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Biomedical subjects

Mike K Chen

Publications and source records attributed to Mike K Chen.

17 recordsLinked to original sources
PubMed2006

One-year outcomes of Roux-en-Y gastric bypass for morbidly obese adolescents: a multicenter study from the Pediatric Bariatric Study Group.

BACKGROUND/PURPOSE: Little is known about the metabolic outcomes of adolescent bariatric surgery. We report changes in weight, metabolic profile, and types of complications seen in a multicenter cohort. METHODS: One-year outcomes were included. For weight loss comparisons, a nonsurgical cohort (n = 12) was used. The primary outcome was weight change (n = 30) and secondary outcomes were metabolic variables (n = 24) and complications (n = 36). Data were analyzed using signed rank or paired t tests. RESULTS: Mean body mass index fell 37% (from 56.5 preoperatively to 35.8 kg/m2; P < .001) in surgical patients and 3% (from 47.2 to 46 kg/m2; P = NS) in nonsurgical patients. Surgical patients showed significant improvements in triglycerides (-65 mg/dL), total cholesterol (-28 mg/dL), fasting blood glucose (-12 mg/dL), and fasting insulin (-21 microM/mL]). Improvement in high-density lipoprotein cholesterol (-3.9 mg/dL) and low-density lipoprotein cholesterol (-8.8 mg/dL) was not statistically significant. Sixty-one percent of surgical patients had no complications. Of 15 patients with complications, 9 had minor complications with no long-term sequelae, 4 had at least 1 moderate complication with sequelae for at least 1 month and 2 had at least 1 severe medical complication with long-term consequences (including beriberi and death). There were no perioperative deaths or other severe surgical complications in this series. CONCLUSIONS: Postoperatively, adolescents lose significant weight and realize major metabolic improvements. The complication profile compares favorably to severely obese (body mass index >40 kg/m2) adults; however, small sample size precludes calculation of complication rates. Although there are considerable risks of bariatric surgery, early experience suggests that risks are offset by health benefits.

Adolescent↗
PubMed2006

Differential response of neuroblastoma cells to TRAIL is independent of PI3K/AKT.

BACKGROUND: In many human tumor cells, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis through caspase activation, whereas activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway prevents apoptosis. We hypothesized that inhibition of PI3K/Akt would increase TRAIL-induced apoptosis in neuroblastoma cells. METHODS: SK-N-AS, SH-SY5Y, and IMR-32 neuroblastoma cells were cultured with either standard media or media with PI3K/Akt inhibitor for 24 hours. These cells were then exposed to 100 ng/mL of TRAIL for 90 minutes and harvested. Cells either underwent flow cytometric analysis of apoptosis, had protein extracted for Western blot, had RNA extracted for reverse transcription-polymerase chain reaction, or had cell lysates analyzed for caspase-3, -8, and -9. RESULTS: Baseline expression of TRAIL receptors and Akt varied among the cell lines. Inhibition of PI3K/Akt decreased caspase-3 activation in the AS and SY cells, but did not alter TRAIL-induced apoptosis in any of the cell lines. Activity of caspase-8 and -9 was also unaffected by PI3K/Akt attenuation. CONCLUSIONS: Inhibition of the PI3K/Akt pathway does not increase the sensitivity of neuroblastoma cell lines to TRAIL-induced apoptosis. Neuroblastoma is unique in that activation of the PI3K/Akt pathway is either not essential to its TRAIL resistance or counteracted because of the multiple repetitive pathways of TRAIL resistance.

Apoptosis↗
PubMed2005

VEGF-mediated survivin expression in neuroblastoma cells.

BACKGROUND: Vascular endothelial growth factor (VEGF) up-regulates a number of cellular survival signals in endothelial cells. We hypothesize that VEGF will up-regulate survivin, a member of the IAP family of anti-apoptotic proteins, via the PI3K/Akt cell signaling pathway in human neuroblastoma cells. MATERIALS AND METHODS: IMR-32 human neuroblastoma cells are cultured with VEGF at varying times and in escalating doses. A specific inhibitor of PI3-kinase, LY294002, is used to block Akt phosphorylation. Immunoblot is used to measure protein expression, and Hoechst staining is used to detect apoptosis. RESULTS: Stimulation of IMR-32 neuroblastoma cells with VEGF results in an increase in survivin protein expression in both a dose- and a time-dependent fashion. Akt phosphorylation is also increased after stimulation with exogenous VEGF. Blockade of Akt phosphorylation with LY294002 abrogates the effects of VEGF upon survivin and phosphorylated Akt protein expression. CONCLUSIONS: VEGF has been shown to up-regulate a number of survival signals in endothelial cells. We have found that exposure of human neuroblastoma cells to exogenous VEGF results in an increased expression of survivin protein and phosphorylated Akt, and inhibition of PI3-kinase abrogates those effects. It appears that VEGF is important for promotion of neuroblastoma cellular survival through the up-regulation of survival proteins, and not only through its angiogenic properties.

