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1.  Phase II Trial of Exemestane in Combination With Fulvestrant in Postmenopausal Women With Advanced, Hormone-Responsive Breast Cancer 
Clinical breast cancer  2012;12(2):151-156.
Exemestane, the irreversible steroidal aromatase inhibitor, and fulvestrant, the pure estrogen antagonist, are active as single drugs in postmenopausal women with advanced hormone-responsive breast cancer. We designed a phase II study with the purpose of determining whether combining these 2 drugs with different and potentially complementary mechanisms of action will improve the clinical benefit.
Patients and Methods
Forty postmenopausal women with hormone-responsive advanced breast cancer received intramuscular injection of fulvestrant 250 mg every 28 days in combination with daily exemestane 25 mg until disease progression. We examined the influence of fulvestrant on exemestane pharmacokinetics and the effect of exemestane and fulvestrant on serum IGF-1 (insulin-like growth factor 1) and IGFBP-3 (IGF-binding protein 3) levels.
The observed proportion of patients free of progressive disease at 6 months after the initiation of treatment with exemestane and fulvestrant was 50%, a rate similar to that achieved with single-agent exemestane or fulvestrant in the first- or second-line setting. Pharmacokinetics parameters showed that coadministration of fulvestrant did not result in clinically relevant changes in exemestane plasma concentrations. A comparison of IGF-1 and IGFBP-3 levels demonstrated the increase of 35% and 12%, respectively, in mean levels from baseline to day 120.
The combination of exemestane and fulvestrant did not improve clinical benefit. The observed lack of improved efficacy was not related to altered drug exposure.
PMCID: PMC5003403  PMID: 22444722
Endocrine therapy; Exemestane; Fulvestrant; IGF-binding protein 3; Insulin-like growth factor; Metastatic breast cancer
2.  Functional Characterization of 9-/13-LOXs in Rice and Silencing Their Expressions to Improve Grain Qualities 
BioMed Research International  2016;2016:4275904.
Lipoxygenases (LOXs) are involved in oxidative rancidity and render rice unsuitable for human consumption. Here, RNA interference- (RNAi-) induced gene expression inhibition was used to analyze the functions of the bran/seed-specific LOXs in rice. r9-LOX1 and L-2 (9-LOX category) were the candidate genes expressing a bran/seed-specific LOX, while RCI-1 was (13-LOX category) a plastid-specific LOX. Real-time PCR showed that three LOXs were cultivar/tissue specific expression on a certain level. r9-LOX1 and L-2 were generally much higher in active bran/seed than in stabilized bran, mature seed, and regenerated plant. RCI-1 was barely expressed in seed. In transgenic lines, r9-LOX1, as well as L-2, expression was dramatically downregulated, compared to the nontransgenic controls. SPME/GC-MS analysis of r9-LOX1 RNAi transgenic lines showed 74.33% decrease in nonanal content (formed during oxidation of linoleic acid by lipoxygenase), but 388.24% increase in acetic acid and 184.84% hexanal (direct products of 13-LOX). These results indicate that r9-LOX1 positively regulates the amount of nonanal but negatively regulates acetic acid and hexanal. The negative regulation may be due to a mechanism of negative feedback between LOX family members. The information will help comprehensively understand the function of the bran/seed-specific LOXs, r9-LOX1, and improve the storage quality in the future.
PMCID: PMC4925972  PMID: 27403427
3.  Comorbid Anxiety and Social Avoidance in Treatment of Severe Childhood Aggression: Response to Adding Risperidone to Stimulant and Parent Training; Mediation of Disruptive Symptom Response 
Objective: In the four-site Treatment of Severe Childhood Aggression (TOSCA) study, addition of risperidone to stimulant and parent training moderately improved parent-rated disruptive behavior disorder (DBD) symptoms. This secondary study explores outcomes other than DBD and attention-deficit/hyperactivity disorder (ADHD) as measured by the Child and Adolescent Symptom Inventory-4R (CASI-4R).
Methods: A total of 168 children ages 6–12 with severe aggression (physical harm), DBD, and ADHD were randomized to parent training plus stimulant plus placebo (basic treatment) or parent training plus stimulant plus risperidone (augmented treatment) for 9 weeks. All received only parent training plus stimulant for the first 3 weeks, then those with room for improvement received a second drug (placebo or risperidone) for 6 weeks. CASI-4R category item means at baseline and week 9 were entered into linear mixed-effects models for repeated measures to evaluate group differences in changes. Mediation of the primary DBD outcome was explored.
Results: Parent ratings were nonsignificant with small/negligible effects, but teacher ratings (n=46 with complete data) showed significant augmented treatment advantage for symptoms of anxiety (p=0.013, d=0.71), schizophrenia spectrum (p=0.017, d=0.45), and impairment in these domains (p=0.02, d=0.26), all remaining significant after false discovery rate correction for multiple tests. Improvement in teacher-rated anxiety significantly (p=0.001) mediated the effect of risperidone augmentation on the primary outcome, the Disruptive-total of the parent-rated Nisonger Child Behavior Rating Form.
