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1.  Combination of Multichannel Single-Voxel MRS Signals Using Generalized Least Squares 
Purpose
To propose using the generalized least square (GLS) algorithm for combining multichannel single-voxel MRS signals.
Materials and Methods
Phantom and in vivo brain MRS experiments on a 7 T scanner equipped with a 32-channel receiver coil, as well as Monte Carlo simulations, were performed to compare the coefficient of variation (CV) of the GLS method with those of two recently reported spectral combination methods.
Results
Compared to the two existing methods, the GLS method significantly reduced CV values for the simulation, phantom, and in vivo experiments.
Conclusion
The GLS method can lead to improved precision of peak quantification.
doi:10.1002/jmri.23941
PMCID: PMC3582859  PMID: 23172656
MRS; multichannel coil; SNR; noise correlation; generalized least squares; GLS
2.  Associations between prefrontal γ-aminobutyric acid concentration and the tryptophan hydroxylase isoform 2 gene, a panic disorder risk allele in women 
Interactions between the central serotonergic and γ-aminobutyric acid (GABA) systems play key roles in the prefrontal cortical regulation of emotion and cognition and in the pathophysiology and pharmacotherapy of highly prevalent psychiatric disorders. The goal of this study was to test the effects of common variants of the tryptophan hydroxylase isoform 2 (TPH2) gene on GABA concentration in the prefrontal cortex (PFC) using magnetic resonance spectroscopy. In this study involving 64 individuals, we examined the associations between prefrontal cortical GABA concentration and 12 single nucleotide polymorphisms (SNPs) spanning the TPH2 gene, including rs4570625 (–703 G/T SNP), a potentially functional TPH2 polymorphism that has been associated with decreased TPH2 mRNA expression and panic disorder. Our results revealed a significant association between increased GABA concentration in the PFC and the T-allele frequencies of 2 TPH2 SNPs, namely, rs4570625 (of –703 G/T) and rs2129575 (p ≤ 0.0004) and the C-allele frequency of 1 TPH2 SNP, namely, rs1386491 (p = 0.0003) in female subjects. We concluded that rs4570625 (–703 G/T), rs2129575, and rs1386491 play a significant role in GABAergic neurotransmission and may contribute to the sex-specific dysfunction of the GABAergic system in the PFC.
doi:10.1017/S1461145713000254
PMCID: PMC4025920  PMID: 23552096
GABA; tryptophan hydroxylase 2; magnetic resonance spectroscopy; single nucleotide polymorphisms; genetics
3.  Age-modulated association between prefrontal NAA and the BDNF gene 
Brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of psychiatric and neurological disorders and in the mechanisms of antidepressant pharmacotherapy. Psychiatric and neurological conditions have also been associated with reduced brain levels of N-acetyl-aspartate (NAA), which has been used as a putative marker of neural integrity. However, few studies have explored the relationship between BDNF polymorphisms and NAA levels directly. Here, we present data from a single-voxel proton magnetic resonance spectroscopy study of 64 individuals and explore the relationship between BDNF polymorphisms and prefrontal NAA level. Our results indicate an association between a single nucleotide polymorphism (SNP) within BDNF, known as rs1519480, and reduced NAA level (p=0.023). NAA levels were further predicted by age and Asian ancestry. There was a significant interaction between rs1519480 and age on NAA level (p=0.031) Specifically, the effect of rs1519480 on NAA level became significant at age ≥ 34.17. NAA level decreased with advancing age for genotype TT (p=0.001) but not for genotype CT (p=0.82) or CC (p=0.34). Additional in silico analysis of 142 postmortem brain samples revealed an association between the same SNP and reduced BDNF mRNA expression in the prefrontal cortex. The rs1519480 SNP influences BDNF mRNA expression and has an impact on prefrontal NAA level over time. This genetic mechanism may contribute to interindividual variation in cognitive performance seen during normal aging, as well as contributing to the risk for developing psychiatric and neurological conditions.
doi:10.1017/S1461145712001204
PMCID: PMC4025926  PMID: 23253771
BDNF; N-acetyl-aspartate; proton magnetic resonance spectroscopy; SNP; genetic variation
4.  Protective Effects of Lipoxin A4 in Testis Injury following Testicular Torsion and Detorsion in Rats 
Mediators of Inflammation  2014;2014:898056.
Purpose. To investigate the protective effects of lipoxin A4 (LXA4) in rat testis injury following testicular torsion/detorsion. Methods. A rat testicular torsion model has been established as described. Rats were randomly divided into 6 groups: sham group, torsion group, torsion/detorsion (T/D) group, and T/D plus LXA4-pretreated groups (3 subgroups). Rats in LXA4-pretreated groups received LXA4 injection (0.1, 1.0, and 10 μg/kg body weight in LXA4-pretreated subgroups 1–3, resp.) at a single dose 1 h before detorsion. Biochemical analysis, apoptosis assessment, and morphologic evaluation were carried out after orchiectomies. Results. GPx and SOD levels significantly increased and MDA levels significantly reduced in LXA4-pretreated groups compared to T/D group. LXA4 also reverted IL-2 and TNF-α to basal levels and improved the expression of IL-4 and IL-10 in LXA4-pretreated groups. Moreover, the expression of NF-κB was downregulated in LXA4-pretreated groups. LXA4 treatment also showed an improved testicular morphology and decreased apoptosis in testes. Conclusion. Lipoxin A4 protects rats against testes injury after torsion/detorsion via modulation of cytokines, oxidative stress, and NF-κB activity.
doi:10.1155/2014/898056
PMCID: PMC4034656  PMID: 24904198
5.  Small nucleolar RNA signatures of lung tumor-initiating cells 
Molecular Cancer  2014;13:104.
