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author:("Li, xiaoi")
1.  Electrophysiological Biomarkers in Spinal Muscular Atrophy: Preclinical Proof of Concept 
Objective
Preclinical therapies that restore survival motor neuron (SMN) protein levels can dramatically extend survival in spinal muscular atrophy (SMA) mouse models. Biomarkers are needed to effectively translate these promising therapies to clinical trials. Our objective was to investigate electrophysiological biomarkers of compound muscle action potential (CMAP), motor unit number estimation (MUNE) and electromyography (EMG) using an SMA mouse model.
Methods
Sciatic CMAP, MUNE, and EMG were obtained in SMNΔ7 mice at ages 3-13 days and at 21 days in mice with SMN selectively reduced in motor neurons (ChATCre). To investigate these measures as biomarkers of treatment response, measurements were obtained in SMNΔ7 mice treated with antisense oligonucleotide (ASO) or gene therapy.
Results
CMAP was significantly reduced in SMNΔ7 mice at days 6-13 (p<0.01), and MUNE was reduced at days 7-13 (p<0.01). Fibrillations were present on EMG in SMNΔ7 mice but not controls (p=0.02). Similar findings were seen at 21 days in ChATCre mice. MUNE in ASO-treated SMNΔ7 mice were similar to controls at day 12 and 30. CMAP reduction persisted in ASO-treated SMNΔ7 mice at day 12 but was corrected at day 30. Similarly, CMAP and MUNE responses were corrected with gene therapy to restore SMN.
Interpretation
These studies confirm features of preserved neuromuscular function in the early postnatal period and subsequent motor unit loss in SMNΔ7 mice. SMN restoring therapies result in preserved MUNE and gradual repair of CMAP responses. This provides preclinical evidence for the utilization of CMAP and MUNE as biomarkers in future SMA clinical trials.
PMCID: PMC3914317  PMID: 24511555
2.  What Does Risperidone Add to Stimulant and Parent Training for Severe Aggression in Child Attention-Deficit/Hyperactivity Disorder? 
Objective
Although combination pharmacotherapy is common in child/adolescent psychiatry, there has been little research evaluating it. We tested the value of adding risperidone to concurrent psychostimulant and parent training (PT) in behavior management for children with severe aggression
Method
We randomized 168 children age 6–12 years (mean 8.89 ±2.01) with severe physical aggression to a 9-week trial of PT, stimulant, and placebo (Basic treatment; n=84) or PT, stimulant, and risperidone (Augmented treatment; n=84). All had diagnoses of attention-deficit/ hyperactivity disorder (ADHD) and either oppositional defiant (n= 124) or conduct disorder (n= 44). Children received psychostimulant (usually OROS methylphenidate) for 3 weeks, titrated for optimal effect, while parents received PT. If there was room for improvement at the end of Week 3, either placebo or risperidone was added. Assessments included parent ratings on the Nisonger Child Behavior Rating Form (NCBRF; Disruptive-Total subscale = Primary outcome) and Antisocial Behavior Scale (ABS); blinded clinicians rated change on the Clinical Global Impressions (CGI) scale.
Results
Compared to Basic treatment (PT + stimulant[STIM][44.8±14.6 mg/day] + placebo [1.88±0.72]), Augmented treatment (PT + STIM[46.1±16.8 mg/day] + risperidone[1.65±0.75]) showed statistically significant improvement on the NCBRF Disruptive–Total subscale (treatment-by-time interaction p= 0.0016), the NCBRF Social Competence subscale (p= 0.0049), and ABS Reactive Aggression (p= 0.01). CGI scores were substantially improved for both groups but did not discriminate between treatments (CGI-I ≤ 2, 70% for Basic treatment vs. 79% for Augmented treatment). Prolactin elevations and gastrointestinal upset occurred more with Augmented; other adverse events differed modestly from Basic treatment; weight gain within the Augmented treatment group was minor.
Conclusions
Risperidone provided moderate but variable improvement in aggressive and other seriously disruptive child behavior when added to PT and optimized stimulant treatment. Clinical trial registration information—Treatment of Severe Childhood Aggression (The TOSCA Study); http://clinicaltrials.gov/; NCT00796302.
doi:10.1016/j.jaac.2013.09.022
PMCID: PMC3984501  PMID: 24342385
disruptive behavior disorders; parent training; physical aggression; psychostimulants; risperidone
3.  Carbohydrate Antigen 19-9 Is a Prognostic and Predictive Biomarker in Patients With Advanced Pancreatic Cancer Who Receive Gemcitabine-Containing Chemotherapy 
Cancer  2012;119(2):285-292.
BACKGROUND
Carbohydrate antigen 19-9 (CA19-9) is a widely used biomarker in pancreatic cancer. There is no consensus on the interpretation of the change in CA19-9 serum levels and its role in the clinical management of patients with pancreatic cancer.
METHODS
Individual patient data from 6 prospective trials evaluating gemcitabine-containing regimens from 3 different institutions were pooled. CA19-9 values were obtained at baseline and after successive cycles of treatment. The objective of this study was to correlate a decline in CA19-9 with outcomes while undergoing treatment.
RESULTS
A total of 212 patients with locally advanced (n = 50) or metastatic (n = 162) adenocarcinoma of the pancreas were included. Median baseline CA19-9 level was 1077 ng/mL (range, 15–492,241 ng/mL). Groups were divided into those levels below (low) or above (high) the median. Median overall survival (mOS) was 8.7 versus 5.2 months (P = .0018) and median time to progression (mTTP) was 5.8 versus 3.7 months (P = .082) in the low versus high groups, respectively. After 2 cycles of chemotherapy, up to a 5% increase versus ≥ 5% increase in CA19-9 levels conferred an improved mOS (10.3 vs 5.1 months, P = .0022) and mTTP (7.5 vs 3.5 months, P = 0.0005).
