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author:("Li, xiaoyan")
1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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
16.  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
17.  Multi-Institutional Phase II Study of Selumetinib in Patients With Metastatic Biliary Cancers 
Journal of Clinical Oncology  2011;29(17):2357-2363.
Purpose
Biliary cancers (BCs) carry a poor prognosis, but targeting the RAS/RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-related kinase (ERK) pathway is of significance. Selumetinib is an inhibitor of MEK1/2, so this trial was designed to determine the safety and efficacy of selumetinib in BC.
Patients and Methods
This was a multi-institutional phase II study of selumetinib at 100 mg given orally twice per day to patients with advanced BC. The primary end point was response rate. All patients were required to provide tissue before enrolling. The levels of phosphorylated ERK (pERK) and AKT (pAKT) were assessed by immunohistochemistry. Tumors were genotyped for the presence of BRAF- and/or RAS-activating mutations.
Results
Twenty-eight eligible patients with a median age of 55.6 years were enrolled. Thirty-nine percent of patients had received one prior systemic therapy. Three patients (12%) had a confirmed objective response. Another 17 patients (68%) experienced stable disease (SD), 14 of whom (56%) experienced prolonged SD (> 16 weeks). Patients gained an average nonfluid weight of 8.6 pounds. Median progression-free survival was 3.7 months (95% CI, 3.5 to 4.9) and median overall survival was 9.8 months (95% CI, 5.97 to not available). Toxicities were mild, with rash (90%) and xerostomia (54%) being most frequent. Only one patient experienced grade 4 toxicity (fatigue). All patients had tissue available for analysis. No BRAF V600E mutations were found. Two patients with short-lived SD had KRAS mutations. Absence of pERK staining was associated with lack of response.
Conclusion
Selumetinib displays interesting activity and acceptable tolerability in patients with metastatic BC. Our results warrant further evaluation of selumetinib in patients with metastatic BC.
doi:10.1200/JCO.2010.33.9473
PMCID: PMC3107751  PMID: 21519026
18.  Allelic Analysis of Sheath Blight Resistance with Association Mapping in Rice 
PLoS ONE  2012;7(3):e32703.
Sheath blight (ShB) caused by the soil-borne pathogen Rhizoctonia solani is one of the most devastating diseases in rice world-wide. Global attention has focused on examining individual mapping populations for quantitative trait loci (QTLs) for ShB resistance, but to date no study has taken advantage of association mapping to examine hundreds of lines for potentially novel QTLs. Our objective was to identify ShB QTLs via association mapping in rice using 217 sub-core entries from the USDA rice core collection, which were phenotyped with a micro-chamber screening method and genotyped with 155 genome-wide markers. Structure analysis divided the mapping panel into five groups, and model comparison revealed that PCA5 with genomic control was the best model for association mapping of ShB. Ten marker loci on seven chromosomes were significantly associated with response to the ShB pathogen. Among multiple alleles in each identified loci, the allele contributing the greatest effect to ShB resistance was named the putative resistant allele. Among 217 entries, entry GSOR 310389 contained the most putative resistant alleles, eight out of ten. The number of putative resistant alleles presented in an entry was highly and significantly correlated with the decrease of ShB rating (r = −0.535) or the increase of ShB resistance. Majority of the resistant entries that contained a large number of the putative resistant alleles belonged to indica, which is consistent with a general observation that most ShB resistant accessions are of indica origin. These findings demonstrate the potential to improve breeding efficiency by using marker-assisted selection to pyramid putative resistant alleles from various loci in a cultivar for enhanced ShB resistance in rice.
doi:10.1371/journal.pone.0032703
PMCID: PMC3299681  PMID: 22427867
19.  Unraveling the Complex Trait of Harvest Index with Association Mapping in Rice (Oryza sativa L.) 
PLoS ONE  2012;7(1):e29350.
