bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of cross-linked aggregates from purified Bacillus subtilislevansucrase mutants for transfructosylation reactions
Authors: Ortiz-Soto Maria Elena , Rudiño-Piñera Enrique , Rodriguez-Alegria Maria Elena , Munguia Agustin Lopez
Published: July 2009

Background

Increasing attention has been focused on inulin and levan-type oligosaccharides, including fructosyl-xylosides and other fructosides due to their nutraceutical properties. Bacillus subtilis levansucrase (LS) catalyzes the synthesis of levan from sucrose, but it may also transfer the fructosyl moiety from sucrose to acceptor molecules included in the reaction medium. To study transfructosylation reactions with highly active and robust derivatives, cross-linked enzyme aggregates (CLEAs) were prepared from wild LS and two mutants. CLEAs combine the catalytic features of pure protein preparations in terms of specific activity with the mechanical behavior of industrial biocatalysts.

Results

Two types of procedures were used for the preparation of biocatalysts from purified wild type LS (WT LS) B. subtilis and the R360K and Y429N LS mutants: purified enzymes aggregated with glutaraldehyde (cross-linked enzyme aggregates: CLEAs), and covalently immobilized enzymes in Eupergit C®. The biocatalysts were characterized and used for fructoside synthesis using xylose as an acceptor model. CLEAs were able to catalyze the synthesis of fructosides as efficiently as soluble enzymes. The specific activity of CLEAs prepared from wild type LS (44.9 U/mg of CLEA), R360K (56.5 U/mg of CLEA) and Y429N (1.2 U/mg of CLEA) mutants were approximately 70, 40 and 200-fold higher, respectively, than equivalent Eupergit C® immobilized enzyme preparations (U/mg of Eupergit), where units refer to global LS activity. In contrast, the specific activity of the free enzymes was 160, 171.2 and 1.5 U/mg of protein, respectively. Moreover, all CLEAs had higher thermal stability than corresponding soluble enzymes. In the long term, the operational stability was affected by levan synthesis.

Conclusion

This is the first report of cross-linked transglycosidases aggregates. CLEAs prepared from purified LS and mutants have the highest specific activity for immobilized fructosyltransferases (FTFs) reported in the literature. CLEAs from R360K and Y429N LS mutants were particularly suitable for fructosyl-xyloside synthesis as the absence of levan synthesis decreases diffusion limitation and increases operational stability.
Efficient generation of long-distance conditional alleles using recombineering and a dual selection strategy in replicate plates
Authors: Voehringer David , Wu Davina , Liang Hong-Erh , Locksley Richard M
Published: July 2009

Background

Conditional knockout mice are a useful tool to study the function of gene products in a tissue-specific or inducible manner. Classical approaches to generate targeting vectors for conditional alleles are often limited by the availability of suitable restriction sites. Furthermore, plasmid-based targeting vectors can only cover a few kB of DNA which precludes the generation of targeting vectors where the two loxP sites are placed far apart. These limitations have been overcome in the recent past by using homologous recombination of bacterial artificial chromosomes (BACs) in Escherichia coli to produce large targeting vector containing two different loxP-flanked selection cassettes so that a single targeting event is sufficient to introduce loxP-sites a great distances into the mouse genome. However, the final targeted allele should be free of selection cassettes and screening for correct removal of selection cassettes can be a laborious task. Therefore, we developed a new strategy to rapidly identify ES cells containing the desired allele.

Results

Using BAC recombineering we generated a single targeting vector which contained two different selection cassettes that were flanked by loxP-loxP sites or by FRT-FRT/loxP sites so that they could be deleted sequentially by Cre- and FLPe-recombinases, respectively. Transfected ES cells were first selected in the presence of both antibiotics in vitro before correctly targeted clones were identified by Southern blot. After transfection of a Cre recombinase expression plasmid ES cell clones were selected on replicate plates to identify those clones which maintained the FRT-FRT/loxP flanked cassette and lost the loxP-loxP flanked cassette. Using this strategy facilitated the identification of ES cell clones containing the desired allele before blastocyst injection.

Conclusion

The strategy of ES cell cultures in replicate plates proved to be very efficient in identifying ES cells that had undergone the correct recombination event. This approach facilitates the generation of conditional knock-out mice when large parts of the genome are intended to be flanked by loxP sites.
Protonated nanostructured aluminosilicate (NSAS) reduces plasma cholesterol concentrations and atherosclerotic lesions in Apolipoprotein E deficient mice fed a high cholesterol and high fat diet
Authors: Sivak Olena , Darlington Jerry , Gershkovich Pavel , Constantinides Panayiotis P , Wasan Kishor M
Published: July 2009

The aim of this work was to assess the effect of chronic administration of protonated nanostructured aluminosilicate (NSAS) on the plasma cholesterol levels and development of atherosclerotic lesions in Apolipoprotein (ApoE) deficient mice fed a high cholesterol and high fat diet. Apolipoprotein E (ApoE) deficient mice were divided into the following treatment groups: protonated NSAS 1.4% (w/w), untreated control and 2% (w/w) stigmastanol mixed with high-cholesterol/high-fat diet. Animals were treated for 12 weeks, blood samples were withdrawn every 4 weeks for determination of plasma cholesterol and triglyceride levels. At the end of the study the aortic roots were harvested for assessment of atherosclerotic lesions. NSAS at 1.4% (w/w) and stigmastanol at 2% (w/w) treatment groups showed significant decreases in plasma cholesterol concentrations at all time points relative to the control animals. The lesion sum area in 1.4% (w/w) NSAS and 2% (w/w) stigmastanol groups were significantly less from the control animals. In conclusion, in this study, the effectiveness of chronic administration of protonated NSAS material in the reduction of plasma cholesterol levels and decrease in development of atherosclerotic lesions was demonstrated in Apo-E deficient mice model.
Mycophenolate pharmacokinetics and pharmacodynamics in belatacept treated renal allograft recipients – a pilot study
Authors: Bremer Sara , Vethe Nils T , Rootwelt Helge , Jørgensen Pål F , Stenstrøm Jean , Holdaas Hallvard , Midtvedt Karsten , Bergan Stein
Published: July 2009

