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1.  Reduced vesicular storage of catecholamines causes progressive degeneration in the locus ceruleus 
Neuropharmacology  2013;76(0 0):97-105.
Parkinson’s disease (PD) is the most common neurodegenerative motor disease. Pathologically, PD is characterized by Lewy body deposition and subsequent death of dopamine neurons in the substantia nigra pars compacta. PD also consistently features degeneration of the locus ceruleus, the main source of norepinephrine in the central nervous system. We have previously reported a mouse model of dopaminergic neurodegeneration based on reduced expression of the vesicular monoamine transporter (VMAT2 LO). To determine if reduced vesicular storage can also cause noradrenergic degeneration, we examined indices of damage to the catecholaminergic systems in brain and cardiac tissue of VMAT2 LO mice. At two months of age, neurochemical analyses revealed substantial reductions in striatal dopamine (94%), cortical dopamine (57%) and norepinephrine (54%), as well as cardiac norepinephrine (97%). These losses were accompanied by increased conversion of dopamine and norepinephrine to their deaminated metabolites. VMAT2 LO mice exhibited loss of noradrenergic innervation in the cortex, as determined by norepinephrine transporter immunoreactivity and 3H-nisoxetine binding. Using unbiased stereological techniques, we observed progressive degeneration in the locus ceruleus that preceded degeneration of the substantia nigra pars compacta. In contrast, the ventral tegmental area, which is spared in human PD, remained unaffected. The coordinate loss of dopamine and norepinephrine neurons in VMAT2-LO mice parallels the pattern of neurodegeneration that occurs in human PD, and demonstrates that insufficient catecholamine storage can cause spontaneous degeneration in susceptible neurons, underscoring cytosolic catecholamine catabolism as a determinant of neuronal susceptibility in PD.
doi:10.1016/j.neuropharm.2013.08.033
PMCID: PMC4049095  PMID: 24025942
VMAT2; norepinephrine; Parkinson’s disease; locus ceruleus
2.  The Potential of panHER Inhibition in Cancer 
Purpose: Hyper-activation of the HER (erbB) family receptors, HER 1-4, leads to up-regulation of the three vital signaling pathways: mitogen activated protein kinase, phosphoinositide 3-kinase/AKT, and Janus kinase/signal transducer and activator of transcription pathways. Blocking HER1/EGFR has a limited anticancer effect due to either secondary mutation e.g., T790M or by-pass signaling of other HER members. The emergence of an anti-panHER approach to blockade of these pathways as a cancer treatment may provide a solution to this resistance. This review aimed to provide an overview of the HER signaling pathways and their involvement in tumor progression and examine the current progress in panHER inhibition.
Methods: Recent literature associated with HER signaling pathways and panHER inhibition was reviewed through PubMed and Medline database, followed by critical comparison and analysis.
Results: Pre-clinical studies and clinical trials of panHER inhibitors show promising results, and the potential to improve patient outcomes in solid cancers.
Conclusion: The use of panHER inhibitors in cancers with HER-family hyper-activation, such as other epithelial cancers and sarcoma, is a new direction to research and has potential in clinical cancer therapy in the future.
doi:10.3389/fonc.2015.00002
PMCID: PMC4309158
targeted therapy; panHER inhibitors; drug resistance; HER signaling pathways; EGFR
3.  Overview of major salivary gland cancer surgery in Ontario (2003–2010) 
Background
The primary objective of this study is to describe variations in incidence rates, resection rates, and types of surgical ablations performed on patients diagnosed with major salivary gland cancers in Ontario.
Methods
All major salivary gland cancer cases in Ontario (2003–2010) were identified from the Ontario Cancer Registry (n = 1,241). Variations in incidence rates, resection rates, and type of surgical therapy were compared by sex, age group, neighbourhood income, community population, health region, and physician specialty.
Results
Eight-year incidence rates per 100,000 vary significantly by sex (male: 15.5, female: 9.7), age (18–54 years: 6.7, 75+ years: 53.4), neighborhood income (lowest quintile: 11.8, highest quintile: 13.7), and community size (cities with a population greater than 1.5 million: 10.6, cities with a population of less than 100,000: 14.7). There was a significant correlation between the likelihood to receive a resection and age with the elderly (75+ years) being the least likely to receive resection (69%). Large differences in incidence and resection rates were observed by health region. Otolaryngology-Head & Neck surgeons provide the majority of total/radical resections (95%).
Conclusions
Major salivary gland cancer incidence rates vary by sex, age, neighborhood income, community size, and health region. Resection rates vary by age and health region. These disparities warrant further evaluation. Otolaryngology-Head & Neck Surgeons provide the majority of major salivary gland cancer surgical care.
doi:10.1186/s40463-014-0050-6
PMCID: PMC4269848  PMID: 25492404
Health services research; Health policy; Salivary gland cancer; Head and neck oncology
4.  Patient-Centered Medical Home Intervention at an Internal Medicine Resident Safety-Net Clinic 
JAMA internal medicine  2013;173(18):1694-1701.