Harvest index is a measure of success in partitioning assimilated photosynthate. An improvement of harvest index means an increase in the economic portion of the plant. Our objective was to identify genetic markers associated with harvest index traits using 203 O. sativa accessions. The phenotyping for 14 traits was conducted in both temperate (Arkansas) and subtropical (Texas) climates and the genotyping used 154 SSRs and an indel marker. Heading, plant height and weight, and panicle length had negative correlations, while seed set and grain weight/panicle had positive correlations with harvest index across both locations. Subsequent genetic diversity and population structure analyses identified five groups in this collection, which corresponded to their geographic origins. Model comparisons revealed that different dimensions of principal components analysis (PCA) affected harvest index traits for mapping accuracy, and kinship did not help. In total, 36 markers in Arkansas and 28 markers in Texas were identified to be significantly associated with harvest index traits. Seven and two markers were consistently associated with two or more harvest index correlated traits in Arkansas and Texas, respectively. Additionally, four markers were constitutively identified at both locations, while 32 and 24 markers were identified specifically in Arkansas and Texas, respectively. Allelic analysis of four constitutive markers demonstrated that allele 253 bp of RM431 had significantly greater effect on decreasing plant height, and 390 bp of RM24011 had the greatest effect on decreasing panicle length across both locations. Many of these identified markers are located either nearby or flanking the regions where the QTLs for harvest index have been reported. Thus, the results from this association mapping study complement and enrich the information from linkage-based QTL studies and will be the basis for improving harvest index directly and indirectly in rice.
doi:10.1371/journal.pone.0029350
PMCID: PMC3264563  PMID: 22291889
20.  The treatment of severe child aggression (TOSCA) study: Design challenges 
Background
Polypharmacy (the concurrent use of more than one psychoactive drug) and other combination interventions are increasingly common for treatment of severe psychiatric problems only partly responsive to monotherapy. This practice and research on it raise scientific, clinical, and ethical issues such as additive side effects, interactions, threshold for adding second drug, appropriate target measures, and (for studies) timing of randomization. One challenging area for treatment is severe child aggression. Commonly-used medications, often in combination, include psychostimulants, antipsychotics, mood stabilizers, and alpha-2 agonists, which vary considerably in terms of perceived safety and efficacy.
Results
In designing our NIMH-funded trial of polypharmacy, we focused attention on the added benefit of a second drug (risperidone) to the effect of the first (stimulant). We selected these two drugs because their associated adverse events might neutralize each other (e.g., sleep delay and appetite decrease from stimulant versus sedation and appetite increase from antipsychotic). Moreover, there was considerable evidence of efficacy for each drug individually for the management of ADHD and child aggression. The study sample comprised children (ages 6-12 years) with both diagnosed ADHD and disruptive behavior disorder (oppositional-defiant or conduct disorder) accompanied by severe physical aggression. In a staged sequence, the medication with the least problematic adverse effects (stimulant) was openly titrated in 3 weeks to optimal effect. Participants whose behavioral symptoms were not normalized received additional double-blind medication, either risperidone or placebo, by random assignment. Thus children whose behavioral symptoms were normalized with stimulant medication were not exposed to an antipsychotic. All families participated in an empirically-supported parent training program for disruptive behavior, so that the actual comparison was stimulant+parent training versus stimulant+antipsychotic+parent training.
Conclusions
We hope that the resolutions of the challenges presented here will be useful to other investigators and facilitate much-needed research on child psychiatric polypharmacy.
Trial Registration
ClinicalTrials.gov NCT00796302
doi:10.1186/1753-2000-5-36
PMCID: PMC3231878  PMID: 22074813
ADHD; disruptive behavior disorder; stimulant; risperidone; drug trial
21.  Phase I trial of non-cytotoxic suramin as a modulator of docetaxel and gemcitabine therapy in previously treated patients with non-small cell lung cancer 
Cancer chemotherapy and pharmacology  2010;66(6):1019-1029.
