Publications by authors named "Brian T Craig"

10 Publications

  • Page 1 of 1

Impact of Referring Hospital Imaging on Mortality at a Level I Trauma Center.

J Surg Res 2019 11 30;243:59-63. Epub 2019 May 30.

Vanderbilt University Medical Center, Division of Trauma & Critical Care, Nashville, Tennessee. Electronic address:

Background: Computed tomography (CT) has become a standard adjunct in the evaluation of patients with trauma. However, utility of imaging at the referring hospital remains controversial. We study the effect of CT scans at referring hospitals on in-hospital mortality at a receiving trauma center.

Materials And Methods: A retrospective cohort study was performed with adult patients with severe trauma transferred to a level I trauma center from regional nontrauma hospitals between 2012 and 2017. Baseline characteristics were compared with Student's t-test and Pearson's chi-squared testing. The primary endpoint was in-hospital mortality. Cox regression, controlling for transfer time, was used to evaluate the effect of imaging on mortality.

Results: Three thousand four hundred and fifteen adult patients with trauma were included: 1135 (33.2%) received a pretransfer CT scan, whereas 2280 (66.8%) did not. Patients who received a pretransfer CT scan were more likely to be older, female, white, have a higher Charlson Comorbidity Index, less severely injured, have a blunt mechanism, and be transferred by ground. There was no difference in distance (58.3 miles versus 57.0 miles, P = 0.34), but transfer times were significantly increased for those who received pretransfer scans (288 versus 213 min, P < 0.005). The adjusted model controlling for multiple variables has a hazard ratio of 0.533 (95% confidence interval 0.42-0.68, P < 0.005).

Conclusions: There is a survival advantage for patients who receive pretransfer CT scans despite having significantly longer transport times. We suggest that this decreased mortality associated with pretransfer imaging may reflect improving trends in referring physician transfer decisions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jss.2019.04.059DOI Listing
November 2019

Isoxazole compound ML327 blocks MYC expression and tumor formation in neuroblastoma.

Oncotarget 2017 Oct 20;8(53):91040-91051. Epub 2017 Jul 20.

Section of Surgical Sciences, Department of Surgery, at Vanderbilt University Medical Center, TN 37232, Nashville, USA.

Neuroblastomas are the most common extracranial solid tumors in children and arise from the embryonic neural crest. -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 (-(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 -amplified and -single copy neuroblastoma cell lines. Moreover, ML327 blocked mRNA levels and tumor progression in established -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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.19406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710904PMC
October 2017

FX11 inhibits aerobic glycolysis and growth of neuroblastoma cells.

Surgery 2017 03 2;161(3):747-752. Epub 2016 Dec 2.

Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN; Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN. Electronic address:

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.surg.2016.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5369647PMC
March 2017

Induced differentiation inhibits sphere formation in neuroblastoma.

Biochem Biophys Res Commun 2016 08 11;477(2):255-9. Epub 2016 Jun 11.

Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA. Electronic address:

Neuroblastoma arises from the neural crest, the precursor cells of the sympathoadrenal axis, and differentiation status is a key prognostic factor used for clinical risk group stratification and treatment strategies. Neuroblastoma tumor-initiating cells have been successfully isolated from patient tumor samples and bone marrow using sphere culture, which is well established to promote growth of neural crest stem cells. However, accurate quantification of sphere-forming frequency of commonly used neuroblastoma cell lines has not been reported. Here, we show that MYCN-amplified neuroblastoma cell lines form spheres more frequently than non-MYCN-amplified cell lines. We also show that sphere formation is directly sensitive to cellular differentiation status. 13-cis-retinoic acid is a clinically used differentiating agent that induces a neuronal phenotype in neuroblastoma cells. Induced differentiation nearly completely blocked sphere formation. Furthermore, sphere formation was specifically FGF-responsive and did not respond to increasing doses of EGF. Taken together, these data suggest that sphere formation is an accurate method of quantifying the stemness phenotype in neuroblastoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2016.06.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5333757PMC
August 2016

Laparoscopic Nissen fundoplication in infants with hypoplastic left heart syndrome.

J Pediatr Surg 2016 Jan 23;51(1):76-80. Epub 2015 Oct 23.

Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address:

Background/purpose: Patients with hypoplastic left heart syndrome (HLHS) experience a higher risk for complications from gastroesophageal reflux, prompting frequent need for fundoplication. Patients between stage I and II palliation ("interstage") are at particularly high operative risk because of the parallel nature of their pulmonary and systemic blood flow. Laparoscopic approach for fundoplication is common for pediatric patients. However, its safety in interstage HLHS is relatively unknown. We examined the perioperative physiologic burden of a laparoscopic fundoplication in HLHS patients.