IMPORTANCE
The patient-centered medical home (PCMH) model holds promise for improving primary care delivery, but it has not been adequately tested in teaching settings.
DESIGN, SETTING, AND PARTICIPANTS
We implemented an intervention guided by PCMH principles at a safety-net teaching clinic with resident physician providers. Two similar clinics served as controls.
MAIN OUTCOMES AND MEASURES
Using a cross-sectional design, we measured the effect on patient and resident satisfaction using the Consumer Assessment of Healthcare Providers and Systems survey and a validated teaching clinic survey, respectively. Both surveys were conducted at baseline and 1 year after the intervention. We also measured the effect on emergency department and hospital utilization.
RESULTS
Following implementation of our intervention, the clinic’s score on the National Committee for Quality Assurance’s PCMH certification tool improved from 35 to 53 of 100 possible points, although our clinic did not achieve all must-pass elements to qualify as a PCMH. During the 1-year study period, 4676 patients were exposed to the intervention; 39.9% of these used at least 1 program component. Compared with baseline, patient-reported access and overall satisfaction improved to a greater extent in the intervention clinic, and the composite satisfaction rating increased from 48% to 65% in the intervention clinic vs from 50% to 59% in the control sites (P = .04). The improvements were particularly notable for questions relating to access. For example, satisfaction with urgent appointment scheduling increased from 12% to 53% in the intervention clinic vs from 14% to 18% in the control clinics (P < .001). Resident satisfaction also improved in the intervention clinic: the composite satisfaction score increased from 39% to 51% in the intervention clinic vs a decrease from 46%to 42% in the control clinics (P = .01). Emergency department utilization did not differ significantly between the intervention and control clinics, and hospitalizations increased from 26 to 27 visits per 1000 patients per month in the intervention clinic vs a decrease from 28 to 25 in the control clinics (P = .02).
CONCLUSIONS AND RELEVANCE
Our PCMH-guided intervention, which represented a modest but substantive step toward the PCMH vision, had favorable effects on patient and resident satisfaction at a safety-net teaching clinic but did not reduce emergency department or hospital utilization in the first year. Our experience may provide lessons for other teaching clinics in safety-net settings hoping to implement PCMH-guided reforms.
doi:10.1001/jamainternmed.2013.9241
PMCID: PMC4254756  PMID: 24006034
5.  Mutations in NGLY1 Cause an Inherited Disorder of the Endoplasmic Reticulum-Associated Degradation (ERAD) Pathway 
Purpose
The endoplasmic reticulum-associated degradation (ERAD) pathway is responsible for the translocation of misfolded proteins across the ER membrane into the cytosol for subsequent degradation by the proteasome. In order to understand the spectrum of clinical and molecular findings in a complex neurological syndrome, we studied a series of eight patients with inherited deficiency of N-glycanase 1 (NGLY1), a novel disorder of cytosolic ERAD dysfunction.
Methods
Whole-genome, whole-exome or standard Sanger sequencing techniques were employed. Retrospective chart reviews were performed in order to obtain clinical data.
Results
All patients had global developmental delay, a movement disorder, and hypotonia. Other common findings included hypo- or alacrima (7/8), elevated liver transaminases (6/7), microcephaly (6/8), diminished reflexes (6/8), hepatocyte cytoplasmic storage material or vacuolization (5/6), and seizures (4/8). The nonsense mutation c.1201A>T (p.R401X) was the most common deleterious allele.
Conclusions
NGLY1 deficiency is a novel autosomal recessive disorder of the ERAD pathway associated with neurological dysfunction, abnormal tear production, and liver disease. The majority of patients detected to date carry a specific nonsense mutation that appears to be associated with severe disease. The phenotypic spectrum is likely to enlarge as cases with a more broad range of mutations are detected.
doi:10.1038/gim.2014.22
PMCID: PMC4243708  PMID: 24651605
NGLY1; alacrima; choreoathetosis; seizures; liver disease
6.  Deficiency of asparagine synthetase causes congenital microcephaly and a progressive form of encephalopathy 
Neuron  2013;80(2):10.1016/j.neuron.2013.08.013.