CONCLUSIONS
In patients who have advanced pancreatic cancer treated with gemcitabine-containing regimens baseline CA19-9 is prognostic for outcome. A decline in CA19-9 after the second cycle of chemotherapy is not predictive of improved mOS or mTTP; thus, CA19-9 decline is not a useful surrogate endpoint in clinical trials. Clinically, a ≥ 5% rise in CA19-9 after 2 cycles of chemotherapy serves as a negative predictive marker.
doi:10.1002/cncr.27734
PMCID: PMC4261189  PMID: 22786786
pancreatic; gemcitabine; carbohydrate antigen 19-9; outcomes; predictive; prognostic
4.  Development of Cymbidium ensifolium genic-SSR markers and their utility in genetic diversity and population structure analysis in cymbidiums 
BMC Genetics  2014;15(1):124.
Background
Cymbidium is a genus of 68 species in the orchid family, with extremely high ornamental value. Marker-assisted selection has proven to be an effective strategy in accelerating plant breeding for many plant species. Analysis of cymbidiums genetic background by molecular markers can be of great value in assisting parental selection and breeding strategy design, however, in plants such as cymbidiums limited genomic resources exist. In order to obtain efficient markers, we deep sequenced the C. ensifolium transcriptome to identify simple sequence repeats derived from gene regions (genic-SSR).
Result
The 7,936 genic-SSR markers were identified. A total of 80 genic-SSRs were selected, and primers were designed according to their flanking sequences. Of the 80 genic-SSR primer sets, 62 were amplified in C. ensifolium successfully, and 55 showed polymorphism when cross-tested among 9 Cymbidium species comprising 59 accessions. Unigenes containing the 62 genic-SSRs were searched against Non-redundant (Nr), Gene Ontology database (GO), eukaryotic orthologous groups (KOGs) and Kyoto Encyclopedia of Genes and Genomes (KEGG) database. The search resulted in 53 matching Nr sequences, of which 39 had GO terms, 18 were assigned to KOGs, and 15 were annotated with KEGG. Genetic diversity and population structure were analyzed based on 55 polymorphic genic-SSR data among 59 accessions. The genetic distance averaged 0.3911, ranging from 0.016 to 0.618. The polymorphic index content (PIC) of 55 polymorphic markers averaged 0.407, ranging from 0.033 to 0.863. A model-based clustering analysis revealed that five genetic groups existed in the collection. Accessions from the same species were typically grouped together; however, C. goeringii accessions did not always form a separate cluster, suggesting that C. goeringii accessions were polyphyletic.
Conclusion
The genic-SSR identified in this study constitute a set of markers that can be applied across multiple Cymbidium species and used for the evaluation of genetic relationships as well as qualitative and quantitative trait mapping studies. Genic-SSR’s coupled with the functional annotations provided by the unigenes will aid in mapping candidate genes of specific function.
Electronic supplementary material
The online version of this article (doi:10.1186/s12863-014-0124-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12863-014-0124-5
PMCID: PMC4276258  PMID: 25481640
Cymbidium ensifolium; Genic-SSR; Genetic diversity; Population structure
5.  Comparative Proteomic Analysis of Labellum and Inner Lateral Petals in Cymbidium ensifolium Flowers 
The labellum in orchids shares homology with the inner lateral petals of the flower. The labellum is a modified petal and often distinguished from other petals and sepals due to its large size and irregular shape. Herein, we combined two-dimensional gel electrophoresis (2-DE) and matrix assisted laser desorption/ionization time of flight/time of flight (MALDI-TOF/TOF) approaches to identify the differentially expressed proteome between labellum and inner lateral petal in one of Orchid species (C. ensifolium). A total of 30 protein spots were identified, which showed more than a two-fold significant difference (p < 0.05) in their expression. Compared with C. ensifolium transcriptome (sequenced in house), 21 proteins matched the translated nucleotide. The proteins identified were classified into 48 categories according to gene ontology (GO). Additionally, these proteins were involved in 18 pathways and 9 possible protein-protein interactions. Serine carboxypeptidase and beta-glucosidase were involved in the phenylpropanoid pathway, which could regulate biosynthesis of floral scent components. Malate dehydrogenase (maeB) and triosephosphate isomerase (TPI) in carbon fixation pathway could regulate the energy metabolism. Xyloglucan endotransglucosylase/hydrolase (XET/XTH) could promote cell wall formation and aid the petal’s morphogenesis. The identification of such differentially expressed proteins provides new targets for future studies; these will assess the proteins’ physiological roles and significance in labellum and inner lateral petals.
doi:10.3390/ijms151119877
PMCID: PMC4264144  PMID: 25365177
labellum; inner lateral petals; orchid; Cymbidium ensifolium; proteome
6.  Transcranial Direct Current Stimulation for the Treatment of Parkinson’s Disease 
Background
Progression of Parkinson’s disease (PD) is characterized by motor deficits, which eventually respond less to dopaminergic therapy and, thus, pose a therapeutic challenge. Deep brain stimulation has proven efficacy, but carries risks and is not possible in all patients. Non-invasive brain stimulation has shown promising results and may provide a therapeutic alternative.
Objective
To investigate the efficacy of transcranial direct current stimulation (tDCS) in the treatment of PD
Design
Randomized, double blind, sham-controlled study.
