inhibits tumorigenesis through autophagy in chemotherapy and radiation resistant neuroblastoma cells." Oncoscience 7, no. 1-2: 1-9.
Neuroblastoma remains one of the most difficult pediatric solid tumors to treat. In particular, the refractory and relapsing neuroblastomas are highly heterogeneous with diverse molecular profiles. We previously demonstrated that AKT2 plays critical roles in the regulation of neuroblastoma tumorigenesis. Here we hypothesize that targeting AKT2 could block the signal transduction pathways enhanced in chemo- and/or radiation-resistant neuroblastoma cancer stem-like cells. We found cell proliferation and survival signaling pathways AKT2/mTOR and MAPK were enhanced in cisplatin (CDDP)- and radiation-resistant neuroblastoma cells. Blocking these two pathways with specific inhibitors, CCT128930 (AKT2 inhibitor) and PD98059 (MEK inhibitor) decreased cell proliferation, angiogenesis, and cell migration in these resistant cells. We further demonstrated that the resistant cells had a higher sphere-forming capacity with increased expression of stem cell markers CD133, SOX2, ALDH, Nestin, Oct4, and Nanog. Importantly, the tumorsphere formation, which is a surrogate assay for self-renewal, was sensitive to the inhibitors of AKT2 and MAPK. Taken together, our findings suggest that CDDP- and radiation-resistant cancer stem-like neuroblastoma cells might serve as a useful tool to improve the understanding of molecular mechanisms of therapeutic resistance. This may aid in the development of more effective novel treatment strategies and better clinical outcomes in patients with neuroblastoma.
Kwang Woon Kim; Julia Y. Kim; Jingbo Qiao; Rachael A. Clark; Camille M. Powers; Hernan Correa; Dai H. Chung; Colin W. Stets; Bryce W. Demoret; Achal Awasthi; Nicholas Grosenbacher; Reena Shakya; John L. Hays; James L. Chen. Dual-Targeting AKT2 and ERK in cancer stem-like cells in neuroblastoma. Oncotarget 2019, 10, 5645 -5659.
AMA StyleKwang Woon Kim, Julia Y. Kim, Jingbo Qiao, Rachael A. Clark, Camille M. Powers, Hernan Correa, Dai H. Chung, Colin W. Stets, Bryce W. Demoret, Achal Awasthi, Nicholas Grosenbacher, Reena Shakya, John L. Hays, James L. Chen. Dual-Targeting AKT2 and ERK in cancer stem-like cells in neuroblastoma. Oncotarget. 2019; 10 (54):5645-5659.
Chicago/Turabian StyleKwang Woon Kim; Julia Y. Kim; Jingbo Qiao; Rachael A. Clark; Camille M. Powers; Hernan Correa; Dai H. Chung; Colin W. Stets; Bryce W. Demoret; Achal Awasthi; Nicholas Grosenbacher; Reena Shakya; John L. Hays; James L. Chen. 2019. "Dual-Targeting AKT2 and ERK in cancer stem-like cells in neuroblastoma." Oncotarget 10, no. 54: 5645-5659.
The lost expression of α-catenin has been found in cancers, and reinstalling α-catenin inhibits tumor growth. Here we hypothesized that the α-N-catenin, a homologous member of α-catenin and neural-specific expressed, functions as a novel tumor suppressor in neural crest-derived tumor, neuroblastoma. We correlated CTNNA2 (encodes α-N-catenin) expression to neuroblastoma disease relapse-free survival probability using publicly accessible human neuroblastoma datasets in R2 platform. The result showed that it negatively correlated to relapse-free survival probability significantly in patients with neuroblastoma with non-MYCN amplified tumor. Conversely, overexpressing CTNNA2 suppressed the neuroblastoma cell proliferation as measuring by the clonogenesis, inhibited anchorage-independent growth with soft agar colony formation assay. Forced expression of CTNNA2 decreased cell migration and invasion. Further, overexpression of CTNNA2 reduced the secretion of angiogenic factor IL-8 and HUVEC tubule formation. Our results show, for the first time, that α-N-catenin is a tumor suppressor in neuroblastoma cells. These findings were further corroborated with in vivo tumor xenograft study, in which α-N-catenin inhibited tumor growth and reduced tumor blood vessel formation. Interestingly, this is only observed in SK-N-AS xenografts lacking MYCN expression, and not in BE(2)-C xenografts with MYCN amplification. Mechanistically, α-N-catenin attenuated NF-κB responsive genes by inhibiting NF-κB transcriptional activity. In conclusion, these data demonstrate that α-N-catenin is a tumor suppressor in non-MYCN-amplified neuroblastomas and it inhibits NF-κB signaling pathway to suppress tumor growth in human neuroblastomas. Therefore, restoring the expression of α-N-catenin can be a novel therapeutic approach for neuroblastoma patients who have the deletion of CTNNA2 and lack of MYCN amplification.
Jingbo Qiao; Eric J. Rellinger; Kwang Woon Kim; Camille M. Powers; Sora Lee; Hernan Correa; Dai H. Chung; Kurt W. Evans; Argun Akcakanat; Erkan Yuca; Coya Tapia; Yasmeen Qamar Rizvi; Ecaterina Ileana Dumbrava; Filip Janku; Funda Meric-Bernstam. Identification of α-N-catenin as a novel tumor suppressor in neuroblastoma. Oncotarget 2019, 10, 5028 -5040.
