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1.  RagA, but not RagB, is essential for embryonic development and adult mice 
Developmental cell  2014;29(3):321-329.
The mechanistic target of rapamycin complex 1 (mTORC1) integrates cues from growth factors and nutrients to control metabolism. In contrast to the growth factor input, genetic disruption of nutrient-dependent activation of mTORC1 in mammals remains unexplored. We engineered mice lacking RagA and RagB genes, which encode the GTPases responsible for mTORC1 activation by nutrients. RagB has limited expression and its loss shows no effects on mammalian physiology. RagA deficiency leads to E10.5 embryonic death, loss of mTORC1 activity, and severe growth defects. Primary cells derived from these mice exhibit no regulation of mTORC1 by nutrients, and maintain high sensitivity to growth factors. Deletion of RagA in adult mice is lethal. Upon RagA loss, a myeloid population expands in peripheral tissues. RagA-specific deletion in liver increases cellular responses to growth factors. These results show the essentiality of nutrient sensing for mTORC1 activity in mice and its suppression of PI3K/Akt signalling.
PMCID: PMC4035553  PMID: 24768164
2.  National trends of perioperative outcomes and cost for open, laparoscopic and robotic pediatric pyeloplasty 
The Journal of urology  2013;191(4):1090-1095.
We performed a population-based study comparing trends in perioperative outcomes and cost for open (OP), laparoscopic (LP), and robotic (RP) pediatric pyeloplasty. Specific billing items contributing to cost were also investigated.
Using the Premier Perspective database, we identified 12,662 pediatric patients who underwent open, laparoscopic and robotic pyeloplasty (ICD-9 55.87) in the United States from 2003 – 2010. Univariate and multivariate statistics were used to evaluate perioperative outcomes, complications, and costs for the competing surgical approaches. Propensity weighting was employed to minimize selection bias. Sampling weights were used to yield a nationally representative sample.
A decrease in OP and a rise in minimally invasive pyeloplasty (MIP) was observed. All procedures had low complication rates. Compared to OP, LP and RP had longer median operating room (OR) times (240 minutes, p<0.0001 and 270 minutes, p<0.0001, respectively). There was no difference in median length of stay (LOS). The median total cost was lower among patients undergoing OP versus RP ($7,221 vs $10,780, p<0.001). This cost difference was largely attributable to robotic supply costs.
During the study period, OP made up a declining majority of cases. LP utilization plateaued, while RP increased. OR time was longer for MIP, while LOS was equivalent across all procedures. A higher cost associated with RP was driven by OR use and robotic equipment costs, which abrogated low room and board cost. This study reflects an adoption period for RP. With time, perioperative outcomes and cost may improve.
PMCID: PMC4154938  PMID: 24513164
minimally invasive pyeloplasty; laparoscopic pyeloplasty; robotic pyeloplasty; pediatric; ureteropelvic junction obstruction; comparative effectiveness
3.  Treating cancer stem cells and cancer metastasis using glucose-coated gold nanoparticles 
Cancer ranks among the leading causes of human mortality. Cancer becomes intractable when it spreads from the primary tumor site to various organs (such as bone, lung, liver, and then brain). Unlike solid tumor cells, cancer stem cells and metastatic cancer cells grow in a non-attached (suspension) form when moving from their source to other locations in the body. Due to the non-attached growth nature, metastasis is often first detected in the circulatory systems, for instance in a lymph node near the primary tumor. Cancer research over the past several decades has primarily focused on treating solid tumors, but targeted therapy to treat cancer stem cells and cancer metastasis has yet to be developed. Because cancers undergo faster metabolism and consume more glucose than normal cells, glucose was chosen in this study as a reagent to target cancer cells. In particular, by covalently binding gold nanoparticles (GNPs) with thio-PEG (polyethylene glycol) and thio-glucose, the resulting functionalized GNPs (Glu-GNPs) were created for targeted treatment of cancer metastasis and cancer stem cells. Suspension cancer cell THP-1 (human monocytic cell line derived from acute monocytic leukemia patients) was selected because it has properties similar to cancer stem cells and has been used as a metastatic cancer cell model for in vitro studies. To take advantage of cancer cells’ elevated glucose consumption over normal cells, different starvation periods were screened in order to achieve optimal treatment effects. Cancer cells were then fed using Glu-GNPs followed by X-ray irradiation treatment. For comparison, solid tumor MCF-7 cells (breast cancer cell line) were studied as well. Our irradiation experimental results show that Glu-GNPs are better irradiation sensitizers to treat THP-1 cells than MCF-7 cells, or Glu-GNPs enhance the cancer killing of THP-1 cells 20% more than X-ray irradiation alone and GNP treatment alone. This finding can help oncologists to design therapeutic strategies to target cancer stem cells and cancer metastasis.