Background
Non-small cell lung cancer (NSCLC) is the number one cancer killer. Tumor-initiating cells (TICs) are responsible for tumor progression and recurrence. Emerging evidences suggest that small nucleolar RNAs (snoRNAs) play malfunctioning roles in lung tumorigenesis. This study aims to determine if snoRNAs have important function in lung TICs by: 1) profiling and comparing snoRNA expression patterns in lung ALDH1+/- cells of 28 primary NSCLC tissues to identify new signatures of TICs; 2) determining prognostic significance of the snoRNA signatures by analyzing the expression in 82 NSCLC tissues with different stages and histological types using quantitative PCR; 3) functionally investigating if the snoRNAs contribute to stemness of lung TICs using in vitro and in vivo assays.
Results
Twenty-two snoRNAs were identified whose changes were specific to the TICs. The expression of two snoRNAs (snoRA3 and snoRA42) was inversely associated with survival of NSCLC patients (P = 0.002, p = 0.001, respectively). Functional analysis indicated that snoRA42 was upregulated in CD133+ cells isolated from NSCLC cell lines compared with the CD133- counterparts. snoRA42 knockdown reduced the proliferation and self-renewal of TICs in vitro. However, ectopic expression of snoRA42 in non-TICs enhanced the potentials of cell proliferation and self-renewal. snoRA42 expression was associated with expression of stem cell-core transcription factors in lung TICs. Blocking snoRA42 expression in TIC xenografts decreased tumorigenesis in mice.
Conclusions
The snoRNA signatures of lung TICs provide potential biomarkers for predicting outcome of NSCLC. snoRA42 is one of the important snoRNAs in regulating features of lung TICs, and thus contributes to lung tumorigenesis.
doi:10.1186/1476-4598-13-104
PMCID: PMC4029979  PMID: 24886050
6.  Using cognitive theory to facilitate medical education 
BMC Medical Education  2014;14:79.
Background
Educators continue to search for better strategies for medical education. Although the unifying theme of reforms was “increasing interest in, attention to, and understanding of the knowledge base structures”, it is difficult to achieve all these aspects via a single type of instruction.
Methods
We used related key words to search in Google Scholar and Pubmed. Related search results on this topic were selected for discussion.
Results
Despite the range of different methods used in medical education, students are still required to memorize much of what they are taught, especially for the basic sciences. Subjects like anatomy and pathology carry a high intrinsic cognitive load mainly because of the large volume of information that must be retained. For these subjects, decreasing cognitive load is not feasible and memorizing appears to be the only strategy, yet the cognitive load makes learning a challenge for many students. Cognitive load is further increased when inappropriate use of educational methods occurs, e.g., in problem based learning which demands clinical reasoning, a high level and complex cognitive skill. It is widely known that experts are more skilled at clinical reasoning than novices because of their accumulated experiences. These experiences are based on the formation of cognitive schemata. In this paper we describe the use of cognitive schemata, developed by experts as worked examples to facilitate medical students’ learning and to promote their clinical reasoning.
Conclusion
We suggest that cognitive load theory can provide a useful framework for understanding the challenges and successes associated with education of medical professionals.
doi:10.1186/1472-6920-14-79
PMCID: PMC3989791  PMID: 24731433
Working memory; Cognitive load theory; Schemata; Clinical reasoning; Worked example; Problem based learning; Clinical presentation curriculum
7.  Soft Constraints in Nonlinear Spectral Fitting with Regularized Lineshape Deconvolution 
This paper presents a novel method for incorporating a priori knowledge into regularized nonlinear spectral fitting as soft constraints. Regularization was recently introduced to lineshape deconvolution as a method for correcting spectral distortions. Here, the deconvoluted lineshape was described by a new type of lineshape model and applied to spectral fitting. The non-linear spectral fitting was carried out in two steps that were subject to hard constraints and soft constraints, respectively. The hard constraints step provided a starting point and, therefore, only the changes of the relevant variables were constrained in the soft constraints step and incorporated into the linear sub-steps of the Levenberg-Marquardt algorithm. The method was demonstrated using localized averaged echo time point resolved spectroscopy (PRESS) proton spectroscopy of human brains.
doi:10.1002/mrm.24337
PMCID: PMC3432296  PMID: 22618964
lineshape; deconvolution; regularization; soft constraints; spectral fitting
8.  Swim therapy reduces mechanical allodynia and thermal hyperalgesia induced by chronic constriction nerve injury in rats 
Pain medicine (Malden, Mass.)  2013;14(4):516-525.