SUMMARY
We analyzed four families that presented with a similar condition characterized by congenital microcephaly, intellectual disability, progressive cerebral atrophy and intractable seizures. We show that recessive mutations in the ASNS gene are responsible for this syndrome. Two of the identified missense mutations dramatically reduce ASNS protein abundance, suggesting that the mutations cause loss of function. Hypomorphic Asns mutant mice have structural brain abnormalities, including enlarged ventricles and reduced cortical thickness, and show deficits in learning and memory mimicking aspects of the patient phenotype. ASNS encodes asparagine synthetase, which catalyzes the synthesis of asparagine from glutamine and aspartate. The neurological impairment resulting from ASNS deficiency may be explained by asparagine depletion in the brain, or by accumulation of aspartate/glutamate leading to enhanced excitability and neuronal damage. Our study thus indicates that asparagine synthesis is essential for the development and function of the brain but not for that of other organs.
doi:10.1016/j.neuron.2013.08.013
PMCID: PMC3820368  PMID: 24139043
7.  Neurogenic Orthostatic Hypotension A Pathophysiological Approach 
Circulation  2009;119(1):139-146.
doi:10.1161/CIRCULATIONAHA.108.805887
PMCID: PMC4182314  PMID: 19124673
hypotension; nervous system; sympathetic; norepinephrine; orthostatic hypotension; tomography
8.  Neuroscience and heart-brain medicine: The year in review 
Cleveland Clinic journal of medicine  2010;77(0 3):S34-S39.
Important recent publications in the area of neuroscience and heart-brain medicine center largely around three topics: (1) mechanisms of cardiac sympathetic denervation in Parkinson disease, (2) cytoplasmic monoamine metabolites as autotoxins, and (3) the validity of power spectral analysis of heart rate variability to indicate cardiac sympathetic tone. Findings by Orimo et al support a centripetal, retrograde pathogenetic process involving alpha-synuclein deposition and degeneration of cardiac noradrenergic neurons in Parkinson disease. Several studies suggest that processes increasing cytoplasmic monoamines lead to neuronal loss from auto-oxidation or enzymatic oxidation. Lack of correlation between commonly used indices from power spectral analysis of heart rate variability and cardiac norepinephrine spillover casts doubt on the validity of power spectral analysis to indicate cardiac sympathetic tone.
doi:10.3949/ccjm.77.s3.06
PMCID: PMC4164387  PMID: 20622073
9.  Hypertension Increases Cerebral 6-18F-Fluorodopa–Derived Radioactivity 
6-18F-fluorodopa PET depicts the striatal dopaminergic lesion characterizing Parkinson disease (PD); however, striatal uptake of 6-18F-fluorodopa–derived radioactivity can be normal. Supine hypertension (SH) might increase 6-18F-fluorodopa uptake.
Methods
We measured putamen, caudate, and occipital cortex 6-18F-fluorodopa–derived radioactivity and supine blood pressure in patients with PD + SH (systolic pressure ≥ 180 mm Hg, n = 8), patients with PD without SH (PD − SH, n = 19), patients with pure autonomic failure (n = 8), and controls (n = 16).
Results
Peak putamen radioactivity correlated with supine systolic pressure across all subjects and among PD patients and was higher in PD + SH than in PD − SH (P = 0.01). Both subgroups had rapid fractional declines in radioactivity between the peak and late values (P < 0.0001, compared with controls). Arterial 6-18F-fluorodopa concentrations were similar in the compared groups.
Conclusion
In PD, SH is associated with augmented striatal 6-18F-fluorodopa–derived radioactivity. Regardless of SH, retention of 6-18F-fluorodopa–derived radioactivity is markedly reduced. A model-independent approach can identify striatal dopaminergic denervation in PD.
doi:10.2967/jnumed.109.062869
PMCID: PMC4164388  PMID: 19690020
fluorodopa; Parkinson; pure autonomic failure; orthostatic hypotension; supine hypertension
10.  Olfactory dysfunction in pure autonomic failure: Implications for the pathogenesis of Lewy body diseases☆ 
Parkinsonism & related disorders  2009;15(7):516-520.
Background
Pure autonomic failure (PAF) and Parkinson disease (PD) both are Lewy body diseases, and both entail substantia nigra dopaminergic, locus ceruleus noradrenergic, and cardiac sympathetic denervation. Multiple system atrophy (MSA) is a non-Lewy body disease in which alpha-synuclein accumulates in glial cells, with central catecholamine deficiency but preserved cardiac sympathetic innervation in most patients. PD is associated with more severe and consistent olfactory dysfunction than in MSA; whether PAF entails olfactory dysfunction has been unknown. In this study we assessed olfactory function in PAF in comparison with the two other synucleinopathies and whether olfactory dysfunction correlates with neuroimaging evidence of cardiac noradrenergic or nigrostriatal dopaminergic denervation.
Method
The University of Pennsylvania Smell Identification Test (UPSIT) was administered to 8 patients with PAF, 23 with PD, and 20 with MSA. 6-[18F]Fluorodopamine positron emission tomographic (PET) scanning was used to indicate cardiac noradrenergic innervation and the putamen:occipital cortex (PUT:OCC) and substantia nigra (SN):OCC ratios of 6-[18F]fluorodopa-derived radioactivity to indicate nigrostriatal dopaminergic innervation.