PMCID: PMC4368028  PMID: 25844037
glucose capped gold nanoparticles; cancer metastasis; cancer stem cells; irradiation therapy; targeted treatment; suspension cancer cells
4.  Clusterin is a Gene Specific Target of MicroRNA-21 in Head and Neck Squamous Cell Carcinoma 
MicroRNA-21 (miRNA-21) has proto-oncogenic properties, though no miRNA-21 specific targets have been found in head and neck squamous cell carcinoma (HNSCC). Further study of miRNA-21 and its specific targets is essential to understanding HNSCC biology.
Experimental Design:
miRNA expression profiles of 10 HNSCC and 10 normal mucosa samples were investigated using a custom miRNA microarray. 13 HNSCC and 5 normal mucosa primary tissue specimens underwent mRNA expression microarray analysis. To identify miRNA-21 downstream targets, oral keratinocyte cells were subjected to microarray analysis after miRNA-21 transient transfection. miRNA and mRNA expression were validated by RT-qPCR in a separate cohort of 16 HNSCC and 15 normal mucosal samples. Microarray and bioinformatics analyses were integrated to identify potential gene targets. In vitro assays looked at the function and interaction of miRNA-21 and its specific gene targets.
miRNA-21 was upregulated in HNSCC and stimulated cell growth. Integrated analyses identified Clusterin (CLU) as a potential miRNA-21 gene target. CLU was downregulated after forced expression of miRNA-21 in normal and HNSCC cell lines. The activity of a luciferase construct containing the 3’UTR of CLU was repressed by the ectopic expression of miRNA-21. CLU was also downregulated in primary HNSCC and correlated with miRNA-21 over-expression. CLU variant 1 (CLU-1) was the predominant splice variant in HNSCC, and showed growth suppression function that was reversed by miRNA-21 over-expression.
CLU is a specific, functional target of oncogenic miRNA-21 in HNSCC. CLU-1 isoform is the predominant growth suppressive variant targeted by miRNA-21.
PMCID: PMC3970211  PMID: 24327270
Clusterin; microRNA-21; gene target; tumor-suppressor gene; head and neck cancer
6.  A Case of Stereotactic Radiation in Skull Base Solitary Fibrous Tumor: More Harm Than Good? 
Objective Due to its location, total resection of a skull base solitary fibrous tumor (SFT) can lead to morbidity with injury to lower cranial nerves, and a decision must be made between subtotal resection with possible stereotactic radiotherapy or total resection with cranial nerve morbidity. We report the long-term outcomes and review the literature of a case of stereotactic radiation in SFT to provide evidence for making this decision.
Design A retrospective case review.
Setting An academic tertiary referral center.
Results We present a case with > 10 years follow-up of radiation following skull base SFT, initially misdiagnosed as schwannoma, where radiotherapy did not improve recurrence or metastatic behavior and led to complications during subsequent surgical resection.
Conclusions SFT often masquerades as schwannoma, especially in the skull base. Careful immunohistochemistry, including CD34 expression, is critical to the diagnosis and management. This case highlights that total tumor resection of SFT remains the gold standard of treatment. Stereotactic radiation is not recommended in the management of skull base SFT.
PMCID: PMC4242816  PMID: 25485216
solitary fibrous tumor; stereotactic radiation
7.  Human brain arteriovenous malformations express lymphatic-associated genes 
Brain arteriovenous malformations (AVMs) are devastating, hemorrhage-prone, cerebrovascular lesions characterized by well-defined feeding arteries, draining vein(s) and the absence of a capillary bed. The endothelial cells (ECs) that comprise AVMs exhibit a loss of arterial and venous specification. Given the role of the transcription factor COUP-TFII in vascular development, EC specification, and pathological angiogenesis, we examined human AVM tissue to determine if COUP-FTII may have a role in AVM disease biology.
We examined 40 human brain AVMs by immunohistochemistry (IHC) and qRT-PCR for the expression of COUP-TFII as well as other genes involved in venous and lymphatic development, maintenance, and signaling. We also examined proliferation and EC tube formation with human umbilical ECs (HUVEC) following COUP-TFII overexpression.
We report that AVMs expressed COUP-TFII, SOX18, PROX1, NFATC1, FOXC2, TBX1, LYVE1, Podoplanin, and vascular endothelial growth factor (VEGF)-C, contained Ki67-positive cells and heterogeneously expressed genes involved in Hedgehog, Notch, Wnt, and VEGF signaling pathways. Overexpression of COUP-TFII alone in vitro resulted in increased EC proliferation and dilated tubes in an EC tube formation assay in HUVEC.