Objective
Neuropathic pain is common and often difficult to treat because it generally does not respond well to the currently available pain medications or nerve blocks. Recent studies in both humans and animals have suggested that exercise may induce a transient analgesia and reduce acute pain in normal healthy individuals. We examined whether swim therapy could alleviate neuropathic pain in rats.
Design
Rats were trained to swim over a two week period in warm water. After the rats were trained, neuropathic pain was induced by constricting the right sciatic nerve and regular swimming was resumed. The sensitivity of each hind paw was monitored using the Hargreaves test and von Frey test to evaluate the withdrawal response thresholds to heat and touch.
Results
The paw ipsilateral to the nerve ligation expressed pain-like behaviors including thermal hyperalgesia and mechanical allodynia. Regular swim therapy sessions significantly reduced the mechanical allodynia and thermal hyperalgesia. Swim therapy had little effect on the withdrawal thresholds for the contralateral paw. In addition, swim therapy alone did not alter the thermal or mechanical thresholds of normal rats.
Conclusions
The results suggest that regular exercise, including swim therapy, may be an effective treatment for neuropathic pain caused by nerve injuries. This study, showing that swim therapy reduces neuropathic pain behavior in rats, provides a scientific rationale for clinicians to test the efficacy of exercise in the management of neuropathic pain. It may prove to be a safe and cost-effective therapy in a variety of neuropathic pain states.
doi:10.1111/pme.12057
PMCID: PMC3625453  PMID: 23438327
Exercise; Neuralgia; Pain Management; Rehabilitation Medicine
9.  Association between Faecalibacterium prausnitzii Reduction and Inflammatory Bowel Disease: A Meta-Analysis and Systematic Review of the Literature 
Background. Laboratory data suggests a reduction of Faecalibacterium prausnitzii (F. prausnitzii) is confirmed both in fecal samples in inflammatory bowel disease (IBD) patients. Numerous observational studies have suspected dysbiosis, an imbalance between protective and harmful bacteria to be relevant to the etiology and pathogenesis of IBD. Methods. Medline, EMBASE, Pubmed, and others. were searched by 2 independent reviewers. Of 48 abstracts reviewed, 11 studies met our inclusion criteria (subject N = 1180). Meta-analysis was performed with Review Manager 5.2. Results. The bacterial count of F. prausnitzii in IBD patients was significantly lower (6.7888 ± 1.8875) log10 CFU/g feces than healthy controls (7.5791 ± 1.5812) log10 CFU/g feces; P < 0.0001. The Standardization Mean Difference of F. prausnitzii in IBD patients was −0.94 (95% confidence interval [CI]: −1.07–−0.80). Subgroup analyses revealed a trend toward a greater effect for CD (SMD: −1.13, 95% CI: −1.32–−0.94) when compared to UC (SMD: −0.78, 95% CI: −0.97–−0.60). Conclusions. The abundance of F. prausnitzii was decreased in IBD patients compared with healthy controls. Furthermore, the reduction of F. prausnitzii and misbalance of the intestinal microbiota are particularly higher in CD patients with ileal involvement.
doi:10.1155/2014/872725
PMCID: PMC3985188  PMID: 24799893
10.  MicroRNAs as Potential Biomarkers in Human Solid Tumors 
Cancer letters  2012;329(2):125-136.
MicroRNAs (miRNAs) regulate the expression of approximately 30% of protein-coding genes. Functions of miRNAs are essential to maintain a steady state of cellular machinery. Dysregulations of miRNAs play pivotal roles in the initiation and progression of malignancies. Abnormal miRNA expressions have been found in a variety of human solid tumors. Furthermore, extracellular miRNAs could circulate in body fluids, and hence show great promise for refining diagnosis and prognosis of cancer. Here we review the progress of analysis of microRNAs as a potential approach for diagnosis and prognosis of solid cancer. We will also discuss obstacles in developing miRNAs as circulating biomarkers.
doi:10.1016/j.canlet.2012.11.001
PMCID: PMC3552101  PMID: 23196059
MicroRNA; biomarkers; diagnosis; prognosis; circulation; cancer
11.  Multivoxel MR Spectroscopy in Acute Ischemic Stroke:Comparison to the Stroke Protocol MRI 
Background and Purpose
Few patients with stroke have been imaged with MR spectroscopy (MRS) within the first few hours after onset. We compared data from current MRI protocols to MRS in subjects with ischemic stroke.
Methods
MRS was incorporated into the standard clinical MRI stroke protocol for subjects <24 hours after onset. MRI and clinical correlates for the metabolic data from MRS were sought.
Results
One hundred thirty-six MRS voxels from 32 subjects were analyzed. Lactate preceded the appearance of the lesion on diffusion-weighted imaging in some voxels but in others lagged behind it. Current protocols may predict up to 41% of the variance of MRS metabolites. Serum glucose concentration and time to maximum partially predicted the concentration of all major metabolites.