Background

Mycophenolic acid (MPA) is widely used as part of immunosuppressive regimens following allograft transplantation. The large pharmacokinetic (PK) and pharmacodynamic (PD) variability and narrow therapeutic range of MPA provide a potential for therapeutic drug monitoring. The objective of this pilot study was to investigate the MPA PK and PD relation in combination with belatacept (2ndgeneration CTLA4-Ig) or cyclosporine (CsA).

Methods

Seven renal allograft recipients were randomized to either belatacept (n = 4) or cyclosporine (n = 3) based immunosuppression. Samples for MPA PK and PD evaluations were collected predose and at 1, 2 and 13 weeks posttransplant. Plasma concentrations of MPA were determined by HPLC-UV. Activity of inosine monophosphate dehydrogenase (IMPDH) and the expressions of twoIMPDHisoforms were measured in CD4+ cells by HPLC-UV and real-time reverse-transcription PCR, respectively. Subsets of T cells were characterized by flow cytometry.

Results

The MPA exposure tended to be higher among belatacept patients than in CsA patients at week 1 (P = 0.057). Further, MPA concentrations (AUC0–9 hand C0) increased with time in both groups and were higher at week 13 than at week 2 (P = 0.031, n = 6). In contrast to the postdose reductions of IMPDH activity observed early posttransplant, IMPDH activity within both treatment groups was elevated throughout the dosing interval at week 13. Transient postdose increments were also observed forIMPDH1expression, starting at week 1. Higher MPA exposure was associated with larger elevations ofIMPDH1(r = 0.81, P = 0.023, n = 7 for MPA andIMPDH1AUC0–9 hat week 1). The maximumIMPDH1expression was 52 (13–177)% higher at week 13 compared to week 1 (P = 0.031, n = 6). One patient showed lower MPA exposure with time and did neither display elevations of IMPDH activity norIMPDH1expression. No difference was observed in T cell subsets between treatment groups.

Conclusion

The significant influence of MPA onIMPDH1expression, possibly mediated through reduced guanine nucleotide levels, could explain the elevations of IMPDH activity within dosing intervals at week 13. The present regulation of IMPDH in CD4+ cells should be considered when interpreting measurements of IMPDH inhibition.
RADAR – A ra ndomised, multi-centre, prospective study comparing best medical treatment versus best medical treatment plus renal artery stenting in patients with haemod ynamically relevant atherosclerotic renal ar tery stenosis
Authors: Schwarzwälder Uwe , Hauk Michael , Zeller Thomas
Published: July 2009

Background

Prospective, international, multi-centre, randomised (1:1) trial to evaluate the clinical impact of percutaneous transluminal renal artery stenting (PTRAS) on the impaired renal function measured by the estimated glomerular filtration rate (eGFR) in patients with haemodynamically significant atherosclerotic renal artery stenosis.

Methods

Patients will be randomised to receive either PTRAS using the Dynamic Renal Stent system plus best medical treatment or best medical treatment. Renal stenting will be performed under angiographic imaging. For patients randomised to best medical treatment the degree of stenosis measured by renal duplex sonography (RDS) will be confirmed by MR angio or multi-slice CT where possible. Best medical treatment will be initiated at randomisation or post procedure (for PTRAS arm only), and adjusted as needed at all visits. Best medical treatment is defined as optimal drug therapy for control of the major risk factors (blood pressure ≤ 125/80 mmHg, LDL cholesterol ≤ 100 mg/dL, HbA1c ≤ 6.5%). Data recordings include serum creatinine values, eGFR, brain natriuretic peptide, patients' medical history and concomitant medication, clinical events, quality of life questionnaire (SF-12v2™), 24 hour ambulatory blood pressure measurement, renal artery duplex ultrasound and echocardiography. Follow-up intervals are at 2, 6, 12 and 36 months following randomisation.

The primary endpoint is the difference between treatments in change of eGFR over 12 months. Major secondary endpoints are technical success, change of renal function based on the eGFR slope change between pre-treatment and post-treatment (i.e. improvement, stabilisation, failure), clinical events overall such as renal or cardiac death, stroke, myocardial infarction, hospitalisation for congestive heart failure, progressive renal insufficiency (i.e. need for dialysis), need of target vessel revascularisation or target lesion revascularisation, change in average systolic and diastolic blood pressure, change in left ventricular mass index calculated from echocardiography, difference in the size of kidney (pole to pole length) measured by renal duplex sonography, total number, drug name, drug class, daily dose, regimen and Defined Daily Dose (DDD), of anti-hypertensive drugs, and change in New York Heart Association (NYHA) classification. Approximately 30 centres in Europe and South America will enrol patients. Duration of enrolment is expected to be 12 months resulting in study duration of 48 months.