This suggests AVM ECs are further losing their arterial/venous specificity and acquiring a partial lymphatic molecular phenotype. There was significant correlation of gene expression with presence of clinical edema and acute hemorrhage. While the precise role of these genes in the formation, stabilization, growth and risk of hemorrhage of AVMs remains unclear, these findings have potentially important implications for patient management and treatment choice, and opens new avenues for future work on AVM disease mechanisms.
PMCID: PMC4284124  PMID: 25574473
8.  The impact of resident involvement in minimally-invasive urologic oncology procedures 
Robotic and laparoscopic surgical training is an integral part of resident education in urology, yet the effect of resident involvement on outcomes of minimally-invasive urologic procedures remains largely unknown. We assess the impact of resident participation on surgical outcomes using a large multi-institutional prospective database.
Relying on the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) Participant User Files (2005–2011), we abstracted the 3 most frequently performed minimally-invasive urologic oncology procedures. These included radical prostatectomy, radical nephrectomy and partial nephrectomy. Multivariable logistic regression models were constructed to assess the impact of trainee involvement (PGY 1–2: junior, PGY 3–4: senior, PGY ≥5: chief) versus attending-only on operative time, length-of-stay, 30-day complication, reoperation and readmission rates.
A total of 5459 minimally-invasive radical prostatectomies, 1740 minimally-invasive radical nephrectomies and 786 minimally-invasive partial nephrectomies were performed during the study period, for which data on resident surgeon involvement was available. In multivariable analyses, resident involvement was not associated with increased odds of overall complications, reoperation, or readmission rates for minimally-invasive prostatectomy, radical and partial nephrectomy. However, operative time was prolonged when residents were involved irrespective of the type of procedure. Length-of-stay was decreased with senior resident involvement in minimally-invasive partial nephrectomies (odds ratio [OR] 0.49, p = 0.04) and prostatectomies (OR 0.68, p = 0.01). The major limitations of this study include its retrospective observational design, inability to adjust for the case complexity and surgeon/hospital characteristics, and the lack of information regarding the minimally-invasive approach utilized (whether robotic or laparoscopic).
Resident involvement is associated with increased operative time in minimally-invasive urologic oncology procedures. However, it does not adversely affect the complication, reoperation or readmission rates, as well as length-of-stay.
PMCID: PMC4216291  PMID: 25408800
9.  Short-term perioperative outcomes of patients treated with radical cystectomy for bladder cancer included in the National Surgical Quality Improvement Program (NSQIP) database 
Canadian Urological Association Journal  2014;8(9-10):E681-E687.
We report the contemporary outcomes of radical cystectomy (RC) in patients with bladder cancer using a national, prospective perioperative database specifically developed to assess the quality of surgical care.
The National Surgical Quality Improvement Program (NSQIP) database was queried from 2006 to 2011 for RC. Data on postoperative complications, operative time, length of stay, blood transfusions, readmission, and mortality within 30 days from surgery were abstracted.
Overall, 1094 patients undergoing RC were identified. Rates of overall complications, transfusions, prolonged length of hospitalization, readmission, and perioperative mortality were 31.1%, 34.4%, 25.9%, 20.2%, and 2.7%, respectively. Body mass index represented an independent predictor of overall complications on multivariate analysis (p = 0.04). Baseline comorbidity status was associated with increased odds of postoperative complications, prolonged operative time, transfusion, prolonged hospitalization, and perioperative mortality. In particular, patients with cardiovascular comorbidities were 2.4 times more likely to die within 30 days following cystectomy compared to their healthier counterparts (p = 0.04). Men had lower odds of prolonged operative time and blood transfusions (p ≤ 0.03). Finally, the receipt of a continent urinary diversion was the only predictor of readmission (p = 0.02). Our results are limited by their retrospective nature and by the lack of adjustment for hospital and tumour volume.
Complications, transfusions, readmission, and perioperative mortality remain relatively common events in patients undergoing RC for bladder cancer. In an era where many advocate the need for prospective multi-institutional data collection as a means of improving quality of care, our study provides data on short-term outcomes after RC from a national quality improvement initiative.
PMCID: PMC4216299  PMID: 25408807
During the past two decades, radiosurgery has arisen as a promising approach to the management of glomus jugulare. In the present study, we report on a systematic review and meta-analysis of the available published data on the radiosurgical management of glomus jugulare tumors.