Setting
Research institution
Methods
We investigated efficacy of anodal tDCS applied to the motor and prefrontal cortices in 8 sessions over 2.5 weeks. Assessment over a 3-month period included timed tests of gait (primary outcome measure) and bradykinesia in the upper extremities, UPDRS, Serial Reaction Time Task, Beck Depression Inventory, Health Survey and self-assessment of mobility.
Results
Twenty-five PD patients were investigated, 13 receiving tDCS and 12 sham stimulation. TDCS improved gait by some measures for a short time and improved bradykinesia in both the on- and off-states for longer than 3 months. Changes in UPDRS, reaction time, physical and mental well-being, and self-assessed mobility did not differ between tDCS and sham intervention.
Conclusion
TDCS of the motor and prefrontal cortices may have therapeutic potential in PD, but better stimulation parameters need to be established to make the technique clinically viable.
doi:10.1136/jnnp.2009.202556
PMCID: PMC4162743  PMID: 20870863
transcranial direct current stimulation (tDCS); non-invasive brain stimulation; therapeutic study; Parkinson’s disease
7.  Pharmacodynamic effects of ivabradine, a negative chronotropic agent, in healthy cats 
Objective
To determine the pharmacodynamic effects of oral ivabradine in cats.
Animals
Eight healthy, adult domestic short hair cats.
Methods
Each cat underwent four study periods of 24 h, receiving either one dose of placebo or ivabradine (0.1 mg/kg, 0.3 mg/kg, and 0.5 mg/kg) in a single-blind randomized crossover study. Clinical tolerance was assessed hourly for the first 8 h, at 12 h, and at the end of the 24-h study period. Heart rate and blood pressure were monitored continuously for 18–24 h via radiotelemetry after each treatment. Response to stress (acoustic startle) was studied before (t = 0) and after treatment (t = 4 h). Statistical comparisons were made using a linear mixed models and 1-way and 2-way repeated measures ANOVA.
Results
Heart rate (min−1) decreased significantly (P < 0.05) in a dose-dependent manner with peak negative chronotropic effects observed 3 h after ivabradine (mean ±SD; placebo, 144 ± 20; ivabradine 0.1 mg/kg, 133 ±22; ivabradine 0.3 mg/kg, 112 ±20; and ivabradine 0.5 mg/kg, 104 ±11). Heart rate (min−1) was still reduced (P < 0.05) 12 h after ivabradine (0.3 mg/kg; 128 ±18 and 0.5 mg/kg; 124 ±16) compared to placebo (141 ±21). The tachycardic response to acoustic startle was significantly (P < 0.01) blunted at all 3 doses of ivabradine. Myocardial oxygen consumption estimated by the rate-pressure product was significantly reduced (P < 0.05) for all doses of ivabradine. No effect of ivabradine on systolic, diastolic, and mean blood pressure was identified and no clinically discernable side effects were observed.
Conclusion
These findings indicate that a single oral dose of ivabradine predictably lowers heart rate, blunts the chronotropic response to stress, and is clinically well tolerated in healthy cats. This makes ivabradine potentially interesting in the treatment of feline heart disease where ischemia is of pathophysiologic importance.
doi:10.1016/j.jvc.2011.06.001
PMCID: PMC4154821  PMID: 22030291
If inhibition; Heart rate; Tachycardia; Feline
8.  Predictive Validity of the Braden Scale for Patients in Intensive Care Units 
Background
Patients in intensive care units are at higher risk for development of pressure ulcers than other patients. In order to prevent pressure ulcers from developing in intensive care patients, risk for development of pressure ulcers must be assessed accurately.
Objectives
To evaluate the predictive validity of the Braden scale for assessing risk for development of pressure ulcers in intensive care patients by using 4 years of data from electronic health records.
Methods
Data from the electronic health records of patients admitted to intensive care units between January 1, 2007, and December 31, 2010, were extracted from the data warehouse of an academic medical center. Predictive validity was measured by using sensitivity, specificity, positive predictive value, and negative predictive value. The receiver operating characteristic curve was generated, and the area under the curve was reported.
Results
A total of 7790 intensive care patients were included in the analysis. A cutoff score of 16 on the Braden scale had a sensitivity of 0.954, specificity of 0.207, positive predictive value of 0.114, and negative predictive value of 0.977. The area under the curve was 0.672 (95% CI, 0.663–0.683). The optimal cutoff for intensive care patients, determined from the receiver operating characteristic curve, was 13.
Conclusions
The Braden scale shows insufficient predictive validity and poor accuracy in discriminating intensive care patients at risk of pressure ulcers developing. The Braden scale may not sufficiently reflect characteristics of intensive care patients. Further research is needed to determine which possibly predictive factors are specific to intensive care units in order to increase the usefulness of the Braden scale for predicting pressure ulcers in intensive care patients.
doi:10.4037/ajcc2013991
PMCID: PMC4042540  PMID: 24186823
9.  The Addition of Radiation to Chemotherapy does not Improve Outcome When Compared to Chemotherapy in the Treatment of Resected Pancreas Cancer: The Results of a Single-Institution Experience 
Annals of surgical oncology  2013;21(3):862-867.
Background
Pancreas cancer is highly lethal even at early stages. Adjuvant therapy with chemotherapy (CT) or chemoradiation (CRT) is standard following surgery to delay recurrence and improve survival. There is no consensus on the added value of radiotherapy (RT). We conducted a retrospective analysis of clinical outcomes in pancreas cancer patients treated with CT or CRT following surgery.
