bluuebunny/crossref_metadata_2025 huggingface dataset:
Volumetric intensity-modulated Arc (RapidArc) therapy for primary hepatocellular carcinoma: comparison with intensity-modulated radiotherapy and 3-D conformal radiotherapy
Authors: Kuo Yu-Cheng , Chiu Ying-Ming , Shih Wen-Pin , Yu Hsiao-Wei , Chen Chia-Wen , Wong Pei-Fong , Lin Wei-Chan , Hwang Jeng-Jong
Published: June 2011

Background

To compare the RapidArc plan for primary hepatocellular carcinoma (HCC) with 3-D conformal radiotherapy (3DCRT) and intensity-modulated radiotherapy (IMRT) plans using dosimetric analysis.

Methods

Nine patients with unresectable HCC were enrolled in this study. Dosimetric values for RapidArc, IMRT, and 3DCRT were calculated for total doses of 45~50.4 Gy using 1.8 Gy/day. The parameters included the conformal index (CI), homogeneity index (HI), and hot spot (V107%) for the planned target volume (PTV) as well as the monitor units (MUs) for plan efficiency, the mean dose (Dmean) for the organs at risk (OAR) and the maximal dose at 1% volume (D1%) for the spinal cord. The percentage of the normal liver volume receiving ≥ 40, > 30, > 20, and > 10 Gy (V40 Gy, V30 Gy, V20 Gy, and V10 Gy) and the normal tissue complication probability (NTCP) were also evaluated to determine liver toxicity.

Results

All three methods achieved comparable homogeneity for the PTV. RapidArc achieved significantly better CI and V107% values than IMRT or 3DCRT (p < 0.05). The MUs were significantly lower for RapidArc (323.8 ± 60.7) and 3DCRT (322.3 ± 28.6) than for IMRT (1165.4 ± 170.7) (p < 0.001). IMRT achieved a significantly lower Dmean of the normal liver than did 3DCRT or RapidArc (p = 0.001). 3DCRT had higher V40 Gy and V30 Gy values for the normal liver than did RapidArc or IMRT. Although the V10 Gy to the normal liver was higher with RapidArc (75.8 ± 13.1%) than with 3DCRT or IMRT (60.5 ± 10.2% and 57.2 ± 10.0%, respectively; p < 0.01), the NTCP did not differ significantly between RapidArc (4.38 ± 2.69) and IMRT (3.98 ± 3.00) and both were better than 3DCRT (7.57 ± 4.36) (p = 0.02).

Conclusions

RapidArc provided favorable tumor coverage compared with IMRT or 3DCRT, but RapidArc is not superior to IMRT in terms of liver protection. Further studies are needed to establish treatment outcome differences between the three approaches.
Cognitive development in patients with Mucopolysaccharidosis type III (Sanfilippo syndrome)
Authors: Valstar Marlies J , Marchal Jan Pieter , Grootenhuis Martha , Colland Vivian , Wijburg Frits A
Published: June 2011

Background

Mucopolysaccharidosis type III (MPS III, Sanfilippo syndrome) is a lysosomal storage disorder caused by a deficiency of one of the enzymes involved in the degradation of heparan sulfate.

MPS III is characterized by progressive mental deterioration resulting in severe dementia. A number of potentially disease-modifying therapies are studied. As preservation of cognitive function is the ultimate goal of treatment, assessment of cognitive development will be essential in order to evaluate treatment efficacy. However, no large scale studies on cognitive levels in MPS III patients, using formal psychometric tests, have been reported.

Methods

We aimed to assess cognitive development in all 73 living patients with MPS III in the Netherlands.

Results

Cognitive development could be assessed in 69 patients. In 39 of them developmental level was estimated > 3 months and formal psychometric testing was attempted. A remarkable variation in the intellectual disability was detected.