Apoptosis↗
PubMed2004

Artificial rearing of mouse pups: development of a mouse pup in a cup model.

Artificial rearing of rat pups has been used in the investigation of the neonatal gut. We propose to adapt the model of artificially rearing rat pups for use in mouse pups, thereby allowing the use of transgenic animals for our research. We hypothesized that gastrostomy catheters may be placed successfully into neonatal mouse pups and that the pups may be artificially reared without significant alterations in their growth or intestinal development. Gastrostomy tubes are placed into 5-d-old mouse pups [artificially reared (AR); n = 32], and the mice are fed rodent milk substitute. Littermate pups [maternally reared (MR); n = 22] are used as controls. After 5 d, pups are killed and their organs are harvested. Intestinal villus measurements, protein content, and DNA content are determined. Data are reported as mean +/- SEM, compared with appropriate statistical methods, and significance is determined at P < 0.05. Initial weights and lengths are not different between the two groups, but after 5 d, MR pups weigh more than their AR counterparts (5.0 +/- 0.13 versus 4.1 +/- 0.14 g, MR versus AR; P < 0.01). However, the pups' length and the intestinal villus height-to-width ratios, protein, and DNA content are not different between the MR and AR pups. To our knowledge, this is the first report of artificially rearing mouse pups. Development of this technique will permit nutritional manipulation in neonatal mice, a mammalian model wherein the genome is sequenced and transgenic mutants are available.

Animals↗
PubMed2004

Expression of VEGF receptors in cocultured neuroblastoma cells.

BACKGROUND: VEGF is best known for its angiogenic properties. We have found that VEGF expression is increased in neuroblastoma cells cocultured with hepatocytes. In addition, we have previously shown that neuroblastoma cells cultured with exogenous VEGF have an increase in the expression of VEGF receptors. Therefore, we hypothesized that the expression of VEGF receptors would be up-regulated in neuroblastoma cells grown in the coculture environment. MATERIALS AND METHODS: Two neuroblastoma cell lines (IMR-32 or SK-N-DZ) are used. These cells are cultured alone and in a coculture system with hepatocytes. Message for VEGF and the VEGF receptors KDR, flt-1, flt-4, neuropilin 1 (NRP-1), and neuropilin 2 (NRP-2) are measured with RT-PCR. Flt-4, NRP-1, and NRP-2 protein expression is measured with Western blot. RESULTS: The receptors KDR and flt-1 are not detected in either cell line in either control or coculture conditions. Message for VEGF and flt-4 is significantly increased in the cocultured IMR-32 cells, while that for NRP-1 and NRP-2 is unchanged in these cells. VEGF and its receptors are unchanged in cocultured SK-N-DZ cells. CONCLUSIONS: Neuroblastoma cells express specific VEGF receptors that are differentially regulated in the different cell lines. These findings suggest that the heterogeneity of neuroblastomas may limit the utility of targeting VEGF and its receptors as sole treatments for the tumor, and that successful therapies will be dependent upon the specific biology of the tumor.

Blotting, Western↗
PubMed2004

Administration of prenatal betamethasone suppresses the adrenal-hypophyseal axis in newborns with congenital diaphragmatic hernia.

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a condition that is characterized by pulmonary hypoplasia and pulmonary hypertension. Prenatal betamethasone often is administered to fetuses with CDH to improve pulmonary function. In this study, the authors investigate the possible role of the adrenal-hypophyseal axis in CDH in an animal model and subsequently in human infants with CDH. METHODS: Twin fetal sheep underwent creation of DH or a sham thoracotomy, and levels of plasma and lung ACTH and plasma cortisol were compared. For the human studies, plasma levels of ACTH, cortisol, and DHEA were measured in cord blood samples collected from 9 CDH (5 that received prenatal betamethasone) and compared with those of 14 normal newborns. In both studies, ACTH and cortisol levels were determined by radioimmunoassay (RIA). Human (DHEA) levels were determined by ELISA. RESULTS: Plasma ACTH and cortisol levels were elevated in fetal DH sheep compared with sham-operated controls; however, levels of ACTH in lung tissues were not different. Human newborns with CDH who have been exposed to prenatal steroids have significantly lower plasma ACTH, cortisol, and DHEA levels than normal newborns and CDH newborns not exposed to prenatal betamethasone. CONCLUSIONS: In an ovine model of CDH, the adrenal-hypophyseal axis appears up-regulated in DH fetuses compared with sham-operated animals. Conversely, the adrenal-hypophyseal axis in human CDH newborns appears normal but is suppressed by the administration of prenatal betamethasone.