AMA StyleJingbo Qiao, Eric J. Rellinger, Kwang Woon Kim, Camille M. Powers, Sora Lee, Hernan Correa, Dai H. Chung, Kurt W. Evans, Argun Akcakanat, Erkan Yuca, Coya Tapia, Yasmeen Qamar Rizvi, Ecaterina Ileana Dumbrava, Filip Janku, Funda Meric-Bernstam. Identification of α-N-catenin as a novel tumor suppressor in neuroblastoma. Oncotarget. 2019; 10 (49):5028-5040.
Chicago/Turabian StyleJingbo Qiao; Eric J. Rellinger; Kwang Woon Kim; Camille M. Powers; Sora Lee; Hernan Correa; Dai H. Chung; Kurt W. Evans; Argun Akcakanat; Erkan Yuca; Coya Tapia; Yasmeen Qamar Rizvi; Ecaterina Ileana Dumbrava; Filip Janku; Funda Meric-Bernstam. 2019. "Identification of α-N-catenin as a novel tumor suppressor in neuroblastoma." Oncotarget 10, no. 49: 5028-5040.
Neuroblastoma, the most common extracranial solid tumor of childhood, has widely variable outcomes dependent on the specific biology of the tumor. In this review, current biologic principles that are used to stratify risk and guide treatment algorithms are discussed. The role for surgical resection in neuroblastoma is also reviewed, including the indications and timing of surgery within the greater treatment plan.
Kyle Van Arendonk; Dai Chung. Neuroblastoma: Tumor Biology and Its Implications for Staging and Treatment. Children 2019, 6, 12 .
AMA StyleKyle Van Arendonk, Dai Chung. Neuroblastoma: Tumor Biology and Its Implications for Staging and Treatment. Children. 2019; 6 (1):12.
Chicago/Turabian StyleKyle Van Arendonk; Dai Chung. 2019. "Neuroblastoma: Tumor Biology and Its Implications for Staging and Treatment." Children 6, no. 1: 12.
Golf cart injuries represent an increasing source of morbidity and mortality in the United States. Characterization of the circumstances of these injuries can inform injury prevention efforts. This study retrospectively reviews a prospective trauma registry at a level-one pediatric trauma center for golf cart-related injuries in patients under 18 years of age admitted to the hospital between 2008 and 2016. The 40 identified crashes were associated with 82 hospital days, 17 ICU days, and more than $1 million in hospital charges over the study period. The median hospital stay was 1.5 days, and the median hospital charge was $20,489. Severe injuries with an Injury Severity Score of >15 were identified in 25% of patients, and moderate injuries with scores between nine and 15 were identified in an additional 30%. The most common injures were head and neck (60%) and external injuries to the body surface (52.5%). Only a single child was wearing a seatbelt, and the vast majority was not using any safety equipment. Children as young as nine years old were driving golf carts, and child drivers were associated with the cart overturning (p = 0.007). Golf cart crashes were a source of substantial morbidity at a level-one trauma center. Increased safety measures, such as higher hip restraints, seatbelts, and front-wheel breaks could substantially increase the safety of golf carts. Increased regulation of driving age as well as driver education may also reduce these injuries.
Joseph R. Starnes; Purnima Unni; Cherie A. Fathy; Kelly A. Harms; Shelby R. Payne; Dai H. Chung. Characterization of pediatric golf cart injuries to guide injury prevention efforts. The American Journal of Emergency Medicine 2018, 36, 1049 -1052.
AMA StyleJoseph R. Starnes, Purnima Unni, Cherie A. Fathy, Kelly A. Harms, Shelby R. Payne, Dai H. Chung. Characterization of pediatric golf cart injuries to guide injury prevention efforts. The American Journal of Emergency Medicine. 2018; 36 (6):1049-1052.
Chicago/Turabian StyleJoseph R. Starnes; Purnima Unni; Cherie A. Fathy; Kelly A. Harms; Shelby R. Payne; Dai H. Chung. 2018. "Characterization of pediatric golf cart injuries to guide injury prevention efforts." The American Journal of Emergency Medicine 36, no. 6: 1049-1052.
Background/Aim: Sirtuins (SIRTs) play crucial roles in various signaling pathways that modulate differentiation and proliferation. We sought to elucidate the role of SIRTs in differentiation and proliferation of human neuroblastoma (NB). Materials and Methods: NB cells were treated with nicotinamide (NAM), a non-specific SIRT inhibitor, SIRT-targeted short hairpin RNAs, and retinoic acid to assess cell growth and differentiation. Results: SIRTs are involved in proliferation and differentiation using NAM in BE(2)-C cells. Specifically, SIRT6 knockdown in BE(2)-C cells reduced cell proliferation, induced neurite extension, corresponding with induction of p21CIP1 expression and G1 cell-cycle arrest. These effects were rescued by forced re-overexpression of SIRT6. SIRT6 expression was reduced in differentiated human NB sections, and RA-induced differentiation in BE(2)-C cells. Conclusion: SIRTs have important oncogenic properties in NB beyond its established functions in aging and genome stability. SIRT6 may represent a novel target for developing future therapeutics for the treatment of aggressive NBs.