Conclusion
MRS may be helpful in acute stroke, especially for lactate detection when perfusion-weighted imaging is unavailable. Current MRI protocols do provide surrogate markers for some indices of metabolic activity.
doi:10.1161/STROKEAHA.112.656058
PMCID: PMC3936472  PMID: 23091121
magnetic resonance spectroscopy; spectroscopy; stroke
12.  Nedaplatin concurrent with three-dimensional conformal radiotherapy for treatment of locally advanced esophageal carcinoma 
AIM: To evaluate the efficacy and toxicity of nedaplatin (NDP) concurrent with radiotherapy in the treatment of locally advanced esophageal carcinoma.
METHODS: Sixty-eight patients with locally advanced esophageal carcinoma were randomized into either a NDP group (n = 34) or a cisplatin (DDP) group (n = 34). The NDP group received NDP 80-100 mg/m2 iv on day 1 + leucovorin (CF) 100 mg/m2 iv on days 1-5 + 5-fluorouracil (5-FU) 500 mg/m2 iv on days 1-5. The DDP group received DDP 30 mg/m2 iv on days 1-3 + CF 100 mg/m2 on days 1-5 + 5-FU 500 mg/m2 iv on days 1-5. The treatment was repeated every 4 wk in both groups. Concurrent radiotherapy [60-66 Gy/(30-33 f)/(6-7 wk)] was given during chemotherapy.
RESULTS: There was no significant difference in the short-term response rate between the NDP group and DDP group (90.9% vs 81.3%, P = 0.528). Although the 1- and 2-year survival rates were higher in the NDP group than in the DDP group (75.8% vs 68.8%, 57.6% vs 50.0%), the difference in the overall survival rate was not statistically significant between the two groups (P = 0.540). The incidences of nausea, vomiting and nephrotoxicity were significantly lower in the NDP group than in the DDP group (17.6% vs 50.0%, P = 0.031; 11.8% vs 47.1%, P = 0.016; 8.8% vs 38.2%, P = 0.039). There was no significant difference in the incidence of myelosuppression, radiation-induced esophagitis or radiation-induced pneumonia between the two groups.
CONCLUSION: NDP-based concurrent chemoradiotherapy is effective and well-tolerated in patients with locally advanced esophageal carcinoma. NDP-based regimen has comparable efficacy to DDP-based regimen but is associated with lower incidences of gastrointestinal and renal toxicity.
doi:10.3748/wjg.v19.i48.9447
PMCID: PMC3882421  PMID: 24409075
Esophageal carcinoma; Chemoradiotherapy; Nedaplatin; Cisplatin
13.  Pilot results of in vivo brain glutathione measurements in stroke patients 
Measurement of glutathione concentration for the study of redox status in subjects with neurological disease has been limited to peripheral markers. We recruited 19 subjects with large strokes. Using magnetic resonance spectroscopy we measured brain glutathione concentration in the stroke region and in healthy tissue to calculate a glutathione-ratio. Elevated glutathione-ratio was observed in subacute (<72 hours) subjects without hemorrhagic transformation (mean=1.19, P=0.03, n=6). No trend was seen when all subjects were considered (n=19, 3 to 754 hours, range=0.45 to 1.41). This technique can detect glutathione changes because of disease, and may be valuable in clinical trials of stroke and other neurological diseases.
doi:10.1038/jcbfm.2012.127
PMCID: PMC3519413  PMID: 23010948
glutathione; magnetic resonance imaging; magnetic resonance spectroscopy; oxidative stress; stroke
14.  Trends and Factors Affecting Hospitalization Costs in Patients with Inflammatory Bowel Disease: A Two-Center Study over the Past Decade 
With the growing number of patients with inflammatory bowel disease (IBD) and hospitalization cases, the overall medical care cost elevates significantly in consequence. A total of 2458 hospitalizations, involving 1401 patients with IBD, were included from two large medical centers. Hospitalization costs and factors impacting cost changes were determined. Patients with IBD and frequency of hospitalizations increased significantly from 2003 to 2011 (P < 0.001). The annual hospitalization cost per patient, cost per hospitalization, and daily cost during hospitalization increased significantly in the past decade (all P < 0.001). However, length of stay decreased significantly (P < 0.001). Infliximab was the most significant factor associated with higher hospitalization cost (OR = 44380.09, P < 0.001). Length of stay (OR = 1.29, P < 0.001), no medical insurance (OR = 1.31, P = 0.017), CD (OR = 3.55, P < 0.001), inflammatory bowel disease unclassified (IBDU) (OR = 4.30, P < 0.0001), poor prognosis (OR = 6.78, P < 0.001), surgery (OR = 3.16, P < 0.001), and endoscopy (OR = 2.44, P < 0.001) were found to be predictors of higher hospitalization costs. Patients with IBD and frequency of hospitalizations increased over the past decade. CD patients displayed a special one peak for age at diagnosis, which was different from UC patients. The increased hospitalization costs of IBD patients may be associated with infliximab, length of stay, medical insurance, subtypes of IBD, prognosis, surgery, and endoscopy.
doi:10.1155/2013/267630
PMCID: PMC3838837  PMID: 24307891
15.  PI3K/Akt Signaling Pathway in the Basolateral Amygdala Mediates the Rapid Antidepressant-like Effects of Trefoil Factor 3 
Neuropsychopharmacology  2012;37(12):2671-2683.