Trial registration

Trial registration number: NCT00640406
Two levels above and one level below pedicle screw fixation for the treatment of unstable thoracolumbar fracture with partial or intact neurology
Authors: Modi Hitesh N , Chung Kook Jin , Seo Il Woo , Yoon Hoi Soo , Hwang Ji Hyo , Kim Hong Kyun , Noh Kyu Cheol , Yoo Jung Han
Published: July 2009

Background

Treatment of unstable thoracolumbar fractures is controversial regarding short or long segment pedicle screw fixation. Although long level fixation is better, it can decrease one motion segment distally, thus increasing load to lower discs.

Methods

We retrospectively analyzed 31 unstable thoracolumbar fractures with partial or intact neurology. All patients were operated with posterior approach using pedicle screws fixed two levels above and one level below the fracture vertebra. No laminectomy, discectomy or decompression procedure was done. Posterior fusion was achieved in all. Post operative and at final follow-up radiological evaluation was done by measuring the correction and maintenance of kyphotic angle at thoracolumbar junction. Complications were also reported including implant failure.

Results

Average follow-up was 34 months. All patients had full recovery at final follow-up. Average kyphosis was improved from 26.7° to 4.1° postoperatively and to 6.3° at final follow-up. And mean pain scale was improved from 7.5 to 3.9 postoperatively and to 1.6 at final follow-up, All patients resumed their activity within six months. Only 4 (12%) complications were noted including only one hardware failure.

Conclusion

Two levels above and one level below pedicle screw fixation in unstable thoracolumbar burst fracture is useful to prevent progressive kyphosis and preserves one motion segment distally.
Construction of an MUC-1 promoter driven, conditionally replicating adenovirus that expresses the sodium iodide symporter for gene therapy of breast cancer
Authors: Trujillo Miguel A , Oneal Michael J , Davydova Julia , Bergert Elizabeth , Yamamoto Masato , Morris John C
Published: July 2009

Introduction

The sodium iodide symporter (NIS) directs the uptake and concentration of iodide in thyroid cells. This in turn allows radioiodine imaging and therapy for thyroid cancer. To extend the use of NIS-mediated radioiodine therapy to other types of cancer, we successfully transferred and expressed the sodium-iodide symporter (NIS) gene in prostate, colon, and breast cancer cells both in vivo and in vitro by using non-replicating adenoviral vectors.

Methods

To improve virotherapy efficiency, we developed a conditionally replicating adenovirus (CRAd) in which the transcriptional cassette RSV promoter-human NIScDNA-bGH polyA was also inserted at the E3 region. The E1a gene is driven by the tumor-specific promoter MUC-1 in the CRAd Ad5AMUCH_RSV-NIS.

Results

In vitro infection of the MUC-1-positive breast cell line T47D resulted in virus replication, cytolysis, and release of infective viral particles. Conversely, the MUC-1-negative breast cancer cell line MDA-MB-231 was refractory to the viral cytopathic effect and did not support viral replication. The data indicate that Ad5AMUCH_RSV-NIS activity is stringently restricted to MUC-1-positive cancer cells. Radioiodine uptake was readily measurable in T47 cells infected with Ad5AMUCH_RSV-NIS 24 hours after infection, thus confirming NIS expression before viral-induced cell death.

Conclusions

This construct may allow multimodal therapy, combining virotherapy with radioiodine therapy to be developed as a novel treatment for breast and other MUC1-overexpressing cancers.
Translocation of bacterial NOD2 agonist and its link with inflammation
Authors: Kim Oh Yoen , Monsel Antoine , Bertrand Michèle , Cavaillon Jean-Marc , Coriat Pierre , Adib-Conquy Minou
Published: July 2009

Introduction

The gut is often considered as the motor of critical illness through bacterial translocation, which amplifies the inflammatory response and alters the immune status. However, systemic bacterial translocation was rarely proven and endotoxin measurement only reflects translocation of Gram-negative-derived products. The process could be more frequently identified if peptidoglycan, derived from both Gram-negative and Gram-positive bacteria, was measured.

Methods

We developed a new tool to detect circulating peptidoglycan-like structure using a NOD2-transfected cell line. We also measured plasma and cell-associated endotoxin and different plasma markers of inflammation. We studied 21 patients undergoing abdominal aortic surgery (AAS), and 21 patients undergoing carotid artery surgery (CAS) were included as negative controls. Patients were sampled during surgery until two days post-surgery.

Results

In 90.5% of the AAS patients, a NOD2 agonist peak was detected in plasma before aortic clamping, but after gut manipulation by the surgeon, and persisted after blood reperfusion. As expected, no peak was detected in plasma from CAS patients (P = 0.003). Leukocyte-bound endotoxin appeared after blood reperfusion in 71% of the AAS patients, and circulating endotoxin was detected for 57% of them. The levels of interleukin (IL)-6, IL-10 and of inflammatory markers (C-reactive protein, procalcitonin) were maximal at postoperative day 1 or 2 in AAS patients. The levels of circulating NOD2 agonist positively correlated with those of cortisol and IL-10.