Methods
Patients with resected pancreas adenocarcinoma were identified in our institutional database. Relevant clinicopathologic and demographic data were collected. Patients were grouped according to adjuvant treatment: group A: no treatment; group B: CT; group C: CRT. The primary endpoint of overall survival was compared between groups B vs. C. Univariate and multivariate analyses of potential prognostic factors were conducted including all patients.
Results
A total of 146 evaluable patients were included (group A: n = 33; group B: n = 45; group C: n = 68). Demographics and pathologic characteristics were comparable. There was no significant survival benefit for CRT compared with CT (mOS 16.8 months vs. 21.5 months, respectively, p = 0.76). Local recurrence rates were similar in all three groups. Univariate analyses identified absence of lymph node involvement (hazards ratio [HR] 1.43, p = 0.0082) and administration of adjuvant therapy (HR 0.496, p = 0.0008) as significant predictors for improved survival. Multivariate analyses suggested that patients without nodal involvement derived the most benefit from adjuvant treatment.
Conclusions
The addition of RT to CT did not improve survival over CT. Lymph node involvement predicts inferior clinical outcome.
doi:10.1245/s10434-013-3266-1
PMCID: PMC4041711  PMID: 24046122
10.  CASME II: An Improved Spontaneous Micro-Expression Database and the Baseline Evaluation 
PLoS ONE  2014;9(1):e86041.
A robust automatic micro-expression recognition system would have broad applications in national safety, police interrogation, and clinical diagnosis. Developing such a system requires high quality databases with sufficient training samples which are currently not available. We reviewed the previously developed micro-expression databases and built an improved one (CASME II), with higher temporal resolution (200 fps) and spatial resolution (about 280×340 pixels on facial area). We elicited participants' facial expressions in a well-controlled laboratory environment and proper illumination (such as removing light flickering). Among nearly 3000 facial movements, 247 micro-expressions were selected for the database with action units (AUs) and emotions labeled. For baseline evaluation, LBP-TOP and SVM were employed respectively for feature extraction and classifier with the leave-one-subject-out cross-validation method. The best performance is 63.41% for 5-class classification.
doi:10.1371/journal.pone.0086041
PMCID: PMC3903513  PMID: 24475068
11.  Deep Sequencing-Based Analysis of the Cymbidium ensifolium Floral Transcriptome 
PLoS ONE  2013;8(12):e85480.
Cymbidium ensifolium is a Chinese Cymbidium with an elegant shape, beautiful appearance, and a fragrant aroma. C. ensifolium has a long history of cultivation in China and it has excellent commercial value as a potted plant and cut flower. The development of C. ensifolium genomic resources has been delayed because of its large genome size. Taking advantage of technical and cost improvement of RNA-Seq, we extracted total mRNA from flower buds and mature flowers and obtained a total of 9.52 Gb of filtered nucleotides comprising 98,819,349 filtered reads. The filtered reads were assembled into 101,423 isotigs, representing 51,696 genes. Of the 101,423 isotigs, 41,873 were putative homologs of annotated sequences in the public databases, of which 158 were associated with floral development and 119 were associated with flowering. The isotigs were categorized according to their putative functions. In total, 10,212 of the isotigs were assigned into 25 eukaryotic orthologous groups (KOGs), 41,690 into 58 gene ontology (GO) terms, and 9,830 into 126 Arabidopsis Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and 9,539 isotigs into 123 rice pathways. Comparison of the isotigs with those of the two related orchid species P. equestris and C. sinense showed that 17,906 isotigs are unique to C. ensifolium. In addition, a total of 7,936 SSRs and 16,676 putative SNPs were identified. To our knowledge, this transcriptome database is the first major genomic resource for C. ensifolium and the most comprehensive transcriptomic resource for genus Cymbidium. These sequences provide valuable information for understanding the molecular mechanisms of floral development and flowering. Sequences predicted to be unique to C. ensifolium would provide more insights into C. ensifolium gene diversity. The numerous SNPs and SSRs identified in the present study will contribute to marker development for C. ensifolium.
doi:10.1371/journal.pone.0085480
PMCID: PMC3877369  PMID: 24392013
12.  Electrophysiological biomarkers in spinal muscular atrophy: proof of concept 
Objective
Preclinical therapies that restore survival motor neuron (SMN) protein levels can dramatically extend survival in spinal muscular atrophy (SMA) mouse models. Biomarkers are needed to effectively translate these promising therapies to clinical trials. Our objective was to investigate electrophysiological biomarkers of compound muscle action potential (CMAP), motor unit number estimation (MUNE) and electromyography (EMG) using an SMA mouse model.
Methods
Sciatic CMAP, MUNE, and EMG were obtained in SMNΔ7 mice at ages 3–13 days and at 21 days in mice with SMN selectively reduced in motor neurons (ChATCre). To investigate these measures as biomarkers of treatment response, measurements were obtained in SMNΔ7 mice treated with antisense oligonucleotide (ASO) or gene therapy.
Results
CMAP was significantly reduced in SMNΔ7 mice at days 6–13 (P < 0.01), and MUNE was reduced at days 7–13 (P < 0.01). Fibrillations were present on EMG in SMNΔ7 mice but not controls (P = 0.02). Similar findings were seen at 21 days in ChATCre mice. MUNE in ASO-treated SMNΔ7 mice were similar to controls at day 12 and 30. CMAP reduction persisted in ASO-treated SMNΔ7 mice at day 12 but was corrected at day 30. Similarly, CMAP and MUNE responses were corrected with gene therapy to restore SMN.