Ha Yong Song; Eric J. Rellinger; Seong-Hoon Park; Pritha Paul; Jingbo Qiao; Athanasios Vasilopoulos; Özkan Özden; David Gius; Dai H. Chung. Inhibition of Sirtuin 6 Induces Neuroblastoma Differentiation. Anticancer Research 2018, 38, 647 -654.
AMA StyleHa Yong Song, Eric J. Rellinger, Seong-Hoon Park, Pritha Paul, Jingbo Qiao, Athanasios Vasilopoulos, Özkan Özden, David Gius, Dai H. Chung. Inhibition of Sirtuin 6 Induces Neuroblastoma Differentiation. Anticancer Research. 2018; 38 (2):647-654.
Chicago/Turabian StyleHa Yong Song; Eric J. Rellinger; Seong-Hoon Park; Pritha Paul; Jingbo Qiao; Athanasios Vasilopoulos; Özkan Özden; David Gius; Dai H. Chung. 2018. "Inhibition of Sirtuin 6 Induces Neuroblastoma Differentiation." Anticancer Research 38, no. 2: 647-654.
Congenital diaphragmatic hernia (CDH) is one of the most common and lethal birth defects. Previous studies using exome sequencing support a significant contribution of codingde novovariants in complex CDH cases with additional anomalies and likely gene-disrupting (LGD) variants in isolated CDH cases. To further investigate the genetic architecture of CDH, we performed exome or genome sequencing in 283 proband-parent trios. Combined with data from previous studies, we analyzed a total of 357 trios, including 148 complex and 209 isolated cases. Complex and isolated cases both have a significant burden of deleteriousde novocoding variants (1.7~fold, p= 1.2×10−5for complex, 1.5~fold, p= 9.0×10−5for isolated). Strikingly, in isolated CDH, almost all of the burden is carried by female cases (2.1~fold, p=0.004 for likely gene disrupting and 1.8~fold, p= 0.0008 for damaging missense variants); whereas in complex CDH, the burden is similar in females and males. Additionally,de novoLGD variants in complex cases are mostly enriched in genes highly expressed in developing diaphragm, but distributed in genes with a broad range of expression levels in isolated cases. Finally, we identified a new candidate risk geneMYRF(4de novovariants, p-value=2×10−10), a transcription factor intolerant of mutations. Patients withMYRFmutations have additional anomalies including congenital heart disease and genitourinary defects, likely representing a novel syndrome.
Hongjian Qi; Lan Yu; Xueya Zhou; Alexander Kitaygorodsky; Julia Wynn; Na Zhu; Gudrun Aspelund; Foong Yen Lim; Timothy Crombleholme; Robert Cusick; Kenneth Azarow; Melissa Ellen Danko; Dai Chung; Brad W. Warner; George B. Mychaliska; Douglas Potoka; Amy J. Wagner; Mahmoud ElFiky; Deborah A. Nickerson; Michael J. Bamshad; Jay M. Wilson; Frances A. High; Mauro Longoni; Patricia Donahoe; Wendy K. Chung; Yufeng Shen. Genetic analysis ofde novovariants reveals sex differences in complex and isolated congenital diaphragmatic hernia and indicatesMYRFas a candidate gene. 2017, 206037 .
AMA StyleHongjian Qi, Lan Yu, Xueya Zhou, Alexander Kitaygorodsky, Julia Wynn, Na Zhu, Gudrun Aspelund, Foong Yen Lim, Timothy Crombleholme, Robert Cusick, Kenneth Azarow, Melissa Ellen Danko, Dai Chung, Brad W. Warner, George B. Mychaliska, Douglas Potoka, Amy J. Wagner, Mahmoud ElFiky, Deborah A. Nickerson, Michael J. Bamshad, Jay M. Wilson, Frances A. High, Mauro Longoni, Patricia Donahoe, Wendy K. Chung, Yufeng Shen. Genetic analysis ofde novovariants reveals sex differences in complex and isolated congenital diaphragmatic hernia and indicatesMYRFas a candidate gene. . 2017; ():206037.
Chicago/Turabian StyleHongjian Qi; Lan Yu; Xueya Zhou; Alexander Kitaygorodsky; Julia Wynn; Na Zhu; Gudrun Aspelund; Foong Yen Lim; Timothy Crombleholme; Robert Cusick; Kenneth Azarow; Melissa Ellen Danko; Dai Chung; Brad W. Warner; George B. Mychaliska; Douglas Potoka; Amy J. Wagner; Mahmoud ElFiky; Deborah A. Nickerson; Michael J. Bamshad; Jay M. Wilson; Frances A. High; Mauro Longoni; Patricia Donahoe; Wendy K. Chung; Yufeng Shen. 2017. "Genetic analysis ofde novovariants reveals sex differences in complex and isolated congenital diaphragmatic hernia and indicatesMYRFas a candidate gene." , no. : 206037.