Conclusions

The measurement of circulating NOD2 agonist gives a higher informative tool than that of circulating endotoxin for early and sensitive detection of the translocation of bacterial products. The data suggest that circulating NOD2 agonist contributes to further enhance the stress response following surgery.
Comparison of monitoring performance of Bioreactance vs. pulse contour during lung recruitment maneuvers
Authors: Squara Pierre , Rotcajg Dominique , Denjean Dominique , Estagnasie Philippe , Brusset Alain
Published: July 2009

Introduction

This study was designed to test the hypothesis of equivalence in cardiac output (CO) and stroke volume (SV) monitoring capabilities of two devices: non invasive transthoracic bioreactance (NICOM), and a pulse contour analysis (PICCO PC) coupled to transpulmonary thermodilution (PICCO TD).

Methods

We included consecutive patients of a single ICU following cardiac surgery. Continuous minute-by-minute hemodynamic variables obtained from NICOM and PICCO PC were recorded and compared in 20 patients at baseline, during a lung recruitment maneuver (20 cmH2O of PEEP) and following withdrawal of PEEP. PICCO TD measurements were also determined. We evaluated the accuracy of these two technologies at baseline using PICCO TD as reference and we estimated the precision by the fluctuation around the mean value (2SD/mean). Then, we assessed time response, amplitude response and reliability for detecting expected decreases when PEEP was applied. Type I and type II errors were analyzed.

Results

CO values (PICCO TD) ranged from 1.6 to 8.0 L.min-1. At baseline, CO values were comparable for NICOM, PICCO PC and PICCO TD: 5.0 ± 1.2, 4.7 ± 1.4 and 4.6 ± 1.3 L.min.-1, respectively (NS). Limits of agreements with PICCO TD were 1.52 L.min.-1 for NICOM and 1.77 L.min.-1 for PICCO PC, NS. The 95% statistical power gives an equivalence with a threshold of 0.52 L.min.-1 for NICOM vs. PICCO PC. The CO precision was 6 ± 3% and 6 ± 5% for NICOM and PICCO PC, respectively, NS. When PEEP was applied, CO was reduced by 33 ± 12%, 31 ± 14% and 32 ± 13%, for NICOM, PICCO PC and PICCO TD, respectively (NS). Time response was 3.2 ± 0.7 minute for NICOM vs. 2 ± 0.5 minute for PICCO PC (NS). SV results were comparable to those for CO.

Conclusions

Although limited to 20 patients, this study has enough power to show comparable CO and SV monitoring capabilities of Bioreactance and pulse contour analysis calibrated by transpulmonary thermodilution.
Late Pelvic Toxicity After Bladder-Sparing Therapy in Patients With Invasive Bladder Cancer: RTOG 89-03, 95-06, 97-06, 99-06
Authors: Efstathiou Jason A. , Bae Kyounghwa , Shipley William U. , Kaufman Donald S. , Hagan Michael P. , Heney Niall M. , Sandler Howard M.
Published: July 2009

Purpose

In selected patients with muscle-invasive bladder cancer, combined-modality therapy (transurethral resection bladder tumor [TURBT], radiation therapy, chemotherapy) with salvage cystectomy, if necessary, can achieve survival rates similar to radical cystectomy. We investigated late pelvic toxicity after chemoradiotherapy for patients treated on prospective protocols.

Patients and Methods

Between 1990 and 2002, 285 eligible patients enrolled on four prospective protocols (Radiation Therapy Oncology Group [RTOG] 8903, 9506, 9706, 9906) and 157 underwent combined-modality therapy, surviving ≥ 2 years from start of treatment with their bladder intact. Rates of late genitourinary (GU) and GI toxicity were assessed using the RTOG Late Radiation Morbidity Schema, with worst toxicity grade (scale 0 to 5) occurring ≥ 180 days after start of consolidation therapy reported for each patient. Persistence of toxicity was defined as grade 3+ toxicity not decreasing by at least one grade. Logistic and Cox regression analyses were performed to evaluate relationship between clinical characteristics, frequency, and time to late grade 3+ pelvic toxicity. Covariates included age, sex, stage, presence of carcinoma in situ, completeness of TURBT, and protocol.

Results

Median follow-up was 5.4 years (range, 2.0 to 13.2 years). Seven percent of patients experienced late grade 3+ pelvic toxicity: 5.7% GU and 1.9% GI. In only one of nine patients did a grade 3+ GU toxicity persist. Notably there were no late grade 4 toxicities and no treatment-related deaths. None of the clinical variables studied predicted for late grade 3+ pelvic toxicity.

Conclusion

Rates of significant late pelvic toxicity for patients completing combined-modality therapy for invasive bladder cancer and retaining their native bladder are low.
Model-Based Prediction of Phase III Overall Survival in Colorectal Cancer on the Basis of Phase II Tumor Dynamics
Authors: Claret Laurent , Girard Pascal , Hoff Paulo M. , Van Cutsem Eric , Zuideveld Klaas P. , Jorga Karin , Fagerberg Jan , Bruno René
Published: July 2009

Purpose

We developed a drug-disease simulation model to predict antitumor response and overall survival in phase III studies from longitudinal tumor size data in phase II trials.

Methods

We developed a longitudinal exposure-response tumor-growth inhibition (TGI) model of drug effect (and resistance) using phase II data of capecitabine (n = 34) and historical phase III data of fluorouracil (FU; n = 252) in colorectal cancer (CRC); and we developed a parametric survival model that related change in tumor size and patient characteristics to survival time using historical phase III data (n = 245). The models were validated in simulation of antitumor response and survival in an independent phase III study (n = 1,000 replicates) of capecitabine versus FU in CRC.