Interpretation
These studies confirm features of preserved neuromuscular function in the early postnatal period and subsequent motor unit loss in SMNΔ7 mice. SMN restoring therapies result in preserved MUNE and gradual repair of CMAP responses. This provides preclinical evidence for the utilization of CMAP and MUNE as biomarkers in future SMA clinical trials.
doi:10.1002/acn3.23
PMCID: PMC3914317  PMID: 24511555
13.  Influence of KRAS Mutation Status in Metachronous and Synchronous Metastatic Colorectal Adenocarcinoma 
Cancer  2012;118(24):10.1002/cncr.27666.
BACKGROUND
Mutations in the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) are present in approximately 30% to 40% of colorectal adenocarcinomas. Wild-type (WT) KRAS mutation status is predictive of tumor response with epidermal growth factor receptor-directed therapies, but the results from studies evaluating the prognostic value of KRAS status in localized disease have been contradictory. The prognostic value of KRAS in metastatic disease, specifically according to whether patients have synchronous or metachronous disease at presentation, is less understood.
METHODS
One-hundred ten consecutive patients with metastatic colorectal adenocarcinoma underwent testing for KRAS exon 2 mutations by polymerase chain reaction amplification and direct nucleotide sequencing. The clinical characteristics, treatments, and outcomes of these patients were then analyzed retrospectively, stratified according to whether patients presented with synchronous or metachronous metastasis and according to KRAS mutation status (WT or mutated).
RESULTS
For the entire cohort, the median overall survival from the date of diagnosis of metastatic disease was 34.3 months (95% confidence interval, 28.3–49.4 months) for patients with WT KRAS (n = 70). The median overall survival for patients with mutated KRAS (n = 40) was 40.3 months (95% confidence interval, 27.9–51.1 months; log-rank P = .91). Kaplan-Meier survival analysis indicated that 3-year overall survival and 5-year overall survival were not statistically different. Within the subgroups of patients with synchronous and metachronous metastatic disease, no significant differences were observed in median overall survival, 3-year overall survival, or 5-year overall survival between the WT KRAS and mutated KRAS groups.
CONCLUSIONS
In this study, KRAS mutation status did not influence overall survival in either synchronous or metachronous metastatic colorectal adenocarcinoma and, as such, had no prognostic role in this disease setting.
doi:10.1002/cncr.27666
PMCID: PMC3839285  PMID: 22674181
metastatic colorectal adenocarcinoma; KRAS; mutation; prognosis
14.  Hedgehog Signaling Is a Novel Therapeutic Target in Tamoxifen-Resistant Breast Cancer Aberrantly Activated by PI3K/AKT Pathway 
Cancer research  2012;72(19):10.1158/0008-5472.CAN-12-1248.
Endocrine resistance is a major challenge in the management of estrogen receptor (ER)-positive breast cancers. Although multiple mechanisms leading to endocrine resistance have been proposed, the poor outcome of patients developing resistance to endocrine therapy warrants additional studies. Here we show that noncanonical Hedgehog (Hh) signaling is an alternative growth promoting mechanism that is activated in tamoxifen-resistant tumors. Importantly, phosphoinositide 3-kinase inhibitor/protein kinase B (PI3K/AKT) pathway plays a key role in regulating Hh signaling by protecting key components of this pathway from proteasomal degradation. The levels of Hh-signaling molecules SMO and GLI1 and the targets were significantly elevated in tamoxifen-resistant MCF-7 cells and T47D cells. Serial passage of the resistant cells in mice resulted in aggressive tumors that metastasized to distant organs with concurrent increases in Hh marker expression and epithelial mesenchymal transition. RNAi-mediated depletion of SMO or GLI1 in the resistant cells resulted in reduced proliferation, clonogenic survival and delayed G1–S transition. Notably, treatment of resistant cells with PI3K inhibitors decreased SMO and GLI1 protein levels and activity that was rescued upon blocking GSK3β and proteasomal degradation. Furthermore, treatment of tamoxifen-resistant xenografts with anti-Hh compound GDC-0449 blocked tumor growth in mice. Importantly, high GLI1 expression correlated inversely with disease-free and overall survival in a cohort of 315 patients with breast cancer. In summary, our results describe a signaling event linking PI3K/AKT pathway with Hh signaling that promotes tamoxifen resistance. Targeting Hh pathway alone or in combination with PI3K/AKT pathway could therefore be a novel therapeutic option in treating endocrine-resistant breast cancer.
doi:10.1158/0008-5472.CAN-12-1248
PMCID: PMC3837449  PMID: 22875023
15.  RUPP AUTISM NETWORK RANDOMIZED CLINICAL TRIAL OF PARENT TRAINING AND MEDICATION: ONE-YEAR FOLLOW-UP 
Objective
To follow up on a 3-site 24-week randomized clinical trial (N=124) comparing antipsychotic medication alone (MED) to antipsychotic plus parent training (PT) in behavior management (COMB) for autism spectrum disorders with severe behavior problems. COMB had shown a significant advantage for child behavioral noncompliance (p=.006, d=.34), irritability (p=.01, d=.48), and hyperactivity/noncompliance (p=.04, d=.55), with a lower medication dose.
Method: A year after each participant’s termination we priority-mailed an assessment packet
with a return-addressed envelope; a phone call alerted the family. Failure to return packets within a month elicited recontact and offers to resend.