Conclusions

Despite special challenges encountered, testing failed in only three patients. The observed broad variation in intellectual disability, should be taken into account when designing therapeutic trials.
Efficacy and outcome of expanded newborn screening for metabolic diseases - Report of 10 years from South-West Germany *
Authors: Lindner Martin , Gramer Gwendolyn , Haege Gisela , Fang-Hoffmann Junmin , Schwab Karl O , Tacke Uta , Trefz Friedrich K , Mengel Eugen , Wendel Udo , Leichsenring Michael , Burgard Peter , Hoffmann Georg F
Published: June 2011

Background

National newborn screening programmes based on tandem-mass spectrometry (MS/MS) and other newborn screening (NBS) technologies show a substantial variation in number and types of disorders included in the screening panel. Once established, these methods offer the opportunity to extend newborn screening panels without significant investment and cost. However, systematic evaluations of newborn screening programmes are rare, most often only describing parts of the whole process from taking blood samples to long-term evaluation of outcome.

Methods

In a prospective single screening centre observational study 373 cases with confirmed diagnosis of a metabolic disorder from a total cohort of 1,084,195 neonates screened in one newborn screening laboratory between January 1, 1999, and June 30, 2009 and subsequently treated and monitored in five specialised centres for inborn errors of metabolism were examined. Process times for taking screening samples, obtaining results, initiating diagnostic confirmation and starting treatment as well as the outcome variables metabolic decompensations, clinical status, and intellectual development at a mean age of 3.3 years were evaluated.

Results

Optimal outcome is achieved especially for the large subgroup of patients with medium-chain acyl-CoA dehydrogenase deficiency. Kaplan-Meier-analysis revealed disorder related patterns of decompensation. Urea cycle disorders, organic acid disorders, and amino acid disorders show an early high and continuous risk, medium-chain acyl-CoA dehydrogenase deficiency a continuous but much lower risk for decompensation, other fatty acid oxidation disorders an intermediate risk increasing towards the end of the first year. Clinical symptoms seem inevitable in a small subgroup of patients with very early disease onset. Later decompensation can not be completely prevented despite pre-symptomatic start of treatment. Metabolic decompensation does not necessarily result in impairment of intellectual development, but there is a definite association between the two.

Conclusions

Physical and cognitive outcome in patients with presymptomatic diagnosis of metabolic disorders included in the current German screening panel is equally good as in phenylketonuria, used as a gold standard for NBS. Extended NBS entails many different interrelated variables which need to be carefully evaluated and optimized. More reports from different parts of the world are needed to allow a comprehensive assessment of the likely benefits, harms and costs in different populations.
CONTIGuator: a bacterial genomes finishing tool for structural insights on draft genomes
Authors: Galardini Marco , Biondi Emanuele G , Bazzicalupo Marco , Mengoni Alessio
Published: June 2011

Recent developments in sequencing technologies have given the opportunity to sequence many bacterial genomes with limited cost and labor, compared to previous techniques. However, a limiting step of genome sequencing is the finishing process, needed to infer the relative position of each contig and close sequencing gaps. An additional degree of complexity is given by bacterial species harboring more than one replicon, which are not contemplated by the currently available programs. The availability of a large number of bacterial genomes allows geneticists to use complete genomes (possibly from the same species) as templates for contigs mapping.

Here we present CONTIGuator, a software tool for contigs mapping over a reference genome which allows the visualization of a map of contigs, underlining loss and/or gain of genetic elements and permitting to finish multipartite genomes. The functionality of CONTIGuator was tested using four genomes, demonstrating its improved performances compared to currently available programs.

Our approach appears efficient, with a clear visualization, allowing the user to perform comparative structural genomics analysis on draft genomes. CONTIGuator is a Python script for Linux environments and can be used on normal desktop machines and can be downloaded from http://contiguator.sourceforge.net.
Comparison between elementary flux modes analysis and 13C-metabolic fluxes measured in bacterial and plant cells
Authors: Beurton-Aimar Marie , Beauvoit Bertrand , Monier Antoine , Vallée François , Dieuaide-Noubhani Martine , Colombié Sophie
Published: June 2011

Background

13C metabolic flux analysis is one of the pertinent ways to compare two or more physiological states. From a more theoretical standpoint, the structural properties of metabolic networks can be analysed to explore feasible metabolic behaviours and to define the boundaries of steady state flux distributions. Elementary flux mode analysis is one of the most efficient methods for performing this analysis. In this context, recent approaches have tended to compare experimental flux measurements with topological network analysis.