Depression is one of the most common and debilitating psychiatric illnesses around the world, but the current antidepressants used to treat depression have many limitations. Progressively more studies have shown that neuropeptide systems are potential novel therapeutic targets for depression. However, whether the neuropeptide trefoil factor 3 (TFF3) participates in the development of depression has not been examined. In the current experiments, we assessed the antidepressant effects of TFF3 using the forced swim test (FST), tail suspension test (TST), and chronic mild stress (CMS) paradigm. Furthermore, we determined the mechanism that underlies the antidepressant-like effects of TFF3 in the rat FST. TFF3 dose-dependently reduced immobility time in both FST and TST. CMS elevated plasma TFF3 and decreased basolateral amygdala (BLA) TFF3 levels in rats, and acute TFF3 (0.1 mg/kg, i.p.) treatment reversed the depressive-like behaviors induced by CMS. Furthermore, TFF3 (0.1 mg/kg, i.p.) significantly increased Fos expression in the BLA, medial prefrontal cortex, and hypothalamus in rats subjected to the FST. Intra-BLA infusions of TFF3 (1 ng/side) exerted rapid antidepressant-like effects in the rat FST. Additionally, acute systemic TFF3 administration increased the level of phosphorylated-Akt (p-Akt) in the BLA. Finally, intra-BLA infusions of LY294002 (5 mM/side), a specific phosphatidylinositol 3-kinase (PI3K) inhibitor, significantly blocked the antidepressant-like effect of TFF3. Our results demonstrated that TFF3 exerts antidepressant-like effects that might be mediated by the PI3K/Akt signaling pathway in the BLA. These findings suggest a novel neuropeptide system target in the development of new antidepressants.
doi:10.1038/npp.2012.131
PMCID: PMC3473333  PMID: 22828749
depression; neuropeptide; trefoil factor 3; basolateral amygdala; phosphatidylinositol 3-kinase; chronic mild stress; animal models; behavioral science; biological psychiatry; chronic stress; depression; unipolar/bipolar; neuropeptide
16.  Preserving the excitation profile of small flip angle RF pulses in the presence of rapid transverse relaxation 
Degradation of excitation profile of selective RF pulses by rapid transverse relaxation has been a long-standing concern. In this report we demonstrate that transverse relaxation can be incorporated into small flip angle RF pulse design based on the linear response theory. Small flip angle pulses that were designed without considering transverse relaxation effects can be transformed for a predefined pulse duration/T2 ratio. The transformed pulses, within the realm of the linear response theory, produce the same transverse frequency response as if there were no relaxation.
doi:10.1016/j.jmr.2012.08.012
PMCID: PMC3578300  PMID: 23000975
RF pulse design; Linear response theory; Relaxation effects
17.  Metabolomic Analysis of Anti-Hypoxia and Anti-anxiety Effects of Fu Fang Jin Jing Oral Liquid 
PLoS ONE  2013;8(10):e78281.
Background
Herba Rhodiolae is a traditional Chinese medicine used by the Tibetan people for treating hypoxia related diseases such as anxiety. Based on the previous work, we developed and patented an anti-anxiety herbal formula Fu Fang Jin Jing Oral Liquid (FJJOL) with Herba Rhodiolae as a chief ingredient. In this study, the anti-hypoxia and anti-anxiety effects of FJJOL in a high altitude forced-swimming mouse model with anxiety symptoms will be elucidated by NMR-based metabolomics.
Methods
In our experiments, the mice were divided randomly into four groups as flatland group, high altitude saline-treated group, high altitude FJJOL-treated group, and high altitude diazepam-treated group. To cause anxiety effects and hypoxic defects, a combination use of oxygen level decreasing (hypobaric cabin) and oxygen consumption increasing (exhaustive swimming) were applied to mice. After a three-day experimental handling, aqueous metabolites of mouse brain tissues were extracted and then subjected to NMR analysis. The therapeutic effects of FJJOL on the hypobaric hypoxia mice with anxiety symptoms were verified.
Results
Upon hypoxic exposure, both energy metabolism defects and disorders of functional metabolites in brain tissues of mice were observed. PCA, PLS-DA and OPLS-DA scatter plots revealed a clear group clustering for metabolic profiles in the hypoxia versus normoxia samples. After a three-day treatment with FJJOL, significant rescue effects on energy metabolism were detected, and levels of ATP, fumarate, malate and lactate in brain tissues of hypoxic mice recovered. Meanwhile, FJJOL also up-regulated the neurotransmitter GABA, and the improvement of anxiety symptoms was highly related to this effect.