Results
Eighty-seven of 124 families (70.2%) participated in follow-up. The improvement difference between treatments attenuated from post-treatment to follow-up for noncompliance (d=0.32 to d=0.12) and irritability (d=0.46 to d=0.03). Follow-up differences were nonsignificant. (The noncompliance difference was nonsignificant also at post-treatment for these 87.) 67% of COMB and 53% of MED were still taking risperidone, the original study medication. Most had needed dose adjustments or additional medication, and COMB no longer had a significantly lower dose. All COMB families but only 39% of MED reported seeking PT post-treatment. Daily living skills improvement during treatment predicted noncompliance improvement at follow-up for COMB, but noncompliance deterioration, and especially hyperactivity/noncompliance deterioration for MED-only children.
Conclusions
Study treatment experience/familiarity greatly influenced follow-up treatment: those who had received PT reported seeking it while those who had not experienced it tended not to seek it. The superiority of COMB over MED at post-treatment attenuated by over half at follow-up.
doi:10.1016/j.jaac.2012.08.028
PMCID: PMC3772659  PMID: 23101743
autism; antipsychotic; parent training; follow-up; clinical trial
16.  Pharmacokinetics and Tissue Disposition of Lenalidomide in Mice 
The AAPS Journal  2012;14(4):872-882.
Lenalidomide is a synthetic derivative of thalidomide exhibiting multiple immunomodulatory activities beneficial in the treatment of several hematological malignancies. Murine pharmacokinetic characterization necessary for translational and further preclinical investigations has not been published. Studies herein define mouse plasma pharmacokinetics and tissue distribution after intravenous (IV) bolus administration and bioavailability after oral and intraperitoneal delivery. Range finding studies used lenalidomide concentrations up to 15 mg/kg IV, 22.5 mg/kg intraperitoneal injections (IP), and 45 mg/kg oral gavage (PO). Pharmacokinetic studies evaluated doses of 0.5, 1.5, 5, and 10 mg/kg IV and 0.5 and 10 mg/kg doses for IP and oral routes. Liquid chromatography–tandem mass spectrometry was used to quantify lenalidomide in plasma, brain, lung, liver, heart, kidney, spleen, and muscle. Pharmacokinetic parameters were estimated using noncompartmental and compartmental methods. Doses of 15 mg/kg IV, 22.5 mg/kg IP, and 45 mg/kg PO lenalidomide caused no observable toxicity up to 24 h postdose. We observed dose-dependent kinetics over the evaluated dosing range. Administration of 0.5 and 10 mg/kg resulted in systemic bioavailability ranges of 90–105% and 60–75% via IP and oral routes, respectively. Lenalidomide was detectable in the brain only after IV dosing of 5 and 10 mg/kg. Dose-dependent distribution was also observed in some tissues. High oral bioavailability of lenalidomide in mice is consistent with oral bioavailability in humans. Atypical lenalidomide tissue distribution was observed in spleen and brain. The observed dose-dependent pharmacokinetics should be taken into consideration in translational and preclinical mouse studies.
doi:10.1208/s12248-012-9401-2
PMCID: PMC3475844  PMID: 22956478
bioavailability; distribution; lenalidomide; mouse; pharmacokinetics
17.  Placebo-Controlled Pilot Trial of Mecamylamine for Treatment of Autism Spectrum Disorders 
Abstract
Objective
To explore possible benefits of a nicotinic acetylcholine receptor (nAChR) agent for autistic symptoms based on postmortem observation of nAChR abnormalities (deficient α4β2 nAChRs, excess α7 nAChRs) in brains of patients with autism.
Method
Mecamylamine, because of its safety record in children with other disorders, was chosen for this first exploration. Twenty children with autism spectrum disorder age 4–12 years were randomly assigned for 14 weeks to placebo (n=8) or mecamylamine (n=12) in ascending fixed doses: 0.5 mg/day for 6 weeks, 2.5 mg for 2 weeks, then 5 mg/day for 6 weeks. Improvement was rated by a blinded independent evaluator. Because of small sample, data analysis was descriptive.
Results
Eighteen participants (10 mecamylamine, 8 placebo) completed the study. All doses were well tolerated; the only side effect of note was constipation (50% compared with 25% of placebo group). Three children had clinically nonsignificant electrocardiographic QT prolongation. Both groups showed modest to moderate improvement, but differences between groups were negligible. On the primary outcome measure, the Ohio Autism Clinical Impressions Scale, 90% of the active treatment group showed improvement at some point (but only 40% sustained it), compared with 62% on placebo. Of the four in active treatment that sustained improvement, three had a maximum dose of 0.13–0.15 mg/kg/day, while those who regressed had doses ≥0.18 mg/kg/day. Graphed means suggested better outcome with lower mg/kg and longer medication duration. Four parents spontaneously reported reduced hyperactivity and irritability and better verbalization and continued mecamylamine at their own expense.
Conclusion
Mecamylamine appeared to be safe, but not very effective in autism. The suggestion of better results at lower doses and longer exposure warrants consideration for future trials. The next step would be exploration of a more specific α4β2 nAChR agonist, such as varenicline.
doi:10.1089/cap.2011.0056
PMCID: PMC3417385  PMID: 22537359
18.  Importance of Tissue Morphology Relative to Patient Reports of Symptoms and Functional Limitations Resulting From Median Nerve Pathology 
Significant data exist for the personal, environmental, and occupational risk factors for carpal tunnel syndrome. Few data, however, explain the interrelationship of tissue morphology to these factors among patients with clinical presentation of median nerve pathology. Therefore, our primary objective was to examine the relationship of various risk factors that may be predictive of subjective reports of symptoms or functional deficits accounting for median nerve morphology. Using diagnostic ultrasonography, we observed real-time median nerve morphology among 88 participants with varying reports of symptoms or functional limitations resulting from median nerve pathology. Body mass index, educational level, and nerve morphology were the primary predictive factors. Monitoring median nerve morphology with ultrasonography may provide valuable information for clinicians treating patients with symptoms of median nerve pathology. Sonographic measurements may be a useful clinical tool for improving treatment planning and provision, documenting patient status, or measuring clinical outcomes of prevention and rehabilitation interventions.