Methods: All patients who underwent open or laparoscopic fundoplication during the interstage period at our institution since 2006 were reviewed. Perioperative physiologic data, echocardiographic findings, survival, and complications were collected from the anesthetic record and patient chart.

Results: Nineteen patients with HLHS had laparoscopic fundoplication, 13 (68%) during the interstage period, compared to 64 performed by the open approach. Ten (77%) of 13 interstage patients had perioperative hemodynamic instability. Incidence of instability between open and laparoscopic groups was not different. One laparoscopic patient required ECMO support for shunt thrombosis.

Conclusions: Despite a high incidence of hemodynamic instability, overall outcomes are consistent with those reported in the literature for this high-risk patient population. Laparoscopic approach for fundoplication during the interstage period appears to be a relatively safe option for these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpedsurg.2015.10.013DOI Listing
January 2016

Antioxidant inhibition of steady-state reactive oxygen species and cell growth in neuroblastoma.

Surgery 2015 Sep 16;158(3):827-36. Epub 2015 Jun 16.

Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN; Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN. Electronic address:

Background: Reactive oxygen species (ROS) contribute to adult tumorigenesis; however, their roles in pediatric solid tumors are unknown. Here, we sought to define the steady-state ROS levels in neuroblastoma and to examine whether aggressive cellular behavior, which may predict treatment failure, is regulated by ROS.

Methods: Neuroblastoma sections were assessed for 4-hydroxynonenal (4-HNE), a marker of intracellular lipid peroxidation and a byproduct of increased levels of ROS. Human neuroblastoma cell lines, MYCN-amplified BE(2)-C and MYCN-nonamplified SK-N-SH, were examined in our study. Superoxide and hydroperoxide oxidation products were detected by staining for dihydroethidium (DHE) and 5, 6-carboxy-2', 7'-dichlorodihydrofluorescein diacetate (CDCFH2), using the oxidation-insensitive analog CDCF as a negative control. Cells were treated with N-acetylcysteine (NAC; 10 mmol/L) daily for 5 days and analyzed.

Results: Greater expression of 4-HNE was observed in undifferentiated tumor sections as compared with the more differentiated tumors. Interestingly, increased levels of ROS were detected in MYCN-amplified BE(2)-C cells. Moreover, gastrin-releasing peptide receptor-induced ROS production stimulated upregulation of the hypoxia inducible factor (HIF)-1α/vascular endothelial growth factor (VEGF) pathway and an increase in cell growth. Antioxidant NAC decreased HIF-1α/VEGF expression and inhibited BE(2)-C cell growth.

Conclusion: We report a novel observation that shifting the redox balance toward greater ROS levels results in a more aggressive neuroblastoma phenotype. Our data suggest that ROS play a critical role in refractory neuroblastoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.surg.2015.03.062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536094PMC
September 2015

Bromodomain and extraterminal inhibition blocks tumor progression and promotes differentiation in neuroblastoma.

Surgery 2015 Sep 9;158(3):819-26. Epub 2015 Jun 9.

Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN; Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN. Electronic address:

Background: MYCN amplification is a key molecular hallmark of high-risk neuroblastoma. Previously considered an "undruggable" target, MYCN transcription can be disrupted by inhibiting the bromodomain and the extraterminal (BET) domain family of proteins that regulates MYCN transcription epigenetically. JQ1 is a potent, small-molecule BET inhibitor that induces cell-cycle arrest and initiates apoptosis in neuroblastoma. Here, we sought to validate the antitumorigenic effects of JQ1 in neuroblastoma and to evaluate whether blocking N-myc expression with JQ1 promotes neural differentiation.

Methods: We determined the effects in vitro of JQ1 treatment on human neuroblastoma cell growth in both monolayer and sphere-forming conditions. Subcutaneous neuroblastoma xenografts were used for an in vivo study. Western blotting and immunohistochemistry were performed to evaluate the effects on neural differentiation and stem cell markers.

Results: JQ1 treatment blocked neuroblastoma cell growth in both monolayer and sphere-forming conditions; JQ1 also attenuated the growth of neuroblastoma xenograft in athymic nude mice. Neurofilament expression was enhanced with JQ1 treatment, indicating that JQ1 induces neuronal differentiation. Sphere forming conditions resulted in increased expression of multiple stem cell markers; these effects were reversed with JQ1 treatment.

Conclusion: BET inhibition attenuates progression and promotes neural differentiation of neuroblastoma in vitro and in vivo in mice, providing insight into potential clinical applications of BET inhibitors in the treatment of patients with neuroblastoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.surg.2015.04.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536146PMC
September 2015

Silencing of CDC42 inhibits neuroblastoma cell proliferation and transformation.