Conclusions
FJJOL ameliorated hypobaric hypoxia effects by regulating energy metabolism, choline metabolism, and improving the symptoms of anxiety. The anti-anxiety therapeutic effects of FJJOL were comparable to the conventional anti-anxiety drug diazepam on the hypobaric hypoxia mice. FJJOL might serve as an alternative therapy for the hypoxia and anxiety disorders.
doi:10.1371/journal.pone.0078281
PMCID: PMC3799728  PMID: 24205180
18.  Glycine site N-methyl-d-aspartate receptor antagonist 7-CTKA produces rapid antidepressant-like effects in male rats 
Background
Glutamate N-methyl-d-aspartate (NMDA) receptor antagonists exert fast-acting antidepressant effects, providing a promising way to develop a new classification of antidepressant that targets the glutamatergic system. In the present study, we examined the potential antidepressant action of 7-chlorokynurenic acid (7-CTKA), a glycine recognition site NMDA receptor antagonist, in a series of behavioural models of depression and determined the molecular mechanisms that underlie the behavioural actions of 7-CTKA.
Methods
We administered the forced swim test, novelty-suppressed feeding test, learned helplessness paradigm and chronic mild stress (CMS) paradigm in male rats to evaluate the possible rapid antidepressant-like actions of 7-CTKA. In addition, we assessed phospho-glycogen synthase kinase-3β (p-GSK3β) level, mammalian target of rapamycin (mTOR) function, and postsynaptic protein expression in the medial prefrontal cortex (mPFC) and hippocampus.
Results
Acute 7-CTKA administration produced rapid antidepressant-like actions in several behavioural tests. It increased p-GSK3β, enhanced mTOR function and increased postsynaptic protein levels in the mPFC. Activation of GSK3β by LY294002 completely blocked the antidepressant-like effects of 7-CTKA. Moreover, 7-CTKA did not produce rewarding properties or abuse potential.
Limitations
It is possible that 7-CTKA modulates glutamatergic transmission, thereby causing enduring alterations of GSK3β and mTOR signalling, although we did not provide direct evidence to support this possibility. Thus, the therapeutic involvement of synaptic adaptions engaged by 7-CTKA requires further study.
Conclusion
Our findings demonstrate that acute 7-CTKA administration produced rapid antidepressant-like effects, indicating that the behavioural response to 7-CTKA is mediated by GSK3β and mTOR signalling function in the mPFC.
doi:10.1503/jpn.120228
PMCID: PMC3756114  PMID: 23611177
19.  Differential Effects of Peripheral versus Central Coadministration of QX-314 and Capsaicin on Neuropathic Pain in Rats 
Anesthesiology  2012;117(2):365-380.
Background
Neuropathic pain is common and difficult to treat. Recently a technique was developed to selectively inhibit nociceptive inputs by simultaneously applying two drugs: capsaicin, a transient receptor potential vanilloid receptor 1 channel activator and QX-314, a lidocaine derivative that intracellularly blocks sodium channels. We used this technique to investigate whether transient receptor potential vanilloid receptor 1-expressing nociceptors contribute to neuropathic pain.
Methods
The rat chronic constriction injury model was used to induce neuropathic pain in order to test the analgesic effects of both peripheral (perisciatic) and central (intrathecal) administration of the QX-314/capsaicin combination. The Hargreaves and von Frey tests were used to monitor evoked pain-like behaviors and visual observations were used to rank spontaneous pain-like behaviors.
Results
Perisciatic injections of the QX-314/capsaicin combination transiently increased the withdrawal thresholds by ~3 fold for mechanical and thermal stimuli in rats (n = 6/group) with nerve injuries suggesting that peripheral transient receptor potential vanilloid receptor 1-expressing nociceptors contribute to neuropathic pain. In contrast, intrathecal administration of the QX-314/capsaicin combination did not alleviate pain-like behaviors (n = 5/group). Surprisingly, intrathecal QX-314 alone (n = 9) or in combination with capsaicin (n = 8) evoked spontaneous pain-like behaviors.
Conclusions
Data from the perisciatic injections suggested that a component of neuropathic pain was mediated by peripheral nociceptive inputs. The role of central nociceptive terminals could not be determined because of the severe side effects of the intrathecal drug combination. We concluded that only peripheral blockade of transient receptor potential vanilloid receptor 1-expressing nociceptive afferents by the QX-314/capsaicin combination was effective at reducing neuropathic allodynia and hyperalgesia.
doi:10.1097/ALN.0b013e318260de41
PMCID: PMC3421838  PMID: 22739765
20.  Prognostic Roles of Cross-Talk between Peritumoral Hepatocytes and Stromal Cells in Hepatocellular Carcinoma Involving Peritumoral VEGF-C, VEGFR-1 and VEGFR-3 
PLoS ONE  2013;8(5):e64598.
Background
Peritumoral liver tissue could play a potential role in hepatocellular carcinoma (HCC) progression and patient survival via angiogenesis- and lymphangiogensis-related factors. The prognostic role of these factors in hepatocytes and stromal cells in HCC patients after curative resection remains to be explored.