Results

The TGI model provided a good fit of longitudinal tumor size data. A lognormal distribution best described the survival time, and baseline tumor size and change in tumor size from baseline at week 7 were predictors (P < .00001). Predicted change of tumor size and survival time distributions in the phase III study for both capecitabine and FU were consistent with observed values, for example, 431 days (90% prediction interval, 362 to 514 days) versus 401 days observed for survival in the capecitabine arm. A modest survival improvement of 39 days (90% prediction interval, −21 to 110 days) versus 35 days observed was predicted for capecitabine.

Conclusion

The modeling framework successfully predicted survival in a phase III trial on the basis of capecitabine phase II data in CRC. It is a useful tool to support end-of-phase II decisions and design of phase III studies.
Final Results of Sequential Doxorubicin Plus Gemcitabine and Ifosfamide, Paclitaxel, and Cisplatin Chemotherapy in Patients With Metastatic or Locally Advanced Transitional Cell Carcinoma of the Urothelium
Authors: Milowsky Matthew I. , Nanus David M. , Maluf Fernando C. , Mironov Svetlana , Shi Weiji , Iasonos Alexia , Riches Jamie , Regazzi Ashley , Bajorin Dean F.
Published: July 2009

Purpose

Sequential chemotherapy with doxorubicin and gemcitabine (AG) followed by ifosfamide, paclitaxel, and cisplatin (ITP) was previously demonstrated to be well tolerated in patients with advanced transitional cell carcinoma (TCC). This study sought to evaluate the efficacy and to additionally define toxicity.

Patients and Methods

Sixty patients with advanced TCC received AG every 2 weeks for five or six cycles followed by ITP every 21 days for four cycles. Granulocyte colony-stimulating factor was given between cycles.

Results

Myelosuppression was seen with 68% of patients who experienced grades 3 to 4 neutropenia and with 25% who experienced febrile neutropenia. Grade 3 or greater nonhematologic toxicities were infrequent. Forty (73%) of 55 evaluable patients (95% CI, 59% to 84%) demonstrated a major response (complete, n = 19; partial, n = 21) and had a median response duration of 11.3 months (range, 1.7 to ≥ 105.6 months). Twenty-seven (79%) of 34 patients with locally advanced disease (ie, T4, N0, M0) or with regional lymph node involvement (ie, T3-4, N1, M0) and 10 (56%) of 18 patients with distant metastases achieved a major response. The median progression-free survival was 12.1 months (95% CI, 9.0 to 14.8 months), and the median overall survival was 16.4 months (95% CI, 14.0 to 22.5 months). At a median follow-up of 76.4 months, seven (11.7%) patients remain alive, and all were disease free.

Conclusion

AG plus ITP is an active regimen in previously untreated patients with advanced TCC; however, it is associated with toxicity and does not clearly offer a benefit compared with other nonsequential, cisplatin-based regimens.
Phase II, Randomized, Double-Blind, Placebo-Controlled Study of Recombinant Human Intestinal Trefoil Factor Oral Spray for Prevention of Oral Mucositis in Patients With Colorectal Cancer Who Are Receiving Fluorouracil-Based Chemotherapy
Authors: Peterson Douglas E. , Barker Nicholas P. , Akhmadullina Lilia I. , Rodionova Irina , Sherman Nailya Z. , Davidenko Irina S. , Rakovskaya Galina N. , Gotovkin Eugeny A. , Shinkarev Sergey A. , Kopp Mikhail V. , Kulikov Eugeny P. , Moiseyenko Vladimir M. , Gertner Joseph M. , Firsov Igor , Tuleneva Tamara , Yarosh Alexander , Woon Chee-Wai
Published: July 2009

Purpose

This study evaluated the safety and efficacy of recombinant human intestinal trefoil factor (rhITF) administered as topical oral spray for prevention and treatment of chemotherapy-induced oral mucositis (OM).

Patients and Methods

Ninety-nine patients with colorectal cancer who had moderate to severe OM (WHO grade ≥ 2) in the first cycle of chemotherapy were randomly assigned to receive either placebo, rhITF 10 mg/mL (ie, low dose), or rhITF 80 mg/mL (ie, high dose) by oral spray (300 μL, eight times each day) for 14 consecutive days in the second chemotherapy cycle. Patients were assessed on days 1, 3, 5, 7, 10, 12, 14, and 21 (± 2 days for the last assessment) for safety and for OM incidence and severity.

Results

Treatment of patients at high risk for developing OM with low- or high-dose rhITF significantly reduced the amount of incidence (75% to 81%; low-dose rhITF P < .001; high-dose rhITF P = .002). Frequencies of WHO grade ≥ 2 OM in the placebo, low-dose rhITF, and high-dose rhITF groups were 48.5%, 9.1%, and 12.1%, respectively. Assessment of the area under the curve revealed statistically significant reductions in OM severity in the rhITF-treated groups versus placebo. Only a minority of patients (6.1%) reported treatment-emergent adverse events (TEAEs), all of which were mild to moderate in intensity and resolved without sequelae. The incidence of TEAEs was not significantly different among treatment groups.