Purpose
In preclinical models, non-cytotoxic suramin (concentrations <50 μM) potentiates the activity of multiple chemotherapeutic agents. The present study evaluated the safety and tolerability of suramin in combination with docetaxel or gemcitabine in previously chemotherapy-treated patients with advanced non-small cell lung cancer.
Methods
Patients received suramin intravenously in combination with either docetaxel on day 1 or gemcitabine on days 1 and 8, of each 21-day treatment cycle. After 3 cycles, patients with partial response (PR) or better continued on the same combination, whereas patients with stable disease (SD) or worse crossed-over to the other combination. Pharmacokinetic analyses were performed before and after each treatment.
Results
Eighteen patients received a total of 79 courses (37 suramin plus docetaxel, 42 suramin plus gemcitabine). The dose-limiting toxicity (DLT) was febrile neutropenia, observed in three of six patients treated with suramin and docetaxel 75 mg/m2. No DLTs were observed with suramin plus docetaxel 56 mg/m2 or suramin plus gemcitabine 1,250 mg/m2. Common adverse events included neutropenia, thrombocytopenia, anemia, fatigue, nausea, vomiting, skin rash, hyperglycemia, and electrolyte abnormalities. The target plasma suramin concentration range of 10–50 μM was achieved in 90% of treatments. Discernable antitumor activity was noted in 11 patients (2 PR, 9 SD).
Conclusions
Non-cytotoxic suramin, in combination with docetaxel 56 mg/m2 or gemcitabine 1,250 mg/m2, was reasonably well-tolerated with a manageable toxicity profile. Target plasma concentrations were correctly predicted by our previously described dosing nomogram. The observed preliminary evidence of antitumor activity encourages evaluation of this strategy in efficacy trials.
doi:10.1007/s00280-010-1252-x
PMCID: PMC2919610  PMID: 20107799
Suramin; Docetaxel; Gemcitabine; Chemosensitizer; Modulator; Non-small cell lung cancer
22.  Prospective evaluation of radiosurgery for hemangioblastomas in von Hippel–Lindau disease 
Neuro-Oncology  2010;12(1):80-86.
To determine the effectiveness of stereotactic radiosurgery (SRS) treatment to central nervous system (CNS) hemangioblastomas in von Hippel–Lindau disease (VHL), we analyzed long-term results in VHL patients treated with SRS. Patients were enrolled in a prospective VHL natural history study, undergoing SRS treatment of CNS hemangioblastomas. Treatment regimens, serial clinical evaluations, and longitudinal imaging data were analyzed. Twenty VHL patients (10 males and 10 females) underwent SRS treatment of 44 CNS hemangioblastomas (39 cerebellar and 5 brainstem). Mean (±SD) age at treatment was 37.5 ± 12.0 years (range: 13–67). Mean follow-up was 8.5 ± 3.2 years (range: 3.0–17.6 years). All patients were alive at last follow-up. Mean treated tumor volume was 0.5 ± 0.7 cm3 (range: 0.01–3.6 cm3). Mean prescription dose was 18.9 Gy (range: 12–24 Gy) at the tumor margin. Local control rate at 2, 5, 10, and 15 years after SRS treatment was 91%, 83%, 61%, and 51%, respectively. Univariate analysis did not identify variables associated (P > .05) with worse tumor control at last follow-up. Thirty-three percent of SRS-treated small (<1.0 cm diameter), asymptomatic tumors progressed over a long-term follow-up. There were no long-term adverse radiation effects. Although SRS treatment of hemangioblastomas in VHL has a low risk for adverse radiation effects, it is associated with diminishing control over a long-term follow-up. These results indicate that SRS should not be used to prophylactically treat asymptomatic tumors and should be reserved for the treatment of tumors that are not surgically resectable.
doi:10.1093/neuonc/nop018
PMCID: PMC2940550  PMID: 20150370
central nervous system hemangioblastoma; radiosurgery; treatment; von Hippel–Lindau disease
23.  Flavopiridol Pharmacogenetics: Clinical and Functional Evidence for the Role of SLCO1B1/OATP1B1 in Flavopiridol Disposition 
PLoS ONE  2010;5(11):e13792.