Adrenocorticotropic Hormone↗
PubMed2004

Extracorporeal membrane oxygenation combined with endovascular embolization for management of neonatal high-output cardiac failure secondary to intracranial arteriovenous fistula. Case report.

The authors describe a novel approach to the management of high-output heart failure secondary to an intracranial high-flow dural arteriovenous fistula (DAVF) by using extracorporeal membrane oxygenation (ECMO). To the best of the authors' knowledge, this represents the first report of an embolization performed in conjunction with the use of an ECMO circuit and the first report in which an ECMO cannula was used for intraarterial access for cerebral angiography. A 2-day-old girl presented with severe, high-output heart failure secondary to a high-flow intracranial DAVF. The patient was neurologically intact and no brain parenchymal abnormalities were revealed on computerized tomography scanning of the head, but she suffered severe heart failure, pulmonary hypertension, and liver and renal dysfunction. The patient underwent three endovascular embolization procedures involving coils and liquid embolic agents. Despite a decrease in the DAVF flow, the patient had only transient improvement in her pulmonary hypertension, and venoarterial ECMO therapy was instituted. Another embolization was performed while the patient was receiving ECMO therapy. Her cardiovascular status improved, she was weaned from ECMO, and she was eventually discharged home to her family. Extracorporeal membrane oxygenation can be used to sustain severely ill neonates with high-output heart failure secondary to intracranial AVFs. Embolization can be performed while the patient is receiving ECMO therapy.

Angiography, Digital Subtraction↗
PubMed2003

Differential expression of Bcl-2 and Bax may enhance neuroblastoma survival.

BACKGROUND/PURPOSE: Aggressive tumors may alter their expression of Bcl-2 proteins to decrease apoptosis and increase survival. The authors reported previously that neuroblastoma cells have diminished apoptosis when placed in coculture with hepatocytes to stimulate a metastatic environment. It was hypothesized that the expression of proapoptotic (Bax) and prosurvival (Bcl-2 and Mcl-1) proteins would be altered in neuroblastoma cells grown in a cell culture model of metastatic neuroblastoma. METHODS: Human neuroblastoma cells (IMR-32) were grown alone or in coculture with human hepatocytes for 2, 3, or 4 days. Bcl-2, Mcl-1, and Bax mRNA were measured with reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: Bcl-2, an antiapoptotic protein, was significantly increased in cocultured neuroblastoma cells by day 4. Bax, a proapoptotic protein, was significantly diminished by day 3. No significant change in Mcl-1 occurred in this study. CONCLUSIONS: When neuroblastoma cells placed in coculture, the prosurvival protein, Bcl-2, is upregulated whereas the proapoptotic protein, Bax, is downregulated. The combination of these changes can maximally enhance the survival rate of neuroblastoma cells in coculture. The propensity for neuroblastoma to either metastasize or regress may be associated with its ability to differentially regulate the expression of different members of the Bcl-2 protein family.

Apoptosis↗
PubMed2003

VEGF receptors are differentially expressed by neuroblastoma cells in culture.

BACKGROUND/PURPOSE: Vascular endothelial growth factor (VEGF) is best known for its angiogenic properties, but its mitogenic capacity may be more important for tumorigenesis. The ability of VEGF to induce specific biologic activities may be dependent on the amount and type of VEGF receptors present. The authors hypothesize that neuroblastoma cells express specific VEGF receptors and that their expression may be altered when the cells are exposed to differing cytokines and culture environments. METHODS: Four groups of human neuroblastoma cells (IMR-32) are studied. (1) Control cells: cultured in standard media. (2) VEGF cells: VEGF added to the media. (3) Tumor necrosis factor alpha (TNF-alpha) cells: TNF-alpha added to the media. (4) Serum starved cells: cultured in serum-depleted media. Reverse transcriptase polymerase chain reaction (RT-PCR) is utilized to measure the VEGF receptors flt-1, KDR/flk-1, flt-4, neuropilin 1 (NRP-1), and neuropilin 2 (NRP-2). RESULTS: Flt-1 and KDR are not detected in any groups. Flt-4, NRP-1, and NRP-2 are present in the IMR-32 cells, and their expression is significantly increased by the administration of VEGF. Neuroblastoma cells cultured with TNF-alpha or in serum-depleted media have a significant decrease in the expression of these receptors. CONCLUSIONS: The authors show that neuroblastoma cells express specific VEGF receptors that may be altered by mitogenic or apoptotic stimuli. Specifically targeting VEGF and its receptors may be another therapeutic strategy for the treatment of neuroblastoma.