doi:10.5014/ajot.2013.005785
PMCID: PMC3654523  PMID: 23245784
carpal tunnel syndrome; median nerve; risk factors; signs and symptoms; tissues; ultrasonography
19.  Screening for Carpal Tunnel Syndrome Using Sonography 
Objectives
The use of sonography in musculoskeletal research and clinical applications is increasing; however, measurement techniques for diagnosing carpal tunnel syndrome with sonography continue to be inconsistent. Novel methods of measurement using internal comparisons to identify swelling of the median nerve require investigation and comparison to currently used techniques.
Methods
The flattening ratio of the median nerve, bowing of the flexor retinaculum, and cross-sectional area of the median nerve were collected in the forearm, at the radio-carpal joint, and at the level of the pisiform in both symptomatic patients and asymptomatic control participants. Electrodiagnostic testing was completed in symptomatic patients as a diagnostic standard.
Results
Median nerve measurements were collected from 166 wrists of symptomatic and asymptomatic participants. The flattening ratio did not show any correlation to electrodiagnostic testing and was identical between both symptomatic and asymptomatic participants. Moderate to strong correlations were noted between electrodiagnostic testing results and sonographic measurements of the cross-sectional area at the pisiform, retinacular bowing, and both the ratio and change of the cross-sectional area between the forearm and pisiform. The area under the curve was large for all receiver operating characteristic curves for each measurement (0.759–0.899), and sensitivity was high (80.4%–82.4%).
Conclusions
Measurement of swelling through a ratio or absolute change had similar diagnostic accuracy as individual measurement of the cross-sectional area within the carpal tunnel. These measures may be useful for improving accuracy in more diverse clinical populations. Further refinement of protocols to identify the largest cross-sectional area within the carpal tunnel region and statistical methods to analyze clustered, multilevel outcome data are recommended to improve diagnostics.
PMCID: PMC3654536  PMID: 22124001
diagnostics; electrodiagnostics; median mononeuropathy; musculoskeletal
20.  Conformational Transition Pathway in the Activation Process of Allosteric Glucokinase 
PLoS ONE  2013;8(2):e55857.
Glucokinase (GK) is a glycolytic enzyme that plays an important role in regulating blood glucose level, thus acting as a potentially attractive target for drug discovery in the treatment of diabetes of the young type 2 and persistent hyperinsulinemic hypoglycemia of infancy. To characterize the activation mechanism of GK from the super-open state (inactive state) to the closed state (active state), a series of conventional molecular dynamics (MD) and targeted MD (TMD) simulations were performed on this enzyme. Conventional MD simulation showed a specific conformational ensemble of GK when the enzyme is inactive. Seven TMD simulations depicted a reliably conformational transition pathway of GK from the inactive state to the active state, and the components important to the conformational change of GK were identified by analyzing the detailed structures of the TMD trajectories. In combination with the inactivation process, our findings showed that the whole conformational pathway for the activation-inactivation-activation of GK is a one-direction circulation, and the active state is less stable than the inactive state in the circulation. Additionally, glucose was demonstrated to gradually modulate its binding pose with the help of residues in the large domain and connecting region of GK during the activation process. Furthermore, the obtained energy barriers were used to explain the preexisting equilibrium and the slow binding kinetic process of the substrate by GK. The simulated results are in accordance with the recent findings from the mutagenesis experiments and kinetic analyses. Our observations reveal a complicated conformational process in the allosteric protein, resulting in new knowledge about the delicate mechanisms for allosteric biological macromolecules that will be useful in drug design for targeting allosteric proteins.
doi:10.1371/journal.pone.0055857
PMCID: PMC3567010  PMID: 23409066
21.  Importance of Tissue Morphology Relative to Patient Reports of Symptoms and Functional Limitations Resulting From Median Nerve Pathology 
Significant data exist for the personal, environmental, and occupational risk factors for carpal tunnel syndrome. Few data, however, explain the interrelationship of tissue morphology to these factors among patients with clinical presentation of median nerve pathology. Therefore, our primary objective was to examine the relationship of various risk factors that may be predictive of subjective reports of symptoms or functional deficits accounting for median nerve morphology. Using diagnostic ultrasonography, we observed real-time median nerve morphology among 88 participants with varying reports of symptoms or functional limitations resulting from median nerve pathology. Body mass index, educational level, and nerve morphology were the primary predictive factors. Monitoring median nerve morphology with ultrasonography may provide valuable information for clinicians treating patients with symptoms of median nerve pathology. Sonographic measurements may be a useful clinical tool for improving treatment planning and provision, documenting patient status, or measuring clinical outcomes of prevention and rehabilitation interventions.
doi:10.5014/ajot.2013.005785
PMCID: PMC3654523  PMID: 23245784
carpal tunnel syndrome; median nerve; risk factors; signs and symptoms; tissues; ultrasonography
22.  Development of Genetic Markers Linked to Straighthead Resistance through Fine Mapping in Rice (Oryza sativa L.) 
PLoS ONE  2012;7(12):e52540.