Methods
Tumor tissue and surrounding peritumoral tissue were obtained from 145 resected HCC patients without lymph node metastasis (LNM) and 37 resected HCC patients with LNM. Tissue microarrays were constructed from duplicate cores of tumor tissue and surrounding peritumoral tissue from each resected specimen. Immunohistochemistry and real-time polymerase chain reaction were used to evaluate the expression of vascular endothelial growth factor-A (VEGF-A), VEGF-C, VEGF receptor-1(VEGFR-1), VEGFR-2, and VEGFR-3. Macrophage infiltration was determined by CD68 staining. Correlations between the expression of these factors and overall survival (OS) and time to recurrence (TTR) were studied.
Results
The peritumoral expression of VEGF-A, VEGF-C, VEGFR-1, VEGFR-2, and VEGFR-3 were significantly higher than expression of these factors in tumors. VEGFR-1 was mostly located in peritumoral macrophages, while VEGF-C and VEGFR-3 were mostly located in peritumoral hepatocytes. HCC with high peritumoral co-expression of VEGF-C, VEGFR-1, and VEGFR-3 was associated with higher peritumoral distribution of macrophages (0.87%±0.26% versus 0.45%±0.20%), LNM (32.4% versus 12.0%), shorter TTR (10.2 months versus 34.5 months), and poor prognosis (19.4 months versus 49.3 months).
Conclusion
Expression of VEGF-C, VEGFR-1, and VEGFR-3 in peritumoral liver tissue is associated with a unique type of HCC that has a poorer outcome after hepatectomy.
doi:10.1371/journal.pone.0064598
PMCID: PMC3667811  PMID: 23737988
21.  In Vivo Detection of 13C Isotopomer Turnover in the Human Brain by Sequential Infusion of 13C Labeled Substrates 
This study demonstrates the feasibility of simultaneously detecting human brain metabolites labeled by two substrates infused in a sequential order. In vivo 13C spectra of carboxylic/amide carbons were acquired only during the infusion of the second substrate. This approach allowed dynamic detection of 13C labeling from two substrates with considerably different labeling patterns. [2-13C]glucose and [U-13C6]glucose were used to generate singlet and doublet signals of the same carboxylic/amide carbon atom, respectively. Because of the large one-bond 13C-13C homonuclear J coupling between a carboxylic/amide carbon and an aliphatic carbon (~50 Hz), the singlet and doublet signals of the same carboxylic/amide carbon were well distinguished. The results demonstrated that different 13C isotopomer patterns could be simultaneously and distinctly measured in vivo in a clinical setting at 3 Tesla.
doi:10.1016/j.jmr.2012.03.012
PMCID: PMC3351698  PMID: 22578550
In vivo 13C MRS; Carboxylic/amide spectral region; Sequential infusion
22.  Applications of MicroRNAs in the Diagnosis and Prognosis of Lung Cancer 
Introduction
Lung cancer is the leading cause of cancer death worldwide, due to its late diagnosis and poor outcome. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the posttranscriptional levels by either degrading or blocking translation of messenger RNA targets. Accumulating evidence indicates that miRNAs play a pivotal role in the development and progression of human malignancies, including lung cancer.
Areas covered
In this review, the authors focus on 1) application of miRNA-based biomarkers to help classify lung cancer, 2) application of the miRNA biomarkers for the early detection of lung cancer, and 3) use of miRNAs as biomarkers to predict outcomes of lung cancer.
Expert Opinion
MiRNAs provide promising biomarkers for the diagnosis and prognosis of lung cancer. The developed miRNA biomarkers should be comprehensively and prospectively validated in clinical trials before being used in laboratory settings.
doi:10.1517/17530059.2012.672970
PMCID: PMC3355762  PMID: 22615714
MiRNAs; biomarker; diagnosis; prognosis; lung cancer
23.  Targeted therapy for human hepatic carcinoma cells using folate-functionalized polymeric micelles loaded with superparamagnetic iron oxide and sorafenib in vitro 
Background
The purpose of this study was to evaluate the inhibitory effect of targeted folate-functionalized micelles containing superparamagnetic iron oxide nanoparticles (SPIONs) and sorafenib on human hepatic carcinoma (HepG2) cells in vitro, and to observe the feasibility of surveillance of this targeting therapeutic effect by magnetic resonance imaging.
Methods
Sorafenib and SPIONs were loaded into polymeric micelles. The targeted nanocarrier was synthesized by functionalizing the micelles with folate. Folate-free micelles loaded with sorafenib and SPIONs were used as control (nontargeted) micelles. Uptake of the nanocarrier by cells was assessed using Prussian blue staining after 1 hour of incubation with the polymeric micelles. The inhibitory effect of the targeted micelles on HepG2 cell proliferation at various concentrations of sorafenib was assessed in vitro using the methyl thiazolyl tetrazolium (MTT) assay and apoptotic analysis using flow cytometry. Magnetic resonance imaging using a clinical 1.5 T scanner was performed to detect changes in the signal intensity of cells after incubation with the targeted micelles.