Culture Media, Serum-Free↗
PubMed2003

Expanded application of extracorporeal membrane oxygenation in a pediatric surgery practice.

OBJECTIVE: To examine the breadth of application and resulting outcomes in a university-based extracorporeal membrane oxygenation (ECMO) program directed by pediatric surgeons. SUMMARY BACKGROUND DATA: Several randomized control trials have supported the use of ECMO in neonates with respiratory failure. No comparable data exist for older children and young adults who may be afflicted with a variety of uncommon conditions. The indications for ECMO in these patients remain controversial. METHODS: Patient data were recorded prospectively and reported to the Extracorporeal Life Support Organization. These data were analyzed by indications and outcomes on all patients treated since the inception of the program. RESULTS: Two hundred sixteen patients were treated with 225 courses of ECMO. Neonates (188 [87%]) outnumbered 28 older patients (aged 6 weeks to 22 years). Overall, 174 patients survived (81%). Sixty-four of 65 (98.5%) neonates with meconium aspiration syndrome survived. ECMO support after heart (3), lung (2), heart-lung (1), and liver (1) transplant yielded a 57% survival to discharge. ECMO also resulted in survival of patients with uncommon conditions, including severe asthma (1), hydrocarbon aspiration (1/2), congestive heart failure due to a cerebral arteriovenous malformation (1), tracheal occlusion incurred during endoscopic stent manipulation (2), meningitis (1), and viral pneumonia (3/5). CONCLUSIONS: ECMO can potentially eliminate mortality for meconium aspiration syndrome. Survival for other causes of respiratory failure in neonates and older children, while not as dramatic, still surpasses that anticipated with conventional therapy. Moreover, survival of transplant patients has been comparable to that achieved in other children.

Adolescent↗
PubMed2003

Neuroblastoma, apoptosis, and growth factors.

Neuroblastoma is the most common extracranial tumor of childhood. This tumor is associated with alterations in apoptosis and is affected by various growth factors and cytokines. In this short review we will discuss recent findings in our laboratory where we have been studying a cell culture model of neuroblastoma.

Apoptosis↗
PubMed2003

Twenty years of progress in congenital diaphragmatic hernia at the University of Florida.

Over the past 20 years the clinical paradigms underlying the care of children with congenital diaphragmatic hernia (CDH) have undergone profound changes. The purpose of this work is to provide an historic review of research and clinical studies related to CDH at the University of Florida (UF) and Shands Children's Hospital during the chairmanship of Edward M. Copeland, III, M.D. and to present our current clinical results. During Dr Copeland's tenure survival for newborns symptomatic with CDH treated at UF/Shands Children's Hospital has improved from less than 20 per cent to 85 per cent. Clinical observations have suggested and research studies at UF using a fetal lamb model have confirmed that fetal distress can occur late in gestation, which may predispose infants with CDH to pulmonary hypertension. However, our patient experience has confirmed that the most significant cause of mortality in human infants is not pulmonary hypertension but iatrogenic injury to their hypoplastic lungs. Strict avoidance of barotrauma in these babies has been the most important clinical advance during these two decades. Significant clinical and research problems remain including defining optimal prenatal care, management of complications during the first few weeks of life, and development of strategies to accelerate lung growth. Dramatic improvements in survival have resulted in children who manifest a number of clinical problems that were not evident when most of these patients died early in infancy. Our experience at Shand's Children's Hospital/UF indicates that feeding problems, respiratory infections, and management of subtle or overt neurologic complications may become major issues for some of these survivors and their families.

Abnormalities, Multiple↗
PubMed2002

Caspase 3 expression is altered in a coculture model of neuroblastoma.

BACKGROUND: Previously, we demonstrated that neuroblastoma cells cocultured with hepatocytes are protected from apoptosis, while apoptosis is upregulated in the hepatocytes. The mechanisms responsible for these findings are unknown. We hypothesize that caspase 3, a cysteine protease central to the apoptotic pathway, will be altered in this coculture model that simulates metastatic neuroblastoma. METHODS: Control human neuroblastoma cells and liver cells are plated in standard media. For the study group, a noncontact, coculture system is used. Hepatocytes are plated on cell culture inserts, placed above a growing layer of neuroblastoma cells, and incubated. Activated caspase 3 is measured after 1, 2, 3, or 4 days. RESULTS: Activated caspase 3 levels are significantly decreased in the cocultured neuroblastoma cells on days 2, 3, and 4. Conversely, cocultured hepatocytes have a significant increase in caspase 3 activation at all time periods, with the largest difference seen after 1 day in coculture. CONCLUSIONS: The capacity for neuroblastoma to differentially alter caspase 3 activation may provide a significant survival advantage for the neuroblastoma cells in metastatic environments. Understanding the mechanisms for this altered regulation may lead to improved and better targeted therapy for this malignancy.