Conclusion

rhITF oral spray formulation was safe and effective when used for the reduction of chemotherapy-associated OM in patients with colorectal cancer. Patients exhibited high compliance in dosing administration. Future clinical study is planned to develop this drug for use in OM management in patients with cancer.
Phase II Study of High-Dose [131I]Metaiodobenzylguanidine Therapy for Patients With Metastatic Pheochromocytoma and Paraganglioma
Authors: Gonias Sara , Goldsby Robert , Matthay Katherine K. , Hawkins Randall , Price David , Huberty John , Damon Lloyd , Linker Charles , Sznewajs Aimee , Shiboski Steve , Fitzgerald Paul
Published: July 2009

Purpose

To evaluate the safety and efficacy of high-dose [131I]metaiodobenzylguanidine ([131I]MIBG) in the treatment of malignant pheochromocytoma (PHEO) and paraganglioma (PGL).

Methods

Fifty patients with metastatic PHEO or PGL, age 10 to 64 years, were treated with [131I]MIBG doses ranging from 492 to 1,160 mCi (median, 12 mCi/kg). Cumulative [131I]MIBG administered ranged from 492 to 3,191 mCi. Autologous hematopoietic stem cells were collected and cryopreserved before treatment with [131I]MIBG greater than 12 mCi/kg or with a total dose greater than 500 mCi. Sixty-nine [131I]MIBG infusions were given, which included infusions to 35 patients treated once and infusions to 15 patients who received two or three treatments. Response was evaluated by [123I]MIBG scans, computed tomography/magnetic resonance imaging, urinary catecholamines/metanephrines, and chromogranin A.

Results

The overall complete response (CR) plus partial response (PR) rate in 49 evaluable patients was 22%. Additionally, 35% of patients achieved a CR or PR in at least one measure of response without progressive disease, and 8% of patients maintained stable disease for greater than 12 months. Thirty-five percent of patients experienced progressive disease within 1 year after therapy. The estimated 5-year overall survival rate was 64%. Toxicities included grades 3 to 4 neutropenia (87%) and thrombocytopenia (83%). Grades 3 to 4 nonhematologic toxicity included acute respiratory distress syndrome (n = 2), bronchiolitis obliterans organizing pneumonia (n = 2), pulmonary embolism (n = 1), fever with neutropenia (n = 7), acute hypertension (n = 10), infection (n = 2), myelodysplastic syndrome (n = 2), and hypogonadism (n = 4).

Conclusion

Although serious toxicity may occur, the survival and response rates achieved with high-dose [131I]MIBG suggest its utility in the management of selected patients with metastatic PHEO and PGL.
Isocitrate Dehydrogenase 1 Codon 132 Mutation Is an Important Prognostic Biomarker in Gliomas
Authors: Sanson Marc , Marie Yannick , Paris Sophie , Idbaih Ahmed , Laffaire Julien , Ducray François , El Hallani Soufiane , Boisselier Blandine , Mokhtari Karima , Hoang-Xuan Khe , Delattre Jean-Yves
Published: July 2009

Purpose

Unexpected mutations affecting the isocitrate dehydrogenase (IDH1) gene at codon 132 have been found in 12% of glioblastomas.

Patients and Methods

IDH1 codon 132 sequencing was performed in a series of 404 patients with glioma (100 grade 2, 121 grade 3, and 183 grade 4 gliomas) and correlated with histology, genomic profile, methylguanyl methyltransferase (MGMT) promoter methylation status, and outcome.

Results

A total of 155 codon 132 mutations were found, of which 131 were Arg132His (88.5%). The IDH1 mutation was inversely correlated with grade, affecting 77% of grade 2, 55% of grade 3, and 6% of grade 4 gliomas (P < 10−15). The IDH1 mutation was tightly associated with a 1p19q codeleted genotype (P < 10−14) and an MGMT methylated status (P < .001) but mutually exclusive with EGFR amplification (P < 10−15) and loss of chromosome 10 (P < 10−15). The presence (v absence) of IDH1 mutation was associated with a better outcome in grade 2 (150.9 v 60.1 months, respectively; P = .01), grade 3 (81.1 v 19.4 months, respectively; P < .001), and grade 4 gliomas (27.4 v 14 months, respectively; P < .01). After adjustment for grade, age, MGMT status, genomic profile, and treatment, multivariate analysis confirmed that IDH1 mutation was an independent favorable prognostic marker (hazard ratio = 0.297; 95% CI, 0.157 to 0.564, P = .00021).

Conclusion

This study indicates that IDH1 codon 132 mutation is closely linked to the genomic profile of the tumor and constitutes an important prognostic marker in grade 2 to 4 gliomas.
A robust tolerance optimization method based on fuzzy quality loss
Authors: Cao Y , Mao J , Ching H , Yang J
Published: July 2009

Using the quality loss function developed by Taguchi, the manufacturing time and cost of a product can be reduced to improve the factory's competitiveness. However, the fuzziness in quality loss has not been considered in the Taguchi method. This article presents a fuzzy quality loss function model. First, fuzzy logic is used to describe the semantic of the quality, and the quality level is divided into several grades. Then the fuzzy quality loss function is developed utilizing the loss in monetary terms, which indicates the quality loss of each quality level and the normalized expected probability to each quality grade. Moreover, a new optimization model for tolerance design under fuzzy quality loss function is established. An example is used to illustrate the validity of the proposed model. The result shows that the proposed method is more flexible and can achieve the balance of quality and cost in tolerance design. It can be easily used in accordance with practical engineering applications.
Improvement in the design of a centrifugal impeller for an oil cooling blower system using computational fluid dynamics
Authors: Mittal A , Gandhi B K , Singh K M
Published: July 2009