Results
Prussian blue staining showed significantly more intracellular SPIONs in cells incubated with the targeted micelles than those incubated with nontargeted micelles. The MTT assay showed that the average inhibitory ratio in the targeted group was significantly higher than that in the nontargeted group (38.13% versus 22.54%, P = 0.028). The mean apoptotic rate in the targeted cells, nontargeted cells, and untreated cells was 17.01%, 11.04%, and 7.89%, respectively. The apoptotic rate in the targeted cells was significantly higher than that in the nontargeted cells (P = 0.043). The T2 signal intensity on magnetic resonance imaging of cells treated with the targeted micelles decreased significantly with increasing concentrations of sorafenib in the cell culture medium, but there was no obvious decrease in signal intensity in cells treated with the nontargeted micelles.
Conclusion
Folate-functionalized polymeric micelles loaded with SPIONs and sorafenib inhibited proliferation and induced apoptosis of HepG2 cells in vitro. The inhibitory events caused by targeted micelles can be monitored using clinical magnetic resonance.
doi:10.2147/IJN.S43263
PMCID: PMC3633582  PMID: 23620667
folic acid; sorafenib; magnetic resonance imaging; superparamagnetic iron oxide nanoparticles
24.  Direct Transformation of Lung Microenvironment by Interferon-α Treatment Counteracts Growth of Lung Metastasis of Hepatocellular Carcinoma 
PLoS ONE  2013;8(3):e58913.
Background
Interferon (IFN)-α is effective in inhibiting tumor growth and metastasis of hepatocellular carcinoma (HCC). However, the biologic mechanisms of IFN-α treatment in lung metastasis are not yet clear.
Methods
The effect of IFN-α treatment was studied by using an orthotopic xenograft model and measuring tumor size and lung metastasis. Pretreatment with IFN-α before implantation of tumor was done to explore the effect of IFN-α on lung tissues. Cytokines and macrophages were measured by immunohistochemistry and/or PCR assay, using human origin or mouse origin primers to differentiate the sources. Circulating tumor cells (CTCs) were also assayed by flow cytometry.
Results
IFN-α treatment did not decrease the number of CTCs (0.075%±0.020% versus 0.063%±0.018%, P = 0.574, IFN-α–treated versus control groups), but did decrease the number and size of lung metastasis (number: 1.75±1.0 versus 28.0±6.3, P = 0.008; size [pixels]: 116.8±72.2 versus 5226.4±1355.7, P = 0.020), and inhibited macrophage infiltration (0.20%±0.04% versus 1.36%±0.21%, P = 0.0058) and alteration of matrix metalloproteinase (MMP)-9 expression (mean integrated optical density (IOD): 5.1±1.7 versus 21.9±0.4, P<0.000) in the lung, which was independent of the primary tumor.
Conclusion
IFN-α inhibited lung metastasis by directly modulating the lung microenvironment.
doi:10.1371/journal.pone.0058913
PMCID: PMC3601095  PMID: 23527047
25.  Acamprosate suppresses magnetic resonance spectroscopy measures of central glutamate in detoxified alcoholics: A randomized controlled experimental medicine study 
Archives of general psychiatry  2010;67(10):1069-1077.
Context
Acamprosate is approved for treatment of alcoholism, but its mechanism of action remains unclear. Animal studies suggest that a persistent hyperglutamatergic state contributes to the pathophysiology of alcoholism, and that acamprosate may exert its actions by intervening in this process. Human translation of these findings is lacking.
Objective
To examine whether acamprosate modulates indices of central glutamate levels in recently abstinent alcohol dependent patients, as measured by proton nuclear magnetic resonance spectroscopy (1H-MRS).
Design
A 4 week, double-blind, placebo-controlled randomized controlled experimental medicine study, with 1H-MRS measures obtained on day 4 and 25.
Setting
NIAAA inpatient research unit at the NIH Clinical Center.
Patients
Thirty three patients who met the DSM-IV criteria for alcohol dependence and were admitted for medically supervised withdrawal from ongoing alcohol use.
Intervention
Four weeks of acamprosate (initial oral loading followed by 1998mg daily) or matched placebo, initiated at the time of admission.
Outcome measures
The main outcome was the glutamate/creatine ratio (Glu) as determined by single voxel 1H-MRS within the anterior cingulate. Exploratory neuroendocrine, biochemical and behavioral outcomes were also collected, as well as safety/tolerability – related measures.
Result
There was a highly significant suppression of Glu over time by acamprosate (time × treatment interaction: F[1, 29]=13.5, p<0.001). Cerebrospinal fluid (CSF) levels of glutamate obtained in a subset of patients 4 weeks into abstinence were uncorrelated with the MRS measures and were unaffected by treatment, but were strongly correlated (R2=0.48, p<0.001) with alcohol dependence severity. Other exploratory outcomes, including repeated Dex/CRH tests, as well as psychiatric ratings were unaffected. Among tolerability measures, gastrointestinal symptoms were significantly greater in acamprosate treated subjects, in agreement with the established profile of acamprosate.
Conclusion
MRS measures of central glutamate are reduced over time when acamprosate is initiated at the onset of alcohol abstinence.
Trial registration
www.clinicaltrials.gov Identifier: NCT00106106
doi:10.1001/archgenpsychiatry.2010.125
PMCID: PMC3583213  PMID: 20921123
acamprosate; alcohol; magnetic resonance spectroscopy; glutamate

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