Cancer Lett 2014 Dec 28;355(2):210-6. Epub 2014 Sep 28.

Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address:

Cell division cycle 42 (CDC42), a small GTPase of the Rho-subfamily, regulates diverse cellular functions including proliferation, cytoskeletal rearrangement and even promotes malignant transformation. Here, we found that increased expression of CDC42 correlated with undifferentiated neuroblastoma as compared to a more benign phenotype. CDC42 inhibition decreased cell growth and soft agar colony formation, and increased cell death in BE(2)-C and BE(2)-M17 cell lines, but not in SK-N-AS. In addition, silencing of CDC42 decreased expression of N-myc in BE(2)-C and BE(2)-M17 cells. Our findings suggest that CDC42 may play a role in the regulation of aggressive neuroblastoma behavior.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.canlet.2014.08.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4301604PMC
December 2014

A critical role for TLR4 induction of autophagy in the regulation of enterocyte migration and the pathogenesis of necrotizing enterocolitis.

J Immunol 2013 Apr 1;190(7):3541-51. Epub 2013 Mar 1.

Division of Pediatric Surgery, Department of Surgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.

Necrotizing enterocolitis (NEC) develops in response to elevated TLR4 signaling in the newborn intestinal epithelium and is characterized by TLR4-mediated inhibition of enterocyte migration and reduced mucosal healing. The downstream processes by which TLR4 impairs mucosal healing remain incompletely understood. In other systems, TLR4 induces autophagy, an adaptive response to cellular stress. We now hypothesize that TLR4 induces autophagy in enterocytes and that TLR4-induced autophagy plays a critical role in NEC development. Using mice selectively lacking TLR4 in enterocytes (TLR4(ΔIEC)) and in TLR4-deficient cultured enterocytes, we now show that TLR4 activation induces autophagy in enterocytes. Immature mouse and human intestine showed increased expression of autophagy genes compared with full-term controls, and NEC development in both mouse and human was associated with increased enterocyte autophagy. Importantly, using mice in which we selectively deleted the autophagy gene ATG7 from the intestinal epithelium (ATG7(ΔIEC)), the induction of autophagy was determined to be required for and not merely a consequence of NEC, because ATG7(ΔIEC) mice were protected from NEC development. In defining the mechanisms involved, TLR4-induced autophagy led to impaired enterocyte migration both in vitro and in vivo, which in cultured enterocytes required the induction of RhoA-mediated stress fibers. These findings depart from current dogma in the field by identifying a unique effect of TLR4-induced autophagy within the intestinal epithelium in the pathogenesis of NEC and identify that the negative consequences of autophagy on enterocyte migration play an essential role in its development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.1202264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3608826PMC
April 2013

Endorectal pull-through for Hirschsprung's disease-a multicenter, long-term comparison of results: transanal vs transabdominal approach.

J Pediatr Surg 2010 Jun;45(6):1213-20

Department of Surgery, Section of Pediatric Surgery, University of Michigan, Ann Arbor, Michigan 48109-0245, USA.

Purpose: Previous studies have reported decreased continence in patients undergoing transanal endorectal pull-through (TERP) for Hirschsprung's disease compared to the older transabdominal approach (TAA). To address this, we examined long-term stooling outcomes in a large, multicenter cohort of patients undergoing either TERP or TAA.

Methods: Data were collected from 5 large pediatric institutions. Patient families were surveyed using a stooling score system (0-40, best to worst total score). Inclusion criteria included patients older than 3 years and those who had more than 6 months of recovery after pull-through. Those with total colonic aganglionosis were excluded. Statistical analysis included univariate and multivariate linear regression (significance, P < .05).

Results: Two hundred eighty-one patients underwent TERP (192) or TAA (89). Interviews were completed in 149 (104 [52%] TERP vs 45 [52%] TAA). The TAA group had a significantly greater number of daily bowel movements for each respective postoperative year and experienced more early complications (3% vs 1% with >1 complication; P = .061) and late complications (19% vs 4% with >1 complication; P < .001). Although the TAA group had a higher mean enterocolitis score (3.3 +/- 0.4 vs 1.8 +/- 0.2; P < .001), this was not borne out by multivariate regression analysis (P = .276). Parental survey showed that there were no significant differences between procedures in mean total, continence, or stooling pattern scores.

Conclusion: Transanal endorectal pull-through was associated with fewer complications and fewer episodes of enterocolitis. In contrast to prior studies, TERP patients did not have a higher rate of incontinence. These results support use of TERP as an excellent surgical approach for children with Hirschsprung's disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpedsurg.2010.02.087DOI Listing
June 2010
-->