Results
The PAF group had a low mean UPSIT score (22 ± 3), similar to that in PD (20 ± 2) and lower than in MSA (31 ± 2, p = 0.004). Individual UPSIT scores correlated positively with cardiac 6-[18F]fluorodopamine-derived radioactivity (r = 0.63 in the septum, p < 0.0001; r = 0.64 in the free wall, p < 0.0001) but not with PUT:OCC or SN:OCC ratios of 6-[18F]fluorodopa-derived radioactivity.
Discussion
In synucleinopathies, olfactory dysfunction is related to Lewy body pathology and cardiac sympathetic denervation, independently of parkinsonism or striatal dopamine deficiency.
doi:10.1016/j.parkreldis.2008.12.009
PMCID: PMC4164391  PMID: 19201246
Olfaction; Parkinson; Multiple system atrophy; Fluorodopa; Fluorodopamine; PET; Biomarker
11.  Clinical laboratory evaluation of autoimmune autonomic ganglionopathy: Preliminary observations 
Several forms of chronic autonomic failure manifest as neurogenic orthostatic hypotension, including autoimmune autonomic ganglionopathy (AAG) and pure autonomic failure (PAF). AAG and PAF are thought to differ in pathogenesis, AAG reflecting decreased ganglionic neurotransmission due to circulating antibodies to the neuronal nicotinic receptor and PAF being a Lewy body disease with prominent loss of sympathetic noradrenergic nerves. AAG therefore would be expected to differ from PAF in terms of clinical laboratory findings indicating postganglionic noradrenergic denervation. Both diseases are rare. Here we report preliminary observations about clinical physiologic, neuropharmacologic, neurochemical, and neuroimaging data that seem to fit with the hypothesized pathogenetic difference between AAG and PAF. Patients with either condition have evidence of baroreflex–sympathoneural and baroreflex–cardiovagal failure. Both disorders feature low plasma levels of catecholamines during supine rest, but plasma levels of the other endogenous catechols, dihydroxyphenylalanine (DOPA), dihydroxyphenylacetic acid (DOPAC), and dihydroxyphenylglycol (DHPG), seem to be lower in PAF than in AAG, probably reflecting decreased norepinephrine synthesis and turnover in PAF, due to diffuse sympathetic noradrenergic denervation. PAF entails cardiac sympathetic denervation, whereas cardiac sympathetic neuroimaging by thoracic 6-[18F]fluorodopamine scanning indicates intact myocardial sympathetic innervation in AAG.
doi:10.1016/j.autneu.2008.12.004
PMCID: PMC4164394  PMID: 19155193
Autonomic failure; Dysautonomia; Sympathetic nervous system; Norepinephrine; Fluorodopamine
12.  Temporary elimination of orthostatic hypotension by norepinephrine infusion 
A cardinal manifestation of chronic autonomic failure is neurogenic orthostatic hypotension (OH), which often is associated with supine hypertension, posing a therapeutic dilemma. We report here success in a first step toward development of a “prosthetic baroreceptor system” to maintain blood pressure during orthostasis without worsening supine hypertension. In all of four patients with neurogenic OH, titrated i.v. NE infusion kept directly recorded intra-arterial pressure at or above baseline during progressive head-up tilt. We conclude that titrated i.v. NE infusion temporarily eliminates OH.
doi:10.1007/s10286-012-0176-4
PMCID: PMC4118053  PMID: 22983778
Norepinephrine; Orthostatic hypotension; Sympathetic nervous system; Baroreflex
13.  Sequencing studies in human genetics: design and interpretation 
Nature reviews. Genetics  2013;14(7):460-470.
Next-gene ration sequencing is becoming the primary discovery tool in human genetics. There have been many clear successes in identifying genes that are responsible for Mendelian diseases, and sequencing approaches are now poised to identify the mutations that cause undiagnosed childhood genetic diseases and those that predispose individuals to more common complex diseases. There are, however, growing concerns that the complexity and magnitude of complete sequence data could lead to an explosion of weakly justified claims of association between genetic variants and disease. Here, we provide an overview of the basic workflow in next-generation sequencing studies and emphasize, where possible, measures and considerations that facilitate accurate inferences from human sequencing studies.
doi:10.1038/nrg3455
PMCID: PMC4117319  PMID: 23752795
14.  Circadian Rhythms in Executive Function during the Transition to Adolescence: The Effect of Synchrony between Chronotype and Time of Day 
Developmental science  2012;15(3):408-416.