Caspase 3↗
PubMed2002

VEGF upregulates Bcl-2 expression and is associated with decreased apoptosis in neuroblastoma cells.

BACKGROUND/PURPOSE: Both the expression of Bcl-2 and the amount of vascular endothelial growth factor (VEGF) are increased in neuroblastoma cells cocultured with hepatocytes. The authors hypothesize that VEGF upregulates Bcl-2 expression by the neuroblastoma cells and protects them from apoptotic stimuli. METHODS: To determine whether VEGF will induce Bcl-2 expression in neuroblastoma cells, the cells are plated with standard media (control) or media supplemented with VEGF. After 24 hours, Bcl-2 expression is measured. To determine whether VEGF protects neuroblastoma cells from apoptosis, the cells are subjected to tumor necrosis factor alpha (TNF-alpha) or serum starvation to induce apoptosis either with or without VEGF added to the culture media. The cells are collected and apoptosis measured using the deoxynucleotidyltransferase-mediated dUTP neck end labeling (TUNEL) method. RESULTS: VEGF increases Bcl-2 expression by 33% over cells cultured in standard media. Serum starving the tumor cells or adding TNF-alpha significantly increases the percentage of apoptotic cells. The addition of VEGF significantly protects the neuroblastoma cells from the apoptotic effects of both serum starvation and TNF-alpha. CONCLUSIONS: VEGF increases the expression of Bcl-2 and also abrogates TNF-alpha and serum starvation-induced apoptosis in neuroblastoma cells in vitro. VEGF may promote neuroblastoma survival not only through angiogenesis, but also by altering apoptosis and its regulating proteins.

Apoptosis↗
PubMed2002

Insulin-like growth factor-I protects neuroblastoma against starvation-induced apoptosis and is associated with increased Bcl-2 expression.

BACKGROUND/PURPOSE: Aggressive neuroblastomas avoid apoptosis and have increased expression of the antiapoptotic protein, Bcl-2. Insulin-like growth factor-I (IGF-I) is mitogenic and may promote tumor survival by inhibiting apoptosis. The authors hypothesize that IGF-I may protect neuroblastoma cells from apoptosis by upregulating their Bcl-2 expression. METHODS: Human neuroblastoma cells (IMR-32) are cultured, and 3 experimental groups are established: 1 group with cells cultured in standard growth media (control), 1 with cells grown in serum-depleted media (starvation), and 1 with neuroblastoma cells cultured in starvation media plus IGF-I. The cells are harvested at 14 and 24 hours, and cytospin slides are made. Bcl-2 expression is measured by immunohistochemistry. Apoptosis is detected with the TUNEL method. RESULTS: Bcl-2 expression is decreased 90% in the serum starved neuroblastoma cells. In addition, apoptosis is 150 times higher in the starved neuroblastoma cells. These changes are abrogated by the addition of IGF-I, where apoptosis is decreased 50% and Bcl-2 is 14-fold higher in the IGF-I-treated group. These changes are most apparent at 24 hours. CONCLUSIONS: IGF-I protects neuroblastoma cells from apoptosis and increases Bcl-2 expression. Growth factors may have a direct role in promoting tumorigenesis by inducing the expression of antiapoptotic proteins by the tumor.

Apoptosis↗
PubMed2002

Small watercraft injuries in children.

The speed and use of small watercraft have increased dramatically in recent years. We report our experience with pediatric trauma resulting from small watercraft accidents. We conducted a retrospective chart review including all children admitted with injuries sustained in small watercraft accidents. Sixteen children were included; nine were injured in jet ski accidents and seven in accidents involving other craft. Jet ski accidents tended to result in more serious injuries (closed-head injuries, hollow and solid viscus injuries, chest trauma, spinal injuries leading to paralysis, and death) than those sustained in accidents with small boats. Skin and soft-tissue injuries and long-bone fractures were the most frequent injuries following accidents with other small boats. Six of eight children (75%) injured on jet skis required operative interventions. Only three of seven (43%) children in other watercraft accidents required surgery (P < 0.05 jet ski vs other watercraft). When compared with children injured in accidents involving small boats those involved in jet ski accidents tended to have more serious injuries and require operative intervention more frequently. A high index of suspicion for serious injuries must be maintained when evaluating children with this mechanism of injury.

Accidents↗