This article presents the computational flow analysis of an axial—centrifugal flow system used for transformer oil cooling in WAP-5 and WAP-7 electric locomotives of Indian Railways. The commercial computational fluid dynamics code ‘FLUENT’ was used for the numerical simulation of the flow system. A standard k—ε turbulence model was employed for turbulence modelling. The flow field through the impeller was analysed to investigate the effect of blade twists and to determine the forces on the blades. A modified impeller design is suggested whose diameter is less than the existing one, which helps in reducing the centrifugal forces. The flow field analysis of the modified impeller shows improvement in the flow through the impeller channels with better performance and reduction in forces on the blades.
A review of wave energy converter technology
Authors: Drew B , Plummer A R , Sahinkaya M N
Published: July 2009

Ocean waves are a huge, largely untapped energy resource, and the potential for extracting energy from waves is considerable. Research in this area is driven by the need to meet renewable energy targets, but is relatively immature compared to other renewable energy technologies. This review introduces the general status of wave energy and evaluates the device types that represent current wave energy converter (WEC) technology, particularly focusing on work being undertaken within the United Kingdom. The possible power take-off systems are identified, followed by a consideration of some of the control strategies to enhance the efficiency of point absorber-type WECs. There is a lack of convergence on the best method of extracting energy from the waves and, although previous innovation has generally focused on the concept and design of the primary interface, questions arise concerning how best to optimize the powertrain. This article concludes with some suggestions of future developments.
An Empirical Analysis of Search Engine Advertising: Sponsored Search in Electronic Markets
Authors: Ghose Anindya , Yang Sha
Published: July 2009

The phenomenon of sponsored search advertising—where advertisers pay a fee to Internet search engines to be displayed alongside organic (nonsponsored) Web search results—is gaining ground as the largest source of revenues for search engines. Using a unique six-month panel data set of several hundred keywords collected from a large nationwide retailer that advertises on Google, we empirically model the relationship between different sponsored search metrics such as click-through rates, conversion rates, cost per click, and ranking of advertisements. Our paper proposes a novel framework to better understand the factors that drive differences in these metrics. We use a hierarchical Bayesian modeling framework and estimate the model using Markov Chain Monte Carlo methods. Using a simultaneous equations model, we quantify the relationship between various keyword characteristics, position of the advertisement, and the landing page quality score on consumer search and purchase behavior as well as on advertiser's cost per click and the search engine's ranking decision. Specifically, we find that the monetary value of a click is not uniform across all positions because conversion rates are highest at the top and decrease with rank as one goes down the search engine results page. Though search engines take into account the current period's bid as well as prior click-through rates before deciding the final rank of an advertisement in the current period, the current bid has a larger effect than prior click-through rates. We also find that an increase in landing page quality scores is associated with an increase in conversion rates and a decrease in advertiser's cost per click. Furthermore, our analysis shows that keywords that have more prominent positions on the search engine results page, and thus experience higher click-through or conversion rates, are not necessarily the most profitable ones—profits are often higher at the middle positions than at the top or the bottom ones. Besides providing managerial insights into search engine advertising, these results shed light on some key assumptions made in the theoretical modeling literature in sponsored search.
An Empirical Analysis of Scarcity Strategies in the Automobile Industry
Authors: Balachander Subramanian , Liu Yan , Stock Axel
Published: July 2009

Recent product introductions such as the Xbox 360, Sony Playstation 2, and PT Cruiser have been characterized by shortage of these products. Some experts have suggested that such scarcity can be a deliberate strategy for making the product more desirable. In this paper, we empirically examine the relationship between introductory inventory levels and consumer preference in the U.S. automobile industry and show that relative scarcity of a car at the time of introduction is associated with higher consumer preference for the product. Furthermore, we perform an empirical test of alternative theories about the rationale for introductory product scarcity. Specifically, we consider two theories of supplier-induced scarcity, namely the buying frenzy theory and the signaling theory, and an alternative theory that suggests that demand uncertainty causes introductory product scarcity. We find more support for the signaling theory of supplier-induced scarcity than the buying frenzy theory or the demand uncertainty theory in our analysis of the automobile market.
Children with autism's perception and understanding of ambiguous figures: Evidence for pictorial metarepresentation, a research note
Authors: Wimmer Marina C. , Doherty Martin J.
Published: July 2009

A large body of autism research over the last 20 years has shown that people with autism have difficulties understanding mental states. This has been conceived of as a metarepresentational deficit. An open question is whether people with autism's metarepresentational deficit is limited to the mental domain. This research explores individuals with autism's understanding of the representational nature of pictures. With the use of ambiguous figures, where a single stimulus is capable of representing two distinct referents, we compared metarepresentational abilities in the pictorial and mental domains and the perception of pictorial ambiguity. Our findings indicate that individuals with autism are impaired in mental metarepresentation but not in pictorial metarepresentation. These findings suggest that children with autism understand the representational nature of pictures. We conclude that children with autism's understanding of the representational nature of pictures is in advance of their metarepresentational understanding of mind. Their perception of figure ambiguity is comparable to the typical population.
Lack of strategy holding: A new pattern of learning deficit in cortical dementias
Authors: Benedet María J. , Lauro‐Grotto Rosapia. , Giotti Chiara.
Published: July 2009