To explore the influence of circadian rhythms on executive function during early adolescence, we administered a battery of executive function measures (including a Go-Nogo Task, the Iowa Gambling Task, a Self-ordered Pointing Task, and an Intra/Extradimensional Shift Task) to Morning-preference and Evening-preference participants (N = 80) between the ages of 11 and 14 years who were tested in the morning or afternoon. Significant Chronotype × Time of Day interactions (controlling for amount of sleep the previous night) revealed that adolescents tested at their optimal times of day performed better than those tested at their nonoptimal times. Implications for our understanding of physiological arousal, sleep, and executive function during adolescence are discussed.
doi:10.1111/j.1467-7687.2012.01137.x
PMCID: PMC4103784  PMID: 22490180
executive function; circadian rhythms; arousal; chronotype; synchrony
15.  Determinants of buildup of the toxic dopamine metabolite DOPAL in Parkinson’s disease 
Journal of neurochemistry  2013;126(5):591-603.
Intra-neuronal metabolism of dopamine (DA) begins with production of 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is toxic. According to the ‘catecholaldehyde hypothesis,’ DOPAL destroys nigrostriatal DA terminals and contributes to the profound putamen DA deficiency that characterizes Parkinson’s disease (PD). We tested the feasibility of using post-mortem patterns of putamen tissue catechols to examine contributions of altered activities of the type 2 vesicular monoamine transporter (VMAT2) and aldehyde dehydrogenase (ALDH) to the increased DOPAL levels found in PD. Theoretically, the DA : DOPA concentration ratio indicates vesicular uptake, and the 3,4-dihydroxyphenylacetic acid : DOPAL ratio indicates ALDH activity. We validated these indices in transgenic mice with very low vesicular uptake (VMAT2-Lo) or with knockouts of the genes encoding ALDH1A1 and ALDH2 (ALDH1A1,2 KO), applied these indices in PD putamen, and estimated the percent decreases in vesicular uptake and ALDH activity in PD. VMAT2-Lo mice had markedly decreased DA:DOPA (50 vs. 1377, p < 0.0001), and ALDH1A1,2 KO mice had decreased 3,4-dihydroxyphenylacetic acid:DOPAL (1.0 vs. 11.2, p < 0.0001). In PD putamen, vesicular uptake was estimated to be decreased by 89% and ALDH activity by 70%. Elevated DOPAL levels in PD putamen reflect a combination of decreased vesicular uptake of cytosolic DA and decreased DOPAL detoxification by ALDH.
doi:10.1111/jnc.12345
PMCID: PMC4096629  PMID: 23786406
DOPAC; DOPAL; dopamine; DOPET; monoamine oxidase; Parkinson’s disease
16.  Complete Longitudinal Analyses of the Randomized, Placebo-controlled, Phase III Trial of Sunitinib in Patients with Gastrointestinal Stromal Tumor Following Imatinib Failure 
Purpose
To analyze final long-term survival and clinical outcomes from the randomized phase III study of sunitinib in gastrointestinal stromal tumor (GIST) patients after imatinib failure; to assess correlative angiogenesis biomarkers with patient outcomes.
Experimental Design
Blinded sunitinib or placebo was given daily on a 4-week-on/2-week-off treatment schedule. Placebo-assigned patients could cross over to sunitinib at disease progression/study unblinding. Overall survival (OS) was analyzed using conventional statistical methods and the rank-preserving structural failure time (RPSFT) method to explore crossover impact. Circulating levels of angiogenesis biomarkers were analyzed.
Results
In total, 243 patients were randomized to receive sunitinib and 118 to placebo, 103 of whom crossed over to open-label sunitinib. Conventional statistical analysis showed that OS converged in the sunitinib and placebo arms (median 72.7 versus 64.9 weeks; hazard ratio [HR], 0.876; P = 0.306) as expected, given the crossover design. RPSFT analysis estimated median OS for placebo of 39.0 weeks (HR, 0.505, 95% CI, 0.262–1.134; P = 0.306). No new safety concerns emerged with extended sunitinib treatment. No consistent associations were found between the pharmacodynamics of angiogenesis-related plasma proteins during sunitinib treatment and clinical outcome.
Conclusions
The crossover design provided evidence of sunitinib clinical benefit based on prolonged time to tumor progression during the double-blind phase of this trial. As expected, following crossover there was no statistical difference in OS. RPSFT analysis modeled the absence of crossover, estimating a substantial sunitinib OS benefit relative to placebo. Long-term sunitinib treatment was tolerated without new adverse events.
doi:10.1158/1078-0432.CCR-11-3005
PMCID: PMC4030710  PMID: 22661587
Phase III; GIST; sunitinib; antiangiogenic; tyrosine kinase inhibitor
17.  A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A 
Human Molecular Genetics  2013;22(9):1903-1910.
Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study (GWAS) in hemophilia patients highly exposed to potentially contaminated factor VIII infusions.