Conclusions: Addition of risperidone to parent training plus stimulant improves not only parent-rated DBD as previously reported, but also teacher-rated anxiety–social avoidance. Improvement in anxiety mediates improvement in DBD, suggesting anxiety-driven fight-or-flight disruptive behavior with aggression, with implications for potential treatment strategies. Clinicians should attend to possible anxiety in children presenting with aggression and DBD.
Clinical Trial Registry: Treatment of Severe Childhood Aggression (The TOSCA Study). NCT00796302.
PMCID: PMC4403224  PMID: 25885010
4.  Risperidone Added to Parent Training and Stimulant Medication: Effects on Attention-Deficit/Hyperactivity Disorder, Oppositional Defiant Disorder, Conduct Disorder, and Peer Aggression 
In this study, we aimed to expand on our prior research into the relative efficacy of combining parent training, stimulant medication and placebo (Basic) versus parent training, stimulant, and risperidone (Augmented) therapy by examining treatment effects for attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and conduct disorder (CD) symptoms and peer aggression, symptom-induced—impairment, and informant discrepancy.
Children (6-12 years; N=168) with severe physical aggression, ADHD, and co-occurring ODD/CD received an open trial of parent training and stimulant medication for 3 weeks. Participants failing to show optimal clinical response were randomly assigned to Basic or Augmented therapy for an additional 6 weeks.
Compared with Basic therapy, children receiving Augmented therapy experienced greater reduction in parent-rated ODD severity (p=.02, Cohen's d=0.27) and peer aggression (p=.02, Cohen's d=0.32), but not ADHD or CD symptoms. Fewer children receiving Augmented (16%) than Basic (40%) therapy were rated by their parents as impaired by ODD symptoms at Week 9/endpoint (p=.008). Teacher ratings indicated greater reduction in ADHD severity (p=.02, Cohen's d =0.61) with Augmented therapy, but not for ODD or CD symptoms or peer aggression. Although both interventions were associated with marked symptom reduction, a relatively large percentage of children were rated impaired for at least one targeted disorder at Week 9/endpoint by parents (Basic 47%; Augmented 27%) and teachers (Basic 48%; Augmented 38%).
Augmented was superior to Basic therapy in reducing severity of ADHD and ODD symptoms, peer aggression, and symptom-induced impairment, but clinical improvement was generally context-specific, and effect sizes ranged from small to moderate.
PMCID: PMC4145805  PMID: 25151418
ADHD; risperidone; stimulant drug; aggression; multiple drug therapy
5.  Characterization and comparative profiling of the small RNA transcriptomes in two phases of flowering in Cymbidium ensifolium 
BMC Genomics  2015;16(1):622.
Cymbidium ensifolium is one of the most important ornamental flowers in China, with an elegant shape, beautiful appearance, and a fragrant aroma. Its unique flower shape has long attracted scientists. MicroRNAs (miRNAs) are critical regulators in plant development and physiology, including floral development. However, to date, few studies have examined miRNAs in C. ensifolium.
In this study, we employed Solexa technology to sequence four small RNA libraries from two flowering phases to identify miRNAs related to floral development. We identified 48 mature conserved miRNA and 71 precursors. These conserved miRNA belonged to 20 families. We also identified 45 novel miRNA which includes 21 putative novel miRNAs*, and 28 hairpin forming precursors. Two trans-acting small interfering RNAs (ta-siRNAs) were identified, one of which was homologous to TAS3a1. TAS3a1 belongs to the TAS3 family, which has been previously reported to target auxin response factors (ARF) and be involved in plant growth and floral development. Moreover, we built a C. ensifolium transctriptome database to identify genes targeted by miRNA, which resulted in 790 transcriptomic target unigenes. The target unigenes were annotated with information from the non-redundant (Nr), gene ontology database (GO), eukaryotic orthologous groups (KOGs) and Kyoto encyclopedia of genes and genomes (KEGG) database. The unigenes included MADS-box transcription factors targeted by miR156, miR172 and miR5179, and various hormone responding factors targeted by miR159. The MADS-box transcription factors are well known to determine the identity of flower organs and hormone responding factors involved in floral development. In expression analysis, three novel and four conserved miRNA were differentially expressed between two phases of flowering. The results were confirmed by RNA-seq and qRT-PCR. The differential expression of two miRNA, miR160 and miR396, targeted ARFs and growth regulating factor (GRF), respectively. However, most of these small RNA were clustered in the uncharacterized group, which suggests there may be many novel small non-coding RNAs yet to be discovered.
Our study provides a diverse set of miRNAs related to cymbidium floral development and serves as a useful resource for investigating miRNA-mediated regulatory mechanisms of floral development.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1764-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4546042  PMID: 26289943
7.  Body Mass Index and Pressure Ulcers: Improved Predictability of Pressure Ulcers in Intensive Care Patients 
Obesity contributes to immobility and subsequent pressure on skin surfaces. Knowledge of the relationship between obesity and development of pressure ulcers in intensive care patients will provide better understanding of which patients are at high risk for pressure ulcers and allow more efficient prevention.