Straighthead, a physiological disorder characterized by sterile florets and distorted spikelets, causes significant yield losses in rice, and occurs in many countries. The current control method of draining paddies early in the season stresses plants, is costly, and wastes water. Development of resistant cultivar is regarded as the most efficient way for its control. We mapped a QTL for straighthead resistance using two recombinant inbred line (RIL) F9 populations that were phenotyped over two years using monosodium methanearsonate (MSMA) to induce the symptoms. One population of 170 RILs was genotyped with 136 SSRs and the other population of 91 RILs was genotyped with 159 SSRs. A major QTL qSH-8 was identified in an overlapping region in both populations, and explained 46% of total variation in one and 67% in another population for straighthead resistance. qSH-8 was fine mapped from 1.0 Mbp to 340 kb using 7 SSR markers and further mapped to 290 kb in a population between RM22573 and InDel 27 using 4 InDel markers. SSR AP3858-1 and InDel 11 were within the fine mapped region, and co-segregated with straighthead resistance in both RIL populations, as well as in a collection of diverse global accessions. These results demonstrate that AP3858-1 and InDel 11 can be used for marker-assisted selection (MAS) for straighthead resistant cultivars, which is especially important because there is no effective way to directly evaluate straighthead resistance.
doi:10.1371/journal.pone.0052540
PMCID: PMC3532058  PMID: 23285082
23.  Using the conditioned fear stress (CFS) animal model to understand the neurobiological mechanisms and pharmacological treatment of anxiety 
Shanghai Archives of Psychiatry  2012;24(5):241-249.
Summary
The mechanisms underlying the etiology and pathophysiology of anxiety disorders — the most prevalent class of mental disorders — remain unclear. Over the last 30 years investigators have used the animal model of conditioned fear stress (CFS) to investigate the brain structures and neurotransmitter systems involved in aversive emotional learning and memory. Recent studies have focused on the neuronal circuitry and cellular mechanisms of fearful emotional experiences. This review describes the CFS paradigm, discusses the neural circuit and neurotransmission underlying CFS, and explains the mechanism of action of pharmacological treatments of CFS. The focus of the review is on the molecular mechanisms of fear extinction, a phenomenon directly implicated in the clinical treatment of anxiety. Based on our assessment of previous work we will conclude by considering potential molecular targets for treating symptoms of anxiety and fear.
doi:10.3969/j.issn.1002-0829.2012.05.001
PMCID: PMC4198872  PMID: 25328347
24.  The Fusiform Face Area Is Engaged in Holistic, Not Parts-Based, Representation of Faces 
PLoS ONE  2012;7(7):e40390.
Numerous studies with functional magnetic resonance imaging have shown that the fusiform face area (FFA) in the human brain plays a key role in face perception. Recent studies have found that both the featural information of faces (e.g., eyes, nose, and mouth) and the configural information of faces (i.e., spatial relation among features) are encoded in the FFA. However, little is known about whether the featural information is encoded independent of or combined with the configural information in the FFA. Here we used multi-voxel pattern analysis to examine holistic representation of faces in the FFA by correlating spatial patterns of activation with behavioral performance in discriminating face parts with face configurations either present or absent. Behaviorally, the absence of face configurations (versus presence) impaired discrimination of face parts, suggesting a holistic representation in the brain. Neurally, spatial patterns of activation in the FFA were more similar among correct than incorrect trials only when face parts were presented in a veridical face configuration. In contrast, spatial patterns of activation in the occipital face area, as well as the object-selective lateral occipital complex, were more similar among correct than incorrect trials regardless of the presence of veridical face configurations. This finding suggests that in the FFA faces are represented not on the basis of individual parts but in terms of the whole that emerges from the parts.
doi:10.1371/journal.pone.0040390
PMCID: PMC3391267  PMID: 22792301
25.  Phase II trial of rituximab and bortezomib in patients with relapsed or refractory mantle cell and follicular lymphoma 
Cancer  2010;117(11):10.1002/cncr.25792.
Background
In vitro studies in mantle cell lymphoma (MCL) cell lines and patient-derived cells have demonstrated synergistic apoptosis with combined rituximab and bortezomib (R-bortezomib), compared to single agent bortezomib. Therefore, we evaluated R-bortezomib in a preclinical model and in a phase II clinical trial.
Methods
A Hu-MCL-SCID model engrafted with the Jeko cell line was treated with R-bortezomib, bortezomib, or rituximab. Twenty-five patients with relapsed follicular (n=11) and MCL (n=14) received 375 mg/m2 rituximab days 1 and 8 and 1.3-1.5 mg/m2 bortezomib days 1, 4, 8, and 11 every 21 days for a median of 3 cycles (range, 1-5).
Results
R-bortezomib resulted in a statistically significant improvement in overall survival in Hu-MCL-SCID mice. In the clinical trial, the overall response rate (ORR) in 25 patients was 40%, with an ORR of 55% and 29% in patients with follicular and MCL, respectively. The estimated 2-year progression-free survival (PFS) was 24% (95% CI 10%, 53%) in all patients and 60% (95% CI 20%, 85%) in responding patients. Thirteen patients (52%) developed grade 3 neurotoxicity consisting of constipation/ileus, sensory or motor neuropathy, or orthostatic hypotension. Patients heterozygous for the CD32a (Fcγ receptor IIa) 131 histidine (H) to arginine (R) polymorphism had a significantly decreased PFS (p=0.009) after R-bortezomib compared to HH and RR homozygotes.
Conclusion
R-bortezomib has significant activity in patients with relapsed or refractory follicular and MCL, although an unexpectedly high incidence of grade 3 neurologic toxicity is a potential limiting factor with this combination.
doi:10.1002/cncr.25792
PMCID: PMC3116936  PMID: 24048792
rituximab; bortezomib; neuropathy; mantle cell lymphoma; follicular lymphoma

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