Individuals with hemophilia A and a documented history of factor VIII infusions before the introduction of viral inactivation procedures (1979–1984) were recruited from 36 hemophilia treatment centers (HTCs), and their genome-wide genetic variants were compared with those from matched HIV-infected individuals. Homozygous carriers of known CCR5 resistance mutations were excluded. Single nucleotide polymorphisms (SNPs) and inferred copy number variants (CNVs) were tested using logistic regression. In addition, we performed a pathway enrichment analysis, a heritability analysis, and a search for epistatic interactions with CCR5 Δ32 heterozygosity.
A total of 560 HIV-uninfected cases were recruited: 36 (6.4%) were homozygous for CCR5 Δ32 or m303. After quality control and SNP imputation, we tested 1 081 435 SNPs and 3686 CNVs for association with HIV-1 serostatus in 431 cases and 765 HIV-infected controls. No SNP or CNV reached genome-wide significance. The additional analyses did not reveal any strong genetic effect.
Highly exposed, yet uninfected hemophiliacs form an ideal study group to investigate host resistance factors. Using a genome-wide approach, we did not detect any significant associations between SNPs and HIV-1 susceptibility, indicating that common genetic variants of major effect are unlikely to explain the observed resistance phenotype in this population.
doi:10.1093/hmg/ddt033
PMCID: PMC3613165  PMID: 23372042
18.  Role of pancreatic stellate cells in chemoresistance in pancreatic cancer 
Pancreatic cancer is highly chemoresistant. A major contributing factor is the characteristic extensive stromal or fibrotic reaction, which comprises up to 90% of the tumor volume. Over the last decade there has been intensive research into the role of the pro-fibrogenic pancreatic stellate cells (PSCs) and their interaction with pancreatic cancer cells. As a result of the significant alterations in the tumor microenvironment following activation of PSCs, tumor progression, and chemoresistance is enhanced. This review will discuss how PSCs contribute to chemoresistance in pancreatic cancer.
doi:10.3389/fphys.2014.00141
PMCID: PMC3988387  PMID: 24782785
pancreatic cancer; chemoresistance; pancreatic stellate cells; stroma; fibrosis; hypoxia
19.  Two BRM promoter insertion polymorphisms increase the risk of early-stage upper aerodigestive tract cancers 
Cancer Medicine  2014;3(2):426-433.
Brahma (BRM) has a key function in chromatin remodeling. Two germline BRM promoter insertion–deletion polymorphisms, BRM-741 and BRM-1321, have been previously associated with an increased risk of lung cancer in smokers and head and neck cancer. To further evaluate their role in cancer susceptibility particularly in early disease, we conducted a preplanned case–control study to investigate the association between the BRM promoter variants and stage I/II upper aerodigestive tract (UADT) cancers (i.e., lung, esophageal, head and neck), a group of early-stage malignancies in which molecular and genetic etiologic factors are poorly understood. The effects of various clinical factors on this association were also studied. We analyzed 562 cases of early-stage UADT cancers and 993 matched healthy controls. The double homozygous BRM promoter variants were associated with a significantly increased risk of early stage UADT cancers (adjusted odds ratio [aOR], 2.46; 95% confidence interval [CI], 1.7–3.8). This association was observed in lung (aOR, 2.61; 95% CI, 1.5–4.9) and head and neck (aOR, 2.75; 95% CI, 1.4–5.6) cancers, but not significantly in esophageal cancer (aOR, 1.66; 95% CI, 0.7–5.8). There was a nonsignificant trend for increased risk in the heterozygotes or single homozygotes. The relationship between the BRM polymorphisms and early-stage UADT cancers was independent of age, sex, smoking status, histology, and clinical stage. These findings suggest that the BRM promoter double insertion homozygotes may be associated with an increased risk of early-stage UADT cancers independent of smoking status and histology, which must be further validated in other populations.
doi:10.1002/cam4.201
PMCID: PMC3987092  PMID: 24519853
BRM; cancer risk; case–control study; esophageal cancer; genetic polymorphisms; head and neck cancer; lung cancer; upper aerodigestive tract cancers
20.  L-DOPS corrects neurochemical abnormalities in a Menkes disease mouse model 
Annals of neurology  2012;73(2):259-265.
Objective
Menkes disease is a lethal neurodegenerative disorder of infancy caused by mutations in a copper-transporting ATPase gene, ATP7A. Among its multiple cellular tasks, ATP7A transfers copper to dopamine-beta-hydroxylase (DBH) within the lumen of the Golgi network or secretory granules, catalyzing the conversion of dopamine to norepinephrine. In a well-established mouse model of Menkes disease, mottled-brindled, we tested whether systemic administration of L-threo-dihydroxyphenylserine (L-DOPS), a drug used successfully to treat autosomal recessive norepinephrine deficiency, would improve brain neurochemical abnormalities and neuropathology.