Background
Flavopiridol is a cyclin-dependent kinase inhibitor in phase II clinical development for treatment of various forms of cancer. When administered with a pharmacokinetically (PK)-directed dosing schedule, flavopiridol exhibited striking activity in patients with refractory chronic lymphocytic leukemia. This study aimed to evaluate pharmacogenetic factors associated with inter-individual variability in pharmacokinetics and outcomes associated with flavopiridol therapy.
Methodology/Principal Findings
Thirty-five patients who received single-agent flavopiridol via the PK-directed schedule were genotyped for 189 polymorphisms in genes encoding 56 drug metabolizing enzymes and transporters. Genotypes were evaluated in univariate and multivariate analyses as covariates in a population PK model. Transport of flavopiridol and its glucuronide metabolite was evaluated in uptake assays in HEK-293 and MDCK-II cells transiently transfected with SLCO1B1. Polymorphisms in ABCC2, ABCG2, UGT1A1, UGT1A9, and SLCO1B1 were found to significantly correlate with flavopiridol PK in univariate analysis. Transport assay results indicated both flavopiridol and flavopiridol-glucuronide are substrates of the SLCO1B1/OATP1B1 transporter. Covariates incorporated into the final population PK model included bilirubin, SLCO1B1 rs11045819 and ABCC2 rs8187710. Associations were also observed between genotype and response. To validate these findings, a second set of data with 51 patients was evaluated, and overall trends for associations between PK and PGx were found to be consistent.
Conclusions/Significance
Polymorphisms in transport genes were found to be associated with flavopiridol disposition and outcomes. Observed clinical associations with SLCO1B1 were functionally validated indicating for the first time its relevance as a transporter of flavopiridol and its glucuronide metabolite. A second 51-patient dataset indicated similar trends between genotype in the SLCO1B1 and other candidate genes, thus providing support for these findings. Further study in larger patient populations will be necessary to fully characterize and validate the clinical impact of polymorphisms in SLCO1B1 and other transporter and metabolizing enzyme genes on outcomes from flavopiridol therapy.
doi:10.1371/journal.pone.0013792
PMCID: PMC2967470  PMID: 21072184
24.  The Part Task of the Part-Spacing Paradigm Is Not a Pure Measurement of Part-Based Information of Faces 
PLoS ONE  2009;4(7):e6239.
Background
Faces are arguably one of the most important object categories encountered by human observers, yet they present one of the most difficult challenges to both the human and artificial visual systems. A variety of experimental paradigms have been developed to study how faces are represented and recognized, among which is the part-spacing paradigm. This paradigm is presumed to characterize the processing of both the featural and configural information of faces, and it has become increasingly popular for testing hypotheses on face specificity and in the diagnosis of face perception in cognitive disorders.
Methodology/Principal Findings
In two experiments we questioned the validity of the part task of this paradigm by showing that, in this task, measuring pure information about face parts is confounded by the effect of face configuration on the perception of those parts. First, we eliminated or reduced contributions from face configuration by either rearranging face parts into a non-face configuration or by removing the low spatial frequencies of face images. We found that face parts were no longer sensitive to inversion, suggesting that the previously reported inversion effect observed in the part task was due in fact to the presence of face configuration. Second, self-reported prosopagnosic patients who were selectively impaired in the holistic processing of faces failed to detect part changes when face configurations were presented. When face configurations were scrambled, however, their performance was as good as that of normal controls.
Conclusions/Significance
In sum, consistent evidence from testing both normal and prosopagnosic subjects suggests the part task of the part-spacing paradigm is not an appropriate task for either measuring how face parts alone are processed or for providing a valid contrast to the spacing task. Therefore, conclusions from previous studies using the part-spacing paradigm may need re-evaluation with proper paradigms.
doi:10.1371/journal.pone.0006239
PMCID: PMC2706049  PMID: 19603077

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