Methods and Materials
To identify eligible studies, systematic searches of all glomus jugulare tumors treated with radiosurgery were conducted in major scientific publication databases. The data search yielded 19 studies, which were included in the meta-analysis. The data from 335 glomus jugulare patients were extracted. The fixed effects pooled proportions were calculated from the data when Cochrane’s statistic was statistically insignificant and the inconsistency among studies was <25%. Bias was assessed using the Egger funnel plot test.
Across all studies, 97% of patients achieved tumor control, and 95% of patients achieved clinical control. Eight studies reported a mean or median follow-up time of >36 months. In these studies, 95% of patients achieved clinical control and 96% achieved tumor control. The gamma knife, linear accelerator, and CyberKnife technologies all exhibited high rates of tumor and clinical control.
The present study reports the results of a meta-analysis for the radiosurgical management of glomus jugulare. Because of its high effectiveness, we suggest considering radiosurgery for the primary management of glomus jugulare tumors.
PMCID: PMC4086637  PMID: 21703782
Glomus jugulare; Radiosurgery; Gamma knife; Paraganglioma; Meta-analysis
11.  Co-occurrence of a cerebral cavernous malformation and an orbital cavernous hemangioma in a patient with seizures and visual symptoms: Rare crossroads for vascular malformations 
Surgical Neurology International  2014;5(Suppl 4):S148-S154.
Cerebral cavernous malformations (CCMs) are angiographically occult vascular malformations of the central nervous system. As a result of hemorrhage and mass effect, patients may present with focal neurologic deficits, seizures, and other symptoms necessitating treatment. Once symptomatic, most often from hemorrhage, CCMs are treated with microsurgical resection. Orbital cavernous hemangiomas (OCHs) are similar but distinct vascular malformations that present within the orbital cavity. Even though CCMs and OCHs are both marked by dilated endothelial-lined vascular channels, they are infrequently seen in the same patient.
Case Description:
We provide a brief overview of the two related pathologies in the context of a patient presenting to our care with concomitant lesions, which were both resected in full without complication.
This is the first known report that describes a case of concomitant CCM and OCH and explores the origins of two pathologies that are rarely encountered together in neurosurgical practice. Recognition of disparate symptomatologies is important for properly managing these patients.
PMCID: PMC4109172  PMID: 25071938
Cavernous hemangioma; cavernous malformation; orbital hemangioma; orbitotomy
12.  Rag GTPase-mediated regulation of mTORC1 by nutrients is necessary for neonatal autophagy and survival 
Nature  2012;493(7434):679-683.
The mTOR Complex 1 (mTORC1) pathway regulates organismal growth in response to many environmental cues, including nutrients and growth factors1. Cell-based studies showed that mTORC1 senses amino acids through the Rag family of GTPases 2,3, but their importance in mammalian physiology is unknown. Here, we generated knock-in mice that express a constitutively active form of RagA (RagAGTP) from its endogenous promoter. RagAGTP/GTP mice develop normally, but fail to survive postnatal day 1. When delivered by Caesarian-section, fasted RagAGTP/GTP neonates die almost twice as rapidly as wild-type littermates. Within an hour of birth, wild-type neonates strongly inhibit mTORC1, which coincides with profound hypoglycaemia and a drop in plasma amino acid levels. In contrast, mTORC1 inhibition does not occur in RagAGTP/GTP neonates, despite identical reductions in blood nutrient levels. With prolonged fasting, wild-type neonates recover their plasma glucose levels, but RagAGTP/GTP mice remain hypoglycaemic until death, despite using glycogen at a faster rate. The glucose homeostasis defect correlates with the inability of fasted RagAGTP/GTP neonates to trigger autophagy and produce amino acids for de novo glucose production. Because profound hypoglycaemia does not inhibit mTORC1 in RagAGTP/GTP neonates, we hypothesized that the Rag pathway signals glucose as well as amino acid sufficiency to mTORC1. Indeed, mTORC1 is resistant to glucose deprivation in RagAGTP/GTP fibroblasts, and glucose, like amino acids, controls its recruitment to the lysosomal surface, the site of mTORC1 activation. Thus, the Rag GTPases signal glucose and amino acid levels to mTORC1, and play an unexpectedly key role in neonates in autophagy induction and thus nutrient homeostasis and viability.
PMCID: PMC4000705  PMID: 23263183
13.  Signaling Regulated Endocytosis and Exocytosis Lead to Mating Pheromone Concentration Dependent Morphologies in Yeast 
FEBS letters  2012;586(23):4208-4214.