Methods
At 8, 10, and 12 days of age, wild type and mo-br mice received intraperi-toneal injections of 200μg/g body weight of L-DOPS, or mock solution. Five hours after the final injection, the mice were euthanized and brains removed. We measured catecholamine metabolites affected by DBH via high-performance liquid chromatography with electrochemical detection, and assessed brain histopathology.
Results
Compared to mock-treated controls, mo-br mice that received intraperitoneal L-DOPS showed significant increases in brain norepinephrine (P<0.001) and its deaminated metabolite, dihydroxyphenylglycol (DHPG, P<0.05). The ratio of a non-beta-hydroxylated metabolite in the catecholamine biosynthetic pathway, dihydroxyphenylacetic acid, to the beta-hydroxylated metabolite, dihydroxyphenylglycol, improved equivalently to results obtained previously with brain-directed ATP7A gene therapy (P<0.01). However, L-DOPS treatment did not arrest global brain pathology or improve somatic growth, as gene therapy had.
Interpretation
We conclude that 1) L-DOPS crosses the blood-brain barrier in mo-br mice and corrects brain neurochemical abnormalities, 2) norepinephrine deficiency is not the cause of neurodegeneration in mo-br mice, and 3) L-DOPS treatment may ameliorate noradrenergic hypofunction in Menkes disease.
doi:10.1002/ana.23787
PMCID: PMC3597755  PMID: 23224983
21.  Potential applications of nanotechnology for the diagnosis and treatment of pancreatic cancer 
Despite improvements in our understanding of pancreatic cancer and the emerging concept of personalized medicine for the treatment of this disease, it is still the fourth most common cause of cancer death in the western world. It is established that pancreatic cancer is a highly heterogeneous disease with a complex tumor microenvironment. Indeed the extensive stroma surrounding the cancer cells has been shown to be important in promoting tumor growth and metastases, as well as sequestering chemotherapeutic agents consequently decreasing delivery to the tumor cells. Nanotechnology has come to the forefront in the areas of medical diagnostics, imaging, and therapeutic drug delivery. This review will focus on the potential applications of nanotechnology for diagnosis, imaging, and delivery of therapeutic agents for the treatment of pancreatic cancer.
doi:10.3389/fphys.2014.00002
PMCID: PMC3900771  PMID: 24478715
pancreatic cancer; nanotechnology; nano-diagnostics; molecular imaging; therapeutic drug delivery; tumor stroma
22.  Single nucleotide polymorphism upstream of interleukin 28B associated with phase 1 and phase 2 of early viral kinetics in patients infected with HCV genotype 1 
Journal of hepatology  2011;56(3):10.1016/j.jhep.2011.10.004.
Background & Aims
We studied the relationship between IL28B gene-related SNP rs12979860 and early viral kinetics (day 0–28) during peginterferon and ribavirin treatment, in 173 African Americans (AA) and 188 Caucasian Americans (CA) with HCV genotype 1.
Methods
We studied the relationship between IL28B 16 gene-related SNP rs12979860 and early viral kinetics (day 0–28) 17 during peginterferon and ribavirin treatment, in 171 African 18 Americans (AA) and 188 Caucasian Americans (CA) with HCV 19 genotype 1.
Results
Compared to non-C/C genotypes, C/C was associated with greater declines in serum HCV RNA during phase 1 (day 0–2), phase 2 (day 7–28), and day 0–28 and higher response (undetected HCV RNA) rates at weeks 4 and 12 in AA and CA. A static phase and increases in HCV RNA from day 2 to 7 were more common in patients with non-C/C genotypes. C/C was also associated with higher week 24, 48, and 72 response rates in CA (p <0.01) but not in AA. At baseline, SNP genotype was the only independent predictor of phase 1; SNP genotype and phase 1 were independent predictors of phase 2 (p<0.001). There were no racial differences in HCV RNA declines during phase 1, day 2–7, phase 2, and day 0–28 with the same SNP genotype. AA with C/C and C/T genotypes had lower week 24, 48, and 72 (SVR) rates than did CA (p = 0.03). SNP C/C predicted higher SVR rates in AA and CA with high baseline HCV RNA (≥ 600,000 IU/ml), and in CA with ≥ 1 log10 IU/ml decrease in HCV RNA from day 0 to 28.
Conclusions
SNP rs12979860 is strongly associated with both phase 1 and phase 2 HCV RNA kinetics in AA and CA with HCV genotype 1.
doi:10.1016/j.jhep.2011.10.004
PMCID: PMC3884806  PMID: 22027585
IL28B gene; Hepatitis C virus; Viral kinetics; Single nucleotide polymorphism
23.  HGV2011: Personalized Genomic Medicine Meets the Incidentalome 
Human mutation  2012;33(3):10.1002/humu.22008.