To examine the incidence of pressure ulcers in patients who differ in body mass index and to determine whether inclusion of body mass index enhanced use of the Braden scale in the prediction of pressure ulcers.
In this retrospective cohort study, data were collected from the medical records of 4 groups of patients with different body mass index values: underweight, normal weight, obese, and extremely obese. Data included patients’ demographics, body weight, score on the Braden scale, and occurrence of pressure ulcers.
The incidence of pressure ulcers in the underweight, normal weight, obese, and extremely obese groups was 8.6%, 5.5%, 2.8%, and 9.9%, respectively. When both the score on the Braden scale and the body mass index were predictive of pressure ulcers, extremely obese patients were about 2 times more likely to experience an ulcer than were normal weight patients. In the final model, the area under the curve was 0.71. The baseline area under the curve for the Braden scale was 0.68.
Body mass index and incidence of pressure ulcers were related in intensive care patients. Addition of body mass index did not appreciably improve the accuracy of the Braden scale for predicting pressure ulcers.
PMCID: PMC4385001  PMID: 25362673
8.  Electrophysiological Biomarkers in Spinal Muscular Atrophy: Preclinical Proof of Concept 
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.
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.
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.
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
9.  What Does Risperidone Add to Stimulant and Parent Training for Severe Aggression in Child Attention-Deficit/Hyperactivity Disorder? 
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
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.
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.
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);; NCT00796302.
PMCID: PMC3984501  PMID: 24342385
disruptive behavior disorders; parent training; physical aggression; psychostimulants; risperidone
10.  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.
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.
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.
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).
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.
PMCID: PMC4261189  PMID: 22786786
pancreatic; gemcitabine; carbohydrate antigen 19-9; outcomes; predictive; prognostic
11.  Development of Cymbidium ensifolium genic-SSR markers and their utility in genetic diversity and population structure analysis in cymbidiums 
BMC Genetics  2014;15:124.
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).
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.
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.
PMCID: PMC4276258  PMID: 25481640
Cymbidium ensifolium; Genic-SSR; Genetic diversity; Population structure
12.  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.
PMCID: PMC4264144  PMID: 25365177
labellum; inner lateral petals; orchid; Cymbidium ensifolium; proteome
13.  Transcranial Direct Current Stimulation for the Treatment of Parkinson’s Disease 
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.
To investigate the efficacy of transcranial direct current stimulation (tDCS) in the treatment of PD
Randomized, double blind, sham-controlled study.
Research institution
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.
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.
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.
PMCID: PMC4162743  PMID: 20870863
transcranial direct current stimulation (tDCS); non-invasive brain stimulation; therapeutic study; Parkinson’s disease
14.  Pharmacodynamic effects of ivabradine, a negative chronotropic agent, in healthy cats 
To determine the pharmacodynamic effects of oral ivabradine in cats.
Eight healthy, adult domestic short hair cats.
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.
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.
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.
PMCID: PMC4154821  PMID: 22030291
If inhibition; Heart rate; Tachycardia; Feline
15.  Predictive Validity of the Braden Scale for Patients in Intensive Care Units 
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.
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.
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.
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.
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.
PMCID: PMC4042540  PMID: 24186823
16.  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.
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.
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.
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.
The addition of RT to CT did not improve survival over CT. Lymph node involvement predicts inferior clinical outcome.
PMCID: PMC4041711  PMID: 24046122
17.  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.
PMCID: PMC3903513  PMID: 24475068
18.  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.
PMCID: PMC3877369  PMID: 24392013
19.  Electrophysiological biomarkers in spinal muscular atrophy: proof of concept 
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.
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.
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.
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
20.  Influence of KRAS Mutation Status in Metachronous and Synchronous Metastatic Colorectal Adenocarcinoma 
Cancer  2012;118(24):10.1002/cncr.27666.
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.
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).
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.
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.
PMCID: PMC3839285  PMID: 22674181
metastatic colorectal adenocarcinoma; KRAS; mutation; prognosis
21.  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.
PMCID: PMC3837449  PMID: 22875023
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.
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.
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.
PMCID: PMC3772659  PMID: 23101743
autism; antipsychotic; parent training; follow-up; clinical trial
23.  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.
PMCID: PMC3475844  PMID: 22956478
bioavailability; distribution; lenalidomide; mouse; pharmacokinetics
24.  Placebo-Controlled Pilot Trial of Mecamylamine for Treatment of Autism Spectrum Disorders 
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.
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.
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.
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.
PMCID: PMC3417385  PMID: 22537359
25.  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.
PMCID: PMC3654523  PMID: 23245784
carpal tunnel syndrome; median nerve; risk factors; signs and symptoms; tissues; ultrasonography

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