Polarized cell morphogenesis requires actin cytoskeleton rearrangement for polarized transport of proteins, organelles and secretory vesicles, which fundamentally underlies cell differentiation and behavior. During yeast mating, S. cerevisiae responds to extracellular pheromone gradients by extending polarized projections, which are likely maintained through vesicle transport to (exocytosis) and from (endocytosis) the membrane. We experimentally demonstrate that the projection morphology is pheromone concentration-dependent, and propose the underlying mechanism through mathematical modeling. The inclusion of membrane flux and dynamically evolving cell boundary into our yeast mating signaling model shows good agreement with experimental measurements, and provides a plausible explanation for pheromone-induced cell morphology.
PMCID: PMC3921116  PMID: 23108052
14.  Contemporary Ventilator Management in Patients With and at Risk of ALI/ARDS 
Respiratory care  2013;58(4):10.4187/respcare.01755.
Ventilator practices in patients at risk for acute lung injury (ALI) and ARDS are unclear. We examined factors associated with choice of set tidal volumes (VT), and whether VT < 8 mL/kg predicted body weight (PBW) relates to the development of ALI/ARDS.
We performed a secondary analysis of a multicenter cohort of adult subjects at risk of lung injury with and without ALI/ARDS at onset of invasive ventilation. Descriptive statistics were used to describe ventilator practices in specific settings and ALI/ARDS risk groups. Logistic regression analysis was used to determine the factors associated with the use of VT < 8 mL/kg PBW and the relationship of VT to ALI/ARDS development and outcome.
Of 829 mechanically ventilated patients, 107 met the criteria for ALI/ARDS at time of intubation, and 161 developed ALI/ARDS after intubation (post-intubation ALI/ARDS). There was significant intercenter variability in initial ventilator settings, and in the incidence of ALI/ARDS and post-intubation ALI/ARDS. The median VT was 7.96 (IQR 7.14–8.94) mL/kg PBW in ALI/ARDS subjects, and 8.45 (IQR 7.50–9.55) mL/kg PBW in subjects without ALI/ARDS (P = .004). VT decreased from 8.40 (IQR 7.38–9.37) mL/kg PBW to 7.97 (IQR 6.90–9.23) mL/kg PBW (P < .001) in those developing post-intubation ALI/ARDS. Among subjects without ALI/ARDS, VT ≥ 8 mL/kg PBW was associated with shorter height and higher body mass index, while subjects with pneumonia were less likely to get ≥ 8 mL/kg PBW. Initial VT ≥ 8 mL/kg PBW was not associated with the post-intubation ALI/ARDS (adjusted odds ratio 1.30, 95% CI 0.74–2.29) or worse outcomes. Post-intubation ALI/ARDS subjects had mortality similar to subjects intubated with ALI/ARDS.
Clinicians seem to respond to ALI/ARDS with lower initial VT. Initial VT, however, was not associated with the development of post-intubation ALI/ARDS or other outcomes.
PMCID: PMC3840036  PMID: 22906363
acute lung injury; ARDS; mechanical ventilation; mortality; tidal volume
15.  The sea lamprey has a primordial accessory olfactory system 
A dual olfactory system, represented by two anatomically distinct but spatially proximate chemosensory epithelia that project to separate areas of the forebrain, is known in several classes of tetrapods. Lungfish are the earliest evolving vertebrates known to have this dual system, comprising a main olfactory and a vomeronasal system (VNO). Lampreys, a group of jawless vertebrates, have a single nasal capsule containing two anatomically distinct epithelia, the main (MOE) and the accessory olfactory epithelia (AOE). We speculated that lamprey AOE projects to specific telencephalic regions as a precursor to the tetrapod vomeronasal system.
To test this hypothesis, we characterized the neural circuits and molecular profiles of the accessory olfactory epithelium in the sea lamprey (Petromyzon marinus). Neural tract-tracing revealed direct and reciprocal connections with the dorsomedial telencephalic neuropil (DTN) which in turn projects directly to the dorsal pallium and the rostral hypothalamus. High-throughput sequencing demonstrated that the main and the accessory olfactory epithelia have virtually identical profiles of expressed genes. Real time quantitative PCR confirmed expression of representatives of all 3 chemoreceptor gene families identified in the sea lamprey genome.
Anatomical and molecular evidence shows that the sea lamprey has a primordial accessory olfactory system that may serve a chemosensory function.
PMCID: PMC3765145  PMID: 23957559
16.  Small Cell Carcinoma ex-Pleomorphic Adenoma of the Parotid Gland 
Head and Neck Pathology  2012;6(4):502-506.