Results

Metabolic networks describing the main pathways of central carbon metabolism were set up for a bacteria species (Corynebacterium glutamicum) and a plant species (Brassica napus) for which experimental flux maps were available. The structural properties of each network were then studied using the concept of elementary flux modes. To do this, coefficients of flux efficiency were calculated for each reaction within the networks by using selected sets of elementary flux modes. Then the relative differences - reflecting the change of substratei.e. a sugar source forC.glutamicumand a nitrogen source forB.napus- of both flux efficiency and flux measured experimentally were compared. For both organisms, there is a clear relationship between these parameters, thus indicating that the network structure described by the elementary flux modes had captured a significant part of the metabolic activity in both biological systems. InB.napus, the extension of the elementary flux mode analysis to an enlarged metabolic network still resulted in a clear relationship between the change in the coefficients and that of the measured fluxes. Nevertheless, the limitations of the method to fit some particular fluxes are discussed.

Conclusion

This consistency between EFM analysis and experimental flux measurements, validated on two metabolic systems allows us to conclude that elementary flux mode analysis could be a useful tool to complement13C metabolic flux analysis, by allowing the prediction of changes in internal fluxes before carbon labelling experiments.
Adaptation of a visualized loop-mediated isothermal amplification technique for field detection of Plasmodium vivax infection
Authors: Tao Zhi-Yong , Zhou Hua-Yun , Xia Hui , Xu Sui , Zhu Han-Wu , Culleton Richard L , Han Eun-Taek , Lu Feng , Fang Qiang , Gu Ya-Ping , Liu Yao-Bao , Zhu Guo-Ding , Wang Wei-Ming , Li Ju-Lin , Cao Jun , Gao Qi
Published: June 2011

Background

Loop-mediated isothermal amplification (LAMP) is a high performance method for detecting DNA and holds promise for use in the molecular detection of infectious pathogens, including Plasmodium spp. However, in most malaria-endemic areas, which are often resource-limited, current LAMP methods are not feasible for diagnosis due to difficulties in accurately interpreting results with problems of sensitive visualization of amplified products, and the risk of contamination resulting from the high quantity of amplified DNA produced. In this study, we establish a novel visualized LAMP method in a closed-tube system, and validate it for the diagnosis of malaria under simulated field conditions.

Methods

A visualized LAMP method was established by the addition of a microcrystalline wax-dye capsule containing the highly sensitive DNA fluorescence dye SYBR Green I to a normal LAMP reaction prior to the initiation of the reaction. A total of 89 blood samples were collected on filter paper and processed using a simple boiling method for DNA extraction, and then tested by the visualized LAMP method for Plasmodium vivax infection.

Results

The wax capsule remained intact during isothermal amplification, and released the DNA dye to the reaction mixture only when the temperature was raised to the melting point following amplification. Soon after cooling down, the solidified wax sealed the reaction mix at the bottom of the tube, thus minimizing the risk of aerosol contamination. Compared to microscopy, the sensitivity and specificity of LAMP were 98.3% (95% confidence interval (CI): 91.1-99.7%) and 100% (95% CI: 88.3-100%), and were in close agreement with a nested polymerase chain reaction method.

Conclusions

This novel, cheap and quick visualized LAMP method is feasible for malaria diagnosis in resource-limited field settings.
Analysis of IL-17+cells in facet joints of patients with spondyloarthritis suggests that the innate immune pathway might be of greater relevance than the Th17-mediated adaptive immune response
Authors: Appel Heiner , Maier René , Wu Peihua , Scheer Rebecca , Hempfing Axel , Kayser Ralph , Thiel Andreas , Radbruch Andreas , Loddenkemper Christoph , Sieper Joachim
Published: June 2011

Introduction

In this study, we analysed the number of IL-17+ cells in facet joints, in the peripheral blood (PB) and synovial fluid (SF) of spondyloarthritis (SpA) patients and compared these results with those of patients with other rheumatic diseases and controls.

Methods

Immunohistochemical analysis of IL-17+ cells was performed in facet joints of 33 ankylosing spondylitis (AS) patients and compared with data from 20 osteoarthritis (OA) patients. The frequency of IL-17+CD4+ T cells in PB and SF of SpA patients (PB n = 30, SF n = 11), rheumatoid arthritis (RA) patients (PB n = 14, SF n = 7), OA patients (PB n = 10) and healthy controls (PB n = 12) was analysed after stimulation with Staphylococcus aureus Enterotoxin B and phorbol 12-myristate 13-acetate/ionomycin and quantified by flow cytometry.