Eric J. Rellinger; Chandrasekhar Padmanabhan; Jingbo Qiao; Hanbing An; Alex G. Waterson; Craig W. Lindsley; R. Daniel Beauchamp; Dai H. Chung. Isoxazole-Based Small Molecule Induces Apoptosis and Sensitizes Ewing Sarcoma Cells to Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand. Journal of the American College of Surgeons 2017, 225, S152 .
AMA StyleEric J. Rellinger, Chandrasekhar Padmanabhan, Jingbo Qiao, Hanbing An, Alex G. Waterson, Craig W. Lindsley, R. Daniel Beauchamp, Dai H. Chung. Isoxazole-Based Small Molecule Induces Apoptosis and Sensitizes Ewing Sarcoma Cells to Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand. Journal of the American College of Surgeons. 2017; 225 (4):S152.
Chicago/Turabian StyleEric J. Rellinger; Chandrasekhar Padmanabhan; Jingbo Qiao; Hanbing An; Alex G. Waterson; Craig W. Lindsley; R. Daniel Beauchamp; Dai H. Chung. 2017. "Isoxazole-Based Small Molecule Induces Apoptosis and Sensitizes Ewing Sarcoma Cells to Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand." Journal of the American College of Surgeons 225, no. 4: S152.
// Pritha Paul 1, 4, * , Eric J. Rellinger 1, 4, * , Jingbo Qiao 1, 4 , Sora Lee 1, 4 , Natasha Volny 1, 4 , Chandrasekhar Padmanabhan 1 , Carmelle V. Romain 1, 4 , Bret Mobley 3 , Hernan Correa 3 and Dai H. Chung 1, 2, 4 1 Section of Surgical Sciences, Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA 2 Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA 3 Department of Pathology, Vanderbilt University Medical Center, Nashville, TN 37232, USA 4 Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA * These authors have contributed equally to this work Correspondence to: Dai H. Chung, email: [email protected] Keywords: TIMP-1, neuroblastoma, metastasis, liver, LM2 Abbreviations: TIMP, tissue inhibitor of metalloproteinases Received: August 16, 2016 Accepted: May 04, 2017 Published: July 28, 2017 ABSTRACT Approximately two-thirds of patients with neuroblastoma are found to have metastatic disease at time of diagnosis with frequent skeletal, lymph node, central nervous system, and liver involvement. Using a serial in vivo splenic injection model, we have isolated an aggressive subclone (BE(2)-C/LM2) from MYCN -amplified neuroblastomas that demonstrate an enhanced propensity to develop metastatic liver lesions. BE(2)-C/LM2 subclone cells demonstrate increased adherent, soft agar colony and tumorsphere growth in vitro . Components of the tumor microenvironment regulate cancer progression, via networks of cytokines and growth factors. Cytokine array analysis identified increased TIMP-1 in the plasma of mice injected with BE(2)-C/LM2 subclone cells, leading us to hypothesize that TIMP-1 may play a role in our observed prometastatic phenotype. Immunoblotting and ELISA demonstrated enhanced endogenous TIMP-1 expression in our isolated neuroblastoma subclone. Silencing endogenous TIMP-1 successfully blocked in vitro proliferation, soft agar colony formation and tumorsphere formation by BE(2)-C/LM2 cells. Stable RNA interference of endogenous TIMP-1 failed to reverse the prometastatic phenotype of our BE(2)-C/LM2 subclone in our liver metastasis model, suggesting that endogenous TIMP-1 levels may not be an essential component of this in vivo behavior. Notably, tissue microarray analysis and Kaplan-Meier by gene expression demonstrates that elevated TIMP-1 expression is correlated with increased disease relapse and mortality in patients with neuroblastoma. Taken together, our study identifies TIMP-1 as a novel soluble factor that is associated with a prometastatic phenotype in our in vivo model and adverse outcomes in patients with neuroblastoma. Pritha Paul1,4,*, Eric J. Rellinger1,4,*, Jingbo Qiao1,4, Sora Lee1,4, Natasha Volny1,4, Chandrasekhar Padmanabhan1, Carmelle V. Romain1,4, Bret Mobley3, Hernan Correa3 and Dai H. Chung1,2,4 1Section of Surgical Sciences, Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA 2Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA 3Department of Pathology, Vanderbilt University Medical Center, Nashville, TN 37232, USA 4Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA *These authors have contributed equally to this work Correspondence to: Dai H. Chung, email: [email protected] Keywords: TIMP-1, neuroblastoma, metastasis, liver, LM2 Abbreviations: TIMP, tissue inhibitor of metalloproteinases Received: August 16, 2016 Accepted: May 04, 2017 Published: July 28, 2017 ABSTRACT Approximately two-thirds of patients with neuroblastoma are found to have metastatic disease at time of diagnosis with frequent skeletal, lymph node, central nervous system, and liver involvement. Using a serial in vivo splenic injection model, we have isolated an aggressive subclone (BE(2)-C/LM2) from MYCN-amplified neuroblastomas that demonstrate an enhanced propensity to develop metastatic liver lesions. BE(2)-C/LM2 subclone cells demonstrate increased adherent, soft agar colony and tumorsphere growth in vitro. Components of the tumor microenvironment regulate cancer progression, via networks of cytokines and growth factors. Cytokine array analysis identified increased TIMP-1 in the plasma of mice injected with BE(2)-C/LM2 subclone cells, leading us to hypothesize that TIMP-1 may play a role in our observed prometastatic phenotype. Immunoblotting and ELISA demonstrated enhanced endogenous TIMP-1 expression in our isolated neuroblastoma subclone. Silencing endogenous TIMP-1 successfully blocked in vitro proliferation, soft agar colony formation and tumorsphere formation by BE(2)-C/LM2 cells. Stable RNA interference of endogenous TIMP-1 failed to reverse the prometastatic phenotype of our BE(2)-C/LM2 subclone in our liver metastasis model, suggesting that endogenous TIMP-1 levels may not be an essential component of this in vivo behavior. Notably, tissue microarray analysis and Kaplan-Meier by gene expression demonstrates that elevated TIMP-1 expression is correlated with increased disease relapse and mortality in patients with neuroblastoma. Taken together, our study identifies TIMP-1 as a novel soluble factor that is associated with a prometastatic phenotype in our in vivo model and adverse outcomes in patients with neuroblastoma.