Small cell carcinoma (SCC) is a high-grade malignancy usually encountered in the lungs but also seen in almost any site including the salivary glands. SCC is important to recognize because it often metastasizes widely and is treated with systemic chemotherapy. Carcinoma ex pleomorphic adenoma is a malignant epithelial neoplasm arising in a pre-existing benign mixed tumor (i.e., pleomorphic adenoma, PA). While virtually any salivary carcinoma can arise from a PA, to our knowledge SCC ex-PA has not been described. We report a case of a woman presenting with fullness of the right neck and a parotid gland mass. The tumor was resected and evaluated grossly, by light microscopy, and by immunohistochemistry. Grossly, a 1.6 cm well-circumscribed nodule was identified within the parotid. Microscopic examination revealed foci of SCC associated with high-grade adenocarcinoma, in the background of a PA. The SCC was immunoreactive for cytokeratin in a dot-like pattern and neuroendocrine markers synaptophysin and CD56. Despite the focal nature of the SCC in the parotid, a pure SCC metastasis was present in one neck level II lymph node. The patient was free of disease with 8 months of follow-up. Our case illustrates that: (1) although rare, in the salivary glands SCC may arise from lower grade neoplasms including PAs; (2) SCC ex PA may metastasize as pure SCC even if the primary SCC component was focal; (3) adequate sampling of PAs is crucial to prevent missing a rare SCC that must be treated with chemotherapy.
PMCID: PMC3500895  PMID: 22736150
Carcinoma ex pleomorphic adenoma; Carcinoma ex mixed tumor; Malignant mixed tumor; Small cell carcinoma; Parotid gland; Salivary glands
17.  Protocols in the management of critical illness 
Critical Care  2012;16(2):306.
Care of the critically ill patient is becoming increasingly complex. Protocols, which standardize care of patients with similar diseases, represent a potential solution to managing multiple simultaneous problems in critically ill patients. In this article, we examine the advantages and disadvantages to care protocolization, and posit that careful and thoughtful implementation of protocols is likely to benefit patients. We also discuss the potential for unintended consequences, and even harm, with protocolization in critically ill patients using the Critical Illness Outcomes Study as a model to examine the effects of protocolization in large populations of intensive care patients.
PMCID: PMC3584719  PMID: 22424130
18.  Gene expression profiling of blood in brain arteriovenous malformation patients 
Translational stroke research  2011;2(4):575-587.
Brain arteriovenous malformations (BAVMs) are an important cause of intracranial hemorrhage (ICH) in young adults. Gene expression profiling of blood has led to the identification of stroke biomarkers, and may help identify BAVM biomarkers and illuminate BAVM pathogenesis. It is unknown whether blood gene expression profiles differ between 1) BAVM patients and healthy controls, or 2) unruptured and ruptured BAVM patients at presentation. We characterized blood transcriptional profiles in 60 subjects (20 unruptured BAVM, 20 ruptured BAVM, and 20 healthy controls) using Affymetrix whole genome expression arrays. Expression differences between groups were tested by ANOVA, adjusting for potential confounders. Genes with absolute fold change ≥ 1.2 (false discovery rate corrected p ≤ 0.1) were selected as differentially expressed and evaluated for over-representation in KEGG biological pathways (p ≤ 0.05). Twenty-nine genes were differentially expressed between unruptured BAVM patients and controls, including 13 which may be predictive of BAVM. Patients with ruptured BAVM compared to unruptured BAVM differed in expression of 1490 genes, with over-representation of genes in 8 pathways including MAPK, VEGF, Wnt signaling and several inflammatory pathways. These results suggest clues to the pathogenesis of BAVM and/or BAVM rupture and point to potential biomarkers or new treatment targets.
PMCID: PMC3241209  PMID: 22184505
arteriovenous malformation; blood; gene expression; intracranial hemorrhage; microarray analysis
19.  Spontaneous intracranial hypotension secondary to anterior thoracic osteophyte: Resolution after primary dural repair via posterior approach 
Spontaneous intracranial hypotension (SIH) is an uncommon syndrome widely attributed to CSF hypovolemia, typically secondary to spontaneous CSF leak. Although commonly associated with postural headache and variable neurological symptoms, one of the most severe consequences of SIH is bilateral subdural hematomas with resultant neurological deterioration.
We present the case of a patient diagnosed with SIH secondary to an anteriorly positioned thoracic osteophyte with resultant dural disruption, who after multiple attempts at nonsurgical management developed bilateral subdural hematomas necessitating emergent surgical intervention. The patient underwent a unilateral posterior repair of his osteophyte with successful anterior decompression. At 36 months follow up, the patient reported completely resolved headaches with no focal neurological deficits.
We outline our posterior approach to repair of the dural defect and review the management algorithm for the treatment of patients with SIH. We also examine the current hypotheses as to the origin, pathophysiology, diagnosis and treatment of this syndrome.