The 12th International Meeting on Human Genome Variation and Complex Genome Analysis (HGV2011: Berkeley, California, USA, 8th–10th September 2011) was a stimulating workshop where researchers from academia and industry explored the latest progress, challenges, and opportunities in genome variation research. Key themes included progress beyond GWAS, variation in human populations, use of sequence data in medical settings, large-scale sequencing data analysis, and bioinformatics approaches to large datasets.
doi:10.1002/humu.22008
PMCID: PMC3867005  PMID: 22170622
human variation; GWAS; SNP; medical genomics
24.  Vesicular Uptake Blockade Generates the Toxic Dopamine Metabolite 3,4-Dihydroxyphenylacetaldehyde in PC12 Cells: Relevance to the Pathogenesis of Parkinson Disease 
Journal of neurochemistry  2012;123(6):932-943.
Parkinson disease entails profound loss of nigrostriatal dopaminergic terminals, decreased vesicular uptake of intra-neuronal catecholamines, and relatively increased putamen tissue concentrations of the toxic dopamine metabolite, 3,4-dihydroxyphenylacetaldehyde (DOPAL). The objective of this study was to test whether vesicular uptake blockade augments endogenous DOPAL production. We also examined whether intracellular DOPAL contributes to apoptosis and, since alpha-synuclein oligomers may be pathogenetic in Parkinson disease, oligomerizes alpha-synuclein. Catechols were assayed in PC12 cells after reserpine to block vesicular uptake, with or without inhibition of enzymes metabolizing DOPAL—daidzein for aldehyde dehydrogenase and AL1576 for aldehyde reductase. Vesicular uptake was quantified by a method based on 6F- or 13C-dopamine incubation; DOPAL toxicity by apoptosis responses to exogenous dopamine, with or without daidzein+AL1576; and DOPAL-induced synuclein oligomerization by synuclein dimer production during DOPA incubation, with or without inhibition of L-aromatic-amino-acid decarboxylase or monoamine oxidase. Reserpine inhibited vesicular uptake by 95–97% and rapidly increased cell DOPAL content (p=0.0008). Daidzein+AL1576 augmented DOPAL responses to reserpine (p=0.004). Intracellular DOPAL contributed to dopamine-evoked apoptosis and DOPA-evoked synuclein dimerization. The findings fit with the “catecholaldehyde hypothesis,” according to which decreased vesicular sequestration of cytosolic catecholamines and impaired catecholaldehyde detoxification contribute to the catecholaminergic denervation that characterizes Parkinson disease.
doi:10.1111/j.1471-4159.2012.07924.x
PMCID: PMC3514596  PMID: 22906103
Dihydroxyphenylacetaldehyde; DOPAL; aldehyde dehydrogenase; reserpine; Parkinson disease; monoamine oxidase
25.  IL28B polymorphisms are associated with histological recurrence and treatment response following liver transplantation in patients with HCV Infection 
Hepatology (Baltimore, Md.)  2011;53(1):10.1002/hep.24074.
Background
Polymorphism in the IL28B gene region, encoding interferon-lambda(λ)-3, is strongly predictive of response to antiviral treatment in the non-transplant setting. We sought to determine the prevalence and impact on clinical outcomes of donor and recipient IL28B genotypes among liver transplant recipients.
Methods
Cohort study including 189 consecutive hepatitis C virus (HCV) patients who underwent liver transplantation between 1-1-1995 and 1-1-2005 in the Mayo Clinic, Rochester. Genotyping of the polymorphism rs12979860 was performed on DNA collected from all donors and recipients in the cohort. 65 patients received IFN-based antiviral therapy.
Results
The CC IL28B variant was less common in the CHC recipients than in non-HCV donor livers (33% vs 47%, P=0.03). IL28B recipient genotype was significantly predictive of fibrosis stage, with TT genotype being associated with more rapid fibrosis (Pearson Chi-square p=0.024 for the comparison G vs A). Donor and recipient IL28B genotype were independently associated with SVR (P<0.005). The presence of IL28B CC variant in either the recipient (R) or donor (D) liver was associated with increased rate of SVR (D-non-CC / R-non-CC = 3/19 (16%) vs D-CC / R-non-CC=11/22 (50%) vs D-non-CC / R-CC=5/12 (42 %) vs R-CC / D-CC=6/7 (86%), P=0.0095). IL28B genotype was not significantly associated with survival (overall / liver related).
Conclusion
Recipient IL28B genotype is associated with more severe histological recurrence of HCV. Recipient and donor liver IL28B genotype are strongly and independently associated with IFN-based treatment response in patients post-OLT. The data suggest that CC donor livers might be preferentially allocated to patients with HCV infection.
doi:10.1002/hep.24074
PMCID: PMC3835596  PMID: 21254179

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