The aim of this study was to demonstrate, by means of systematic research and qualitative data analysis, the presence, among a group of patients with fronto‐temporal lobar degeneration of a subgroup that, at variance with the standard pattern, is able to devise and implement learning strategies, but appear impaired at carrying them on from a trial to the next. In order to provide evidence of the existence of a group of patients showing this type of learning disability, that we refer to as lack of strategy holding, we performed a stepwise hierarchical cluster analysis of a set of variables whose scores were selected from the subject's performance at the Test de Aprendizaje Verbal España‐Complutense. Results substantiate the segregation of three groups of subjects characterized by the following patterns of performance: normal elderly individuals, who show a quite preserved ability to discover a semantic strategy along the learning trials and to carry it from a trial to the next, patients presenting with a deficit in implementing semantic learning strategies and possibly use of serial and/or phonological strategies to perform the task, and to patients who, although able to generate and implement appropriate learning strategies, appear unable to carry them over the learning trials. The presence of this new pattern raises a few questions that seem worth trying to address.
Communications in Spectrochemical Analysis
Authors: Fry D. L.
Published: July 2009

Writing standard methods of spectrochemical analysis that are tied down only at the essential points is a goal that ASTM Committee E-2 on Emission Spectroscopy has set for itself. Our successes and failures are well illustrated in the “Methods for Emission Spectrochemical Analysis” [1]. We will assume for this paper that the 200 members of Committee E-2 have agreed that a given method is the best one for the analysis of a certain alloy. The problem involved is: 1. How do we tell others what the method will do in terms of reliability of results? 2. How can we tell another spectrographer what to do without unnecessarily limiting his selection of equipment or restricting his individuality to routinely following a lot of unnecessary rules? and 3. How can we be sure that all the necessary information is present and clearly stated? It is the purpose of this paper to indicate what Committee E-2 has done concerning these problems, where our solutions are not good enough, and how much information we have to help us over the more thorny issues.
Spectroscopy in the Region 175 to 200 mμ
Authors: Kaye Wilbur
Published: July 2009

The region of the electromagnetic spectrum below 200 mμ has great potential for analytical and molecular structure studies. Difficult instrumental problems must be overcome in obtaining spectra below 200 mμ, but the Beckman DK spectrophotometer has been modified to perform acceptably as far as 175 mμ. Two recent reviews have appeared on the instrumentation of far ultraviolet spectroscopy [1,2]. The most recent reviews summarizing the spectral studies on organic compounds are considerably older [3,4]. All materials absorb intensely somewhere in the far ultraviolet. The spectra are often very discrete—a condition that favors analysis. Absorption occurs through electronic, vibrational, and rotational transitions of molecules so that very complex looking spectra can be obtained from simple molecules. Ionization occurs usually below 175 mμ. Almost all of the published spectra below 175 mμ have been of gases; however, solvents are available with sufficient transparency in thin cells to obtain solution spectra to 175 mμ. Water, cyclohexane and purified perfluoro hydrocarbons can be used. Of course these solvents must be pure [5]. Of the common elements, oxygen, nitrogen, sulfur, bromine and iodine absorb in the 175 to 200 mμ region. Most of the organic and inorganic compounds containing these elements will absorb in this region. In the vapor phase, these compounds may absorb discretely. In condensed phases the absorption is usually diffuse. The atomic nature of the absorption is usually not sufficiently characteristic in shape or wavelength to identify the atom in an unknown compound.
Band Nomenclature for the Ultraviolet Spectra of Conjugated Organic Compounds
Authors: Forbes W. F. , Shilton R.
Published: July 2009

Several systems of band nomenclature for use in the ultraviolet region have been proposed by various authors, giving rise to confusion and, sometimes, ambiguity. For example, the main absorption band in the ultraviolet region is variously referred to as the first primary band, the C-band, the B-band, or as the K-band. This leads to difficulty in establishing relationships between structure and spectral property since it is frequently not immediately evident which band is referred to by a particular author. Band identification, even apart from the problem of different systems of band nomenclature, cannot always be carried out with certainty, and it is, therefore, not surprising that a number of incorrect assignments appear in the literature. The present paper gives examples of bands being given doubtful assignments, partly on account of the confusion of nomenclature, and summarizes the available methods of band identification. It is strongly recommended that in the future only one system of band nomenclature should be used, and in order to facilitate the choice of one particular system of band nomenclature the advantages and disadvantages of each of the presently used systems are discussed.
Some Comments Concerning Quantitative Infrared Spectroscopy
Authors: Steele Warren C. , Wilson M. Kent
Published: July 2009

It is obvious to all consumers of infrared spectral data that the direct transference of quantitative intensities from one instrument to another would be a tremendous boon. It is equally clear that this transference is not possible at the present time [1]. For many reasons it is convenient to use the extinction coefficients at band peaks in quantitative analyses, but these coefficients are strongly affected by experimental conditions—notably the finite slit width. Unfortunately, the method of calculating the “effective” slit width from the mechanical slit width has not been established [2,3]. Recently, Russell and Thompson [4] have concluded that the effective slit width employed must be less than one fifth of the band width at half-peak optical density if the band-peak extinction coefficients are to be obtained. This means for spectra in solution a slit width of 1 cm−1 which is considerably less than that obtainable with standard prism spectrometers. It is not surprising, in view of the above comments, that spectra taken of the same substance with instruments of different optical design are not superposable. However, Copelin's results [1] clearly indicate that instruments of the same make operating presumably under identical conditions yield extinction coefficients that are alarmingly dissimilar. It has not yet been demonstrated whether this variation is due to inconsistencies in the slit width or to other variations in the instrument. The development of a dependable “standard sample” is a critical step in unraveling the instrument problem.