A posterior approach was utilized to repair the dural defect caused by an anterior thoracic osteophyte in a patient with severe SIH complicated by bilateral subdural hematomas. This approach minimizes morbidity compared to an anterior approach and allowed for removal of the osteophyte and repair of the dural defect.
PMCID: PMC3537944  PMID: 23108168
Spontaneous intracranial hypotension; CSF leak; Thoracic osteophyte; Posterior repair
20.  Detection of Promoter Hypermethylation in Salivary Rinses as a Biomarker for Head and Neck Squamous Cell Carcinoma Surveillance 
Hypermethylation of tumor suppressor gene promoters has been found in head and neck squamous carcinoma (HNSCC) and other solid tumors. We evaluated these alterations in pretreatment salivary rinses from HNSCC patients by using real-time quantitative methylation-specific PCR (Q-MSP).
Experimental Design
Pretreatment saliva DNA samples from HNSCC patients were evaluated for patterns of hypermethylation by using Q-MSP. Target tumor suppressor gene promoter regions were selected based on a previous study describing a screening panel for HNSCC in a high-risk population subjects. The selected genes were: DAPK, DCC, MINT-31, TIMP-3, p16, MGMT, CCNA1.
We analyzed the panel in a cohort of 61 HNSCC patients. Thirty-three of the analyzed patients (54.1%) showed methylation of at least one of the selected genes in the saliva DNA. Pretreatment methylated saliva DNA was not significantly associated with tumor site (P = 0.209) nor clinical stage (P = 0.299). However, local disease control and overall survival were significantly lower in patients presenting hypermethylation in saliva rinses (P = 0.010 and P = 0.015, respectively). Multivariate analysis confirmed that this hypermethylation pattern remained as an independent prognostic factor for local recurrence (HR = 12.2; 95% CI = 1.8–80.6; P = 0.010) and overall survival (HR = 2.8; 95% CI = 1.2–6.5; P = 0.016).
We were able to confirm an elevated rate of promoter hypermethylation in HNSCC saliva of patients by using a panel of gene promoters previously described as methylated specifically in HNSCC. Detection of hypermethylation in pretreatment saliva DNA seems to be predictive of local recurrence and overall survival. This finding has potential to influence treatment and surveillance of HNSCC patients.
PMCID: PMC3215270  PMID: 21628494
21.  Intramedullary spinal cord metastasis from prostate carcinoma: a case report 
Although vertebral and epidural metastases are common, intradural metastases and intramedullary spinal cord metastases are rare. The indications for the treatment of intramedullary spinal cord metastases remain controversial. We present the first biopsy-proven case of an intramedullary spinal cord metastasis from adenocarcinoma of the prostate.
Case presentation
Our patient was a 68-year-old right-handed Caucasian man with a Gleason grade 4 + 3 prostate adenocarcinoma who had previously undergone a prostatectomy, androgen blockade and transurethral debulking. He presented with new-onset saddle anesthesia and fecal incontinence. Magnetic resonance imaging demonstrated a spindle-shaped intramedullary lesion of the conus medullaris. Our patient underwent decompression and an excisional biopsy; the lesion’s pathology was consistent with metastatic adenocarcinoma of the prostate. Postoperatively, our patient received CyberKnife® radiosurgery to the resection cavity at a marginal dose of 27Gy to the 85% isodose line. At three months follow-up, our patient remains neurologically stable with no new deficits or lesions.
We review the literature and discuss the indications for surgery and radiosurgery for intramedullary spinal cord metastases. We also report the novel use of stereotactic radiosurgery to sterilize the resection cavity following an excisional biopsy of the metastasis.
PMCID: PMC3419088  PMID: 22657386
22.  Carcinoma ex Pleomorphic Adenoma of the Nasal Cavity 
Head and Neck Pathology  2011;5(4):405-409.
Carcinoma ex pleomorphic adenoma (CXPA) is a malignant epithelial neoplasm arising in a benign mixed tumor (i.e., pleomorphic adenoma or PA); it accounts for approximately 3–4% of all salivary gland neoplasms. CXPA is exceedingly rare in the nasal cavity, with only three cases previously documented.
We report two cases of women presenting with masses of the nasal cavity. The tumors were resected and evaluated grossly and by routine microscopy.
Both patients presented with nasal obstruction, and one patient reported epistaxis. Grossly, the tumors were 2.5 and 3 cm in greatest dimension, respectively. In each case, microscopic examination of the tumor revealed an infiltrating carcinoma arising in association with foci of benign PA. The carcinoma types were adenoid cystic carcinoma and high grade adenocarcinoma, not otherwise specified. Both cases were widely (i.e., >1.5 mm) invasive beyond the preexisting PA. The findings were diagnostic of CXPA.