Pritha Paul; Eric J. Rellinger; Jingbo Qiao; Sora Lee; Natasha Volny; Chandrasekhar Padmanabhan; Carmelle V. Romain; Bret Mobley; Hernan Correa; Dai H. Chung. Elevated TIMP-1 expression is associated with a prometastatic phenotype, disease relapse, and poor survival in neuroblastoma. Oncotarget 2017, 8, 82609 -82620.
AMA StylePritha Paul, Eric J. Rellinger, Jingbo Qiao, Sora Lee, Natasha Volny, Chandrasekhar Padmanabhan, Carmelle V. Romain, Bret Mobley, Hernan Correa, Dai H. Chung. Elevated TIMP-1 expression is associated with a prometastatic phenotype, disease relapse, and poor survival in neuroblastoma. Oncotarget. 2017; 8 (47):82609-82620.
Chicago/Turabian StylePritha Paul; Eric J. Rellinger; Jingbo Qiao; Sora Lee; Natasha Volny; Chandrasekhar Padmanabhan; Carmelle V. Romain; Bret Mobley; Hernan Correa; Dai H. Chung. 2017. "Elevated TIMP-1 expression is associated with a prometastatic phenotype, disease relapse, and poor survival in neuroblastoma." Oncotarget 8, no. 47: 82609-82620.
// Eric J. Rellinger 1, 6 , Chandrasekhar Padmanabhan 1 , Jingbo Qiao 1, 6 , Brian T. Craig 1, 6 , Hanbing An 1 , Jing Zhu 1 , Hernán Correa 2 , Alex G. Waterson 3 , Craig W. Lindsley 3 , R. Daniel Beauchamp 1, 4, 5 and Dai H. Chung 1, 4, 6 1 Section of Surgical Sciences, Department of Surgery, at Vanderbilt University Medical Center, TN 37232, Nashville, USA 2 Department of Pathology, at Vanderbilt University Medical Center, TN 37232, Nashville, USA 3 Department of Pharmacology and Vanderbilt Institute of Chemical Biology, at Vanderbilt University Medical Center, TN 37232, Nashville, USA 4 Department of Cancer Biology, at Vanderbilt University Medical Center, TN 37232, Nashville, USA 5 Department of Cell and Developmental Biology, at Vanderbilt University Medical Center, TN 37232, Nashville, USA 6 Department of Pediatric Surgery, at Vanderbilt University Medical Center, TN 37232, Nashville, USA Correspondence to: Dai H. Chung, email: [email protected] R. Daniel Beauchamp, email: [email protected] Keywords: ML327, neuroblastoma, MYCN, neural crest, epithelial-to-mesenchymal transition Received: April 13, 2017 Accepted: July 03, 2017 Published: July 20, 2017 ABSTRACT Neuroblastomas are the most common extracranial solid tumors in children and arise from the embryonic neural crest. MYCN -amplification is a feature of ~30% of neuroblastoma tumors and portends a poor prognosis. Neural crest precursors undergo epithelial-to-mesenchymal transition (EMT) to gain migratory potential and populate the sympathoadrenal axis. Neuroblastomas are posited to arise due to a blockade of neural crest differentiation. We have recently reported effects of a novel MET inducing compound ML327 ( N -(3-(2-hydroxynicotinamido) propyl)-5-phenylisoxazole-3-carboxamide) in colon cancer cells. Herein, we hypothesized that forced epithelial differentiation using ML327 would promote neuroblastoma differentiation. In this study, we demonstrate that ML327 in neuroblastoma cells induces a gene signature consistent with both epithelial and neuronal differentiation features with adaptation of an elongated phenotype. These features accompany induction of cell death and G1 cell cycle arrest with blockage of anchorage-independent growth and neurosphere formation. Furthermore, pretreatment with ML327 results in persistent defects in proliferative potential and tumor-initiating capacity, validating the pro-differentiating effects of our compound. Intriguingly, we have identified destabilization of MYC signaling as an early and consistent feature of ML327 treatment that is observed in both MYCN -amplified and MYCN -single copy neuroblastoma cell lines. Moreover, ML327 blocked MYCN mRNA levels and tumor progression in established MYCN -amplified xenografts. As such, ML327 may have potential efficacy, alone or in conjunction with existing therapeutic strategies against neuroblastoma. Future identification of the specific intracellular