Carcinomatous transformation of a PA in the nasal cavity is extremely rare, but does occur. Accordingly, PAs of this site should be thoroughly sampled and closely examined to exclude the possibility of malignant transformation.
PMCID: PMC3210223  PMID: 21505850
Carcinoma ex pleomorphic adenoma; Carcinoma ex mixed tumor; Malignant mixed tumor; Nasal cavity; Nasal septum
23.  Potential application of hydrogen in traumatic and surgical brain injury, stroke and neonatal hypoxia-ischemia 
Medical Gas Research  2012;2:11.
This article summarized findings of current preclinical studies that implemented hydrogen administration, either in the gas or liquid form, as treatment application for neurological disorders including traumatic brain injury (TBI), surgically induced brain injury (SBI), stroke, and neonatal hypoxic-ischemic brain insult (HI). Most reviewed studies demonstrated neuroprotective effects of hydrogen administration. Even though anti-oxidative potentials have been reported in several studies, further neuroprotective mechanisms of hydrogen therapy remain to be elucidated. Hydrogen may serve as an adjunct treatment for neurological disorders.
PMCID: PMC3353846  PMID: 22515516
Hydrogen; Neuroprotection; Oxidative stress; Reactive oxygen species
24.  The Role of MAGEA2 in Head and Neck Cancer 
To examine the role of MAGEA2 in the tumorigenesis of head and neck squamous cell carcinoma (HNSCC).
Primary tissue microarray data and quantitative reverse transcription–polymerase chain reaction (RT-PCR) showed that MAGEA2 is differentially over-expressed in HNSCC. Functional analyses were then performed using MAGEA2 transfections and small-interfering RNA knockdowns with subsequent anchorage-dependent growth studies and cell cycle analyses. Quantitative RT-PCR was used to evaluate expression changes in p53 downstream targets after transfection of MAGEA2 into normal upper aerodigestive cell lines.
MAGEA2 is differentially overexpressed in HNSCC. In addition, MAGEA2 promotes growth in normal oral keratinocytes, whereas knockdown of MAGEA2 in HNSCC cells decreases growth. Using the HCT116 p53 wt and null cell line system, transfection of MAGEA2 induced growth in the p53 wt cell line while providing no growth advantage in the p53 mutant cells. Subsequently, transfection of MAGEA2 induced a decrease in messenger RNA expression of the p53 downstream targets CDKN1A and BAX and decreased G1 arrest in cells allowed to remain confluent for longer than 48 hours.
These data suggest that MAGEA2 is differentially expressed in HNSCC and functions, in part, through the p53 pathway by increasing cellular proliferation and abrogating cell cycle arrest. This improved understanding of MAGEA2 function and expression patterns will potentially allow for the improved ability to use MAGEA2 for detection, surveillance, and targeted therapeutics.
PMCID: PMC3309612  PMID: 21422315
25.  Early Identification of Patients at Risk of Acute Lung Injury 
Rationale: Accurate, early identification of patients at risk for developing acute lung injury (ALI) provides the opportunity to test and implement secondary prevention strategies.
Objectives: To determine the frequency and outcome of ALI development in patients at risk and validate a lung injury prediction score (LIPS).
Methods: In this prospective multicenter observational cohort study, predisposing conditions and risk modifiers predictive of ALI development were identified from routine clinical data available during initial evaluation. The discrimination of the model was assessed with area under receiver operating curve (AUC). The risk of death from ALI was determined after adjustment for severity of illness and predisposing conditions.
Measurements and Main Results: Twenty-two hospitals enrolled 5,584 patients at risk. ALI developed a median of 2 (interquartile range 1–4) days after initial evaluation in 377 (6.8%; 148 ALI-only, 229 adult respiratory distress syndrome) patients. The frequency of ALI varied according to predisposing conditions (from 3% in pancreatitis to 26% after smoke inhalation). LIPS discriminated patients who developed ALI from those who did not with an AUC of 0.80 (95% confidence interval, 0.78–0.82). When adjusted for severity of illness and predisposing conditions, development of ALI increased the risk of in-hospital death (odds ratio, 4.1; 95% confidence interval, 2.9–5.7).
Conclusions: ALI occurrence varies according to predisposing conditions and carries an independently poor prognosis. Using routinely available clinical data, LIPS identifies patients at high risk for ALI early in the course of their illness. This model will alert clinicians about the risk of ALI and facilitate testing and implementation of ALI prevention strategies.
Clinical trial registered with (NCT00889772).
PMCID: PMC3056224  PMID: 20802164
respiratory distress syndrome, adult; prevention; prediction model; acute respiratory failure

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