target of ML327 may inform future drug discovery efforts and enhance our understanding of MYC regulation. Eric J. Rellinger1,6, Chandrasekhar Padmanabhan1, Jingbo Qiao1,6, Brian T. Craig1,6, Hanbing An1, Jing Zhu1, Hernán Correa2, Alex G. Waterson3, Craig W. Lindsley3, R. Daniel Beauchamp1,4,5 and Dai H. Chung1,4,6 1Section of Surgical Sciences, Department of Surgery, at Vanderbilt University Medical Center, TN 37232, Nashville 2Department of Pathology, at Vanderbilt University Medical Center, TN 37232, Nashville 3Department of Pharmacology and Vanderbilt Institute of Chemical Biology, at Vanderbilt University Medical Center, TN 37232, Nashville 4Department of Cancer Biology, at Vanderbilt University Medical Center, TN 37232, Nashville 5Department of Cell and Developmental Biology, at Vanderbilt University Medical Center, TN 37232, Nashville 6Department of Pediatric Surgery, at Vanderbilt University Medical Center, TN 37232, Nashville Correspondence to: Dai H. Chung, email: [email protected] R. Daniel Beauchamp, email: [email protected] Keywords: ML327, neuroblastoma, MYCN, neural crest, epithelial-to-mesenchymal transition Received: April 13, 2017 Accepted: July 03, 2017 Published: July 20, 2017 ABSTRACT Neuroblastomas are the most common extracranial solid tumors in children and arise from the embryonic neural crest. MYCN-amplification is a feature of ~30% of neuroblastoma tumors and portends a poor prognosis. Neural crest precursors undergo epithelial-to-mesenchymal transition (EMT) to gain migratory potential and populate the sympathoadrenal axis. Neuroblastomas are posited to arise due to a blockade of neural crest differentiation. We have recently reported effects of a novel MET inducing compound ML327 (N-(3-(2-hydroxynicotinamido) propyl)-5-phenylisoxazole-3-carboxamide) in colon cancer cells. Herein, we hypothesized that forced epithelial differentiation using ML327 would promote neuroblastoma differentiation. In this study, we demonstrate that ML327 in neuroblastoma cells induces a gene signature consistent with both epithelial and neuronal differentiation features with adaptation of an elongated phenotype. These features accompany induction of cell death and G1 cell cycle arrest with blockage of anchorage-independent growth and neurosphere formation. Furthermore, pretreatment with ML327 results in persistent defects in proliferative potential and tumor-initiating capacity, validating the pro-differentiating effects of our compound. Intriguingly, we have identified destabilization of MYC signaling as an early and consistent feature of ML327 treatment that is observed in both MYCN-amplified and MYCN-single copy neuroblastoma cell lines. Moreover, ML327 blocked MYCN mRNA levels and tumor progression in established MYCN-amplified xenografts. As such, ML327 may have potential efficacy, alone or in conjunction with existing therapeutic strategies against neuroblastoma. Future identification of the specific intracellular target of ML327...
Eric J. Rellinger; Chandrasekhar Padmanabhan; Jingbo Qiao; Brian T. Craig; Hanbing An; Jing Zhu; Hernan Correa; Alex G. Waterson; Craig W. Lindsley; R. Daniel Beauchamp; Dai H. Chung. Isoxazole compound ML327 blocks MYC expression and tumor formation in neuroblastoma. Oncotarget 2017, 8, 91040 -91051.
AMA StyleEric J. Rellinger, Chandrasekhar Padmanabhan, Jingbo Qiao, Brian T. Craig, Hanbing An, Jing Zhu, Hernan Correa, Alex G. Waterson, Craig W. Lindsley, R. Daniel Beauchamp, Dai H. Chung. Isoxazole compound ML327 blocks MYC expression and tumor formation in neuroblastoma. Oncotarget. 2017; 8 (53):91040-91051.
Chicago/Turabian StyleEric J. Rellinger; Chandrasekhar Padmanabhan; Jingbo Qiao; Brian T. Craig; Hanbing An; Jing Zhu; Hernan Correa; Alex G. Waterson; Craig W. Lindsley; R. Daniel Beauchamp; Dai H. Chung. 2017. "Isoxazole compound ML327 blocks MYC expression and tumor formation in neuroblastoma." Oncotarget 8, no. 53: 91040-91051.
Ewing sarcomas are rare mesenchymal-derived bone and soft tissue tumors in children. Afflicted children with distant metastases have poor survival despite aggressive therapeutics. Epithelial-to-mesenchymal transition in epithelial carcinomas is associated with loss of E-cadherin and resistance to apoptosis. ML327 is a novel small molecule that we have previously shown to reverse epithelial-to-mesenchymal transition features in both epithelial and neural crest-derived cancers. Herein, we sought to evaluate the effects of ML327 on mesenchymal-derived Ewing sarcoma cells, hypothesizing that ML327 initiates growth arrest and sensitizes to TNF-related apoptosis-inducing ligand. ML327 induced protein expression changes, increased E-cadherin and decreased vimentin, consistent with partial induction of mesenchymal-to-epithelial transition in multiple Ewing Sarcoma cell lines (SK-N-MC, TC71, and ES-5838). Induction of epithelial features was associated with apoptosis, as demonstrated by PARP and Caspase 3 cleavage by immunoblotting. Cell cycle analysis validated these findings by marked induction of the subG0 cell population. In vitro combination treatment with TRAIL demonstrated additive induction of apoptotic markers. Taken together, these findings establish a rationale for further in vivo trials of ML327 in cells of mesenchymal origin both alone and in combination with TRAIL.
Eric J. Rellinger; Chandrasekhar Padmanabhan; Jingbo Qiao; Andrew Appert; Alex G. Waterson; Craig W. Lindsley; R. Daniel Beauchamp; Dai H. Chung. ML327 induces apoptosis and sensitizes Ewing sarcoma cells to TNF-related apoptosis-inducing ligand. Biochemical and Biophysical Research Communications 2017, 491, 463 -468.
AMA StyleEric J. Rellinger, Chandrasekhar Padmanabhan, Jingbo Qiao, Andrew Appert, Alex G. Waterson, Craig W. Lindsley, R. Daniel Beauchamp, Dai H. Chung. ML327 induces apoptosis and sensitizes Ewing sarcoma cells to TNF-related apoptosis-inducing ligand. Biochemical and Biophysical Research Communications. 2017; 491 (2):463-468.
Chicago/Turabian StyleEric J. Rellinger; Chandrasekhar Padmanabhan; Jingbo Qiao; Andrew Appert; Alex G. Waterson; Craig W. Lindsley; R. Daniel Beauchamp; Dai H. Chung. 2017. "ML327 induces apoptosis and sensitizes Ewing sarcoma cells to TNF-related apoptosis-inducing ligand." Biochemical and Biophysical Research Communications 491, no. 2: 463-468.
Background The MYC family of proteins promotes neuroblastoma tumorigenesis at least in part through the induction of aerobic glycolysis by promoting the transcription of key glycolytic enzymes, such as LDHA. FX11 is a selective inhibitor of LDHA that has demonstrated preclinical efficacy in adult cancers. Herein, we hypothesized that FX11 would inhibit aerobic glycolysis and block growth of neuroblastoma cells. Methods We surveyed 3 MYCN–single copy and 5 MYCN-amplified neuroblastoma cell lines to correlate C-MYC/N-MYC protein levels with LDHA expression. Cell viability was measured with FX11 using a tetrazolium-based assay. Cell cycle analysis using propidium iodide with flow cytometry was performed to evaluate for growth arrest. Immunoblotting demonstrated PARP and Caspase 3 cleavage as evidence of apoptosis. Results LDHA is frequently expressed in both MYCN--amplified and MYCN-single copy cell lines. N-MYC and C-MYC protein levels did not correlate with LDHA protein expression. FX11 inhibits aerobic glycolysis and growth in three MYCN-amplified and one MYCN–single copy neuroblastoma cell lines. FX11 induces modest G1 cell cycle arrest with selective induction of apoptosis. Conclusion Small molecule LDHA inhibition is capable of blocking aerobic glycolysis and growth of neuroblastoma cell lines in vitro and merits further in vivo evaluation of its preclinical efficacy in neuroblastomas.
Eric J. Rellinger; Brian T. Craig; Alexandra L. Alvarez; Haley L. Dusek; Kwang W. Kim; Jingbo Qiao; Dai H. Chung. FX11 inhibits aerobic glycolysis and growth of neuroblastoma cells. Surgery 2016, 161, 747 -752.
AMA StyleEric J. Rellinger, Brian T. Craig, Alexandra L. Alvarez, Haley L. Dusek, Kwang W. Kim, Jingbo Qiao, Dai H. Chung. FX11 inhibits aerobic glycolysis and growth of neuroblastoma cells. Surgery. 2016; 161 (3):747-752.
Chicago/Turabian StyleEric J. Rellinger; Brian T. Craig; Alexandra L. Alvarez; Haley L. Dusek; Kwang W. Kim; Jingbo Qiao; Dai H. Chung. 2016. "FX11 inhibits aerobic glycolysis and growth of neuroblastoma cells." Surgery 161, no. 3: 747-752.
Brian T. Craig; Eric J. Rellinger; Elizabeth G. Martinez; Syamal D. Bhattacharya; Hernan Correa; David P. Bichell; Dai H. Chung. Retrocardiac mediastinal foregut duplication cyst. Journal of Pediatric Surgery Case Reports 2016, 14, 45 -48.
AMA StyleBrian T. Craig, Eric J. Rellinger, Elizabeth G. Martinez, Syamal D. Bhattacharya, Hernan Correa, David P. Bichell, Dai H. Chung. Retrocardiac mediastinal foregut duplication cyst. Journal of Pediatric Surgery Case Reports. 2016; 14 ():45-48.
Chicago/Turabian StyleBrian T. Craig; Eric J. Rellinger; Elizabeth G. Martinez; Syamal D. Bhattacharya; Hernan Correa; David P. Bichell; Dai H. Chung. 2016. "Retrocardiac mediastinal foregut duplication cyst." Journal of Pediatric Surgery Case Reports 14, no. : 45-48.
Eric J. Rellinger; Chandrasekhar Padmanabhan; Brian T. Craig; Hanbing An; Jingbo Qiao; Alex G. Waterson; Craig W. Lindsley; R. Daniel Beauchamp; Dai H. Chung. ML327 Blocks N-MYC Expression and Tumor Formation in MYCN-Amplified Neuroblastomas. Journal of the American College of Surgeons 2016, 223, S88 -S89.
AMA StyleEric J. Rellinger, Chandrasekhar Padmanabhan, Brian T. Craig, Hanbing An, Jingbo Qiao, Alex G. Waterson, Craig W. Lindsley, R. Daniel Beauchamp, Dai H. Chung. ML327 Blocks N-MYC Expression and Tumor Formation in MYCN-Amplified Neuroblastomas. Journal of the American College of Surgeons. 2016; 223 (4):S88-S89.
Chicago/Turabian StyleEric J. Rellinger; Chandrasekhar Padmanabhan; Brian T. Craig; Hanbing An; Jingbo Qiao; Alex G. Waterson; Craig W. Lindsley; R. Daniel Beauchamp; Dai H. Chung. 2016. "ML327 Blocks N-MYC Expression and Tumor Formation in MYCN-Amplified Neuroblastomas." Journal of the American College of Surgeons 223, no. 4: S88-S89.
Brian T. Craig; Eric J. Rellinger; Yan Guo; Jingbo Qiao; Dai H. Chung. Growth Differentiation Factor 15 is a Novel Regulator of the Stem Cell-Like Phenotype in Neuroblastoma. Journal of the American College of Surgeons 2016, 223, S87 .
AMA StyleBrian T. Craig, Eric J. Rellinger, Yan Guo, Jingbo Qiao, Dai H. Chung. Growth Differentiation Factor 15 is a Novel Regulator of the Stem Cell-Like Phenotype in Neuroblastoma. Journal of the American College of Surgeons. 2016; 223 (4):S87.
Chicago/Turabian StyleBrian T. Craig; Eric J. Rellinger; Yan Guo; Jingbo Qiao; Dai H. Chung. 2016. "Growth Differentiation Factor 15 is a Novel Regulator of the Stem Cell-Like Phenotype in Neuroblastoma." Journal of the American College of Surgeons 223, no. 4: S87.
Congenital liver anomalies are uncommon. Symptomatic accessory hepatic lobes (AHL), either in continuity with the liver or ectopically located, are even less common. AHL have been reported in individuals spanning from neonates to octogenarians and are typically asymptomatic, however when symptomatic often require surgical intervention. We report three new cases of AHL in children (mean = 14.6 years). All three presented with sudden onset of abdominal pain and were diagnosed preoperatively by imaging findings. All three patients had symptom resolution following resection of the torsed accessory liver lobes. We report here the largest series of pediatric AHL torsion at a single institution to date, review the classification schemes, identify diagnostic imaging findings, and summarize associated congenital disorders that should raise suspicion for accessory hepatic lobes.
Natasha Corbitt; Eric J. Rellinger; Marta Hernanz-Schulman; Dai H. Chung. Accessory hepatic lobes in the pediatric population: A report of three cases of torsion and literature review. Journal of Pediatric Surgery Case Reports 2016, 16, 15 -18.
AMA StyleNatasha Corbitt, Eric J. Rellinger, Marta Hernanz-Schulman, Dai H. Chung. Accessory hepatic lobes in the pediatric population: A report of three cases of torsion and literature review. Journal of Pediatric Surgery Case Reports. 2016; 16 ():15-18.
Chicago/Turabian StyleNatasha Corbitt; Eric J. Rellinger; Marta Hernanz-Schulman; Dai H. Chung. 2016. "Accessory hepatic lobes in the pediatric population: A report of three cases of torsion and literature review." Journal of Pediatric Surgery Case Reports 16, no. : 15-18.
Eric J. Rellinger; Brian T. Craig; Laura D. Craig-Owens; M. Cristina Pacheco; Dai H. Chung; Melissa E. Danko. Clostridium sordellii necrotizing omphalitis: A case report and literature review. Journal of Pediatric Surgery Case Reports 2016, 10, 35 -38.
AMA StyleEric J. Rellinger, Brian T. Craig, Laura D. Craig-Owens, M. Cristina Pacheco, Dai H. Chung, Melissa E. Danko. Clostridium sordellii necrotizing omphalitis: A case report and literature review. Journal of Pediatric Surgery Case Reports. 2016; 10 ():35-38.
Chicago/Turabian StyleEric J. Rellinger; Brian T. Craig; Laura D. Craig-Owens; M. Cristina Pacheco; Dai H. Chung; Melissa E. Danko. 2016. "Clostridium sordellii necrotizing omphalitis: A case report and literature review." Journal of Pediatric Surgery Case Reports 10, no. : 35-38.