Results

In AS facet joints, the frequency of IL-17-secreting cells was significantly higher than in samples obtained from OA patients (P < 0.001), with a slight predominance of IL-17+ cells among the mononuclear cells (61.5% ± 14.9%) compared to cells with polysegmental nuclei. Immunofluorescence microscopy revealed that the majority of IL-17+ cells were myeloperoxidase-positive (35.84 ± 13.06/high-power field (HPF) and CD15+ neutrophils (24.25 ± 10.36/HPF), while CD3+ T cells (0.51 ± 0.49/HPF) and AA-1+ mast cells (2.28 ± 1.96/HPF) were less often IL-17-positive. The frequency of IL-17+CD4+ T cells in the PB and SF of SpA patients did not differ significantly compared to RA patients, OA patients or healthy controls.

Conclusions

Our data suggest an important role for IL-17 in the inflammatory processes in AS. However, the innate immune pathway might be of greater relevance than the Th17-mediated adaptive immune response.
Tiludronate treatment improves structural changes and symptoms of osteoarthritis in the canine anterior cruciate ligament model
Authors: Moreau Maxim , Rialland Pascale , Pelletier Jean-Pierre , Martel-Pelletier Johanne , Lajeunesse Daniel , Boileau Christielle , Caron Judith , Frank Diane , Lussier Bertrand , del Castillo Jerome RE , Beauchamp Guy , Gauvin Dominique , Bertaim Thierry , Thibaud Dominique , Troncy Eric
Published: June 2011

Introduction

The aim of this prospective, randomized, controlled, double-blind study was to evaluate the effects of tiludronate (TLN), a bisphosphonate, on structural, biochemical and molecular changes and function in an experimental dog model of osteoarthritis (OA).

Methods

Baseline values were established the week preceding surgical transection of the right cranial/anterior cruciate ligament, with eight dogs serving as OA placebo controls and eight others receiving four TLN injections (2 mg/kg subcutaneously) at two-week intervals starting the day of surgery for eight weeks. At baseline, Week 4 and Week 8, the functional outcome was evaluated using kinetic gait analysis, telemetered locomotor actimetry and video-automated behaviour capture. Pain impairment was assessed using a composite numerical rating scale (NRS), a visual analog scale, and electrodermal activity (EDA). At necropsy (Week 8), macroscopic and histomorphological analyses of synovium, cartilage and subchondral bone of the femoral condyles and tibial plateaus were assessed. Immunohistochemistry of cartilage (matrix metalloproteinase (MMP)-1, MMP-13, and a disintegrin and metalloproteinase domain with thrombospondin motifs (ADAMTS5)) and subchondral bone (cathepsin K) was performed. Synovial fluid was analyzed for inflammatory (PGE2 and nitrite/nitrate levels) biomarkers. Statistical analyses (mixed and generalized linear models) were performed with an α-threshold of 0.05.

Results

A better functional outcome was observed in TLN dogs than OA placebo controls. Hence, TLN dogs had lower gait disability (P = 0.04 at Week 8) and NRS score (P = 0.03, group effect), and demonstrated behaviours of painless condition with the video-capture (P < 0.04). Dogs treated with TLN demonstrated a trend toward improved actimetry and less pain according to EDA. Macroscopically, both groups had similar level of morphometric lesions, TLN-treated dogs having less joint effusion (P = 0.01), reduced synovial fluid levels of PGE2 (P = 0.02), nitrites/nitrates (P = 0.01), lower synovitis score (P < 0.01) and a greater subchondral bone surface (P < 0.01). Immunohistochemical staining revealed lower levels in TLN-treated dogs of MMP-13 (P = 0.02), ADAMTS5 (P = 0.02) in cartilage and cathepsin K (P = 0.02) in subchondral bone.

Conclusion

Tiludronate treatment demonstrated a positive effect on gait disability and joint symptoms. This is likely related to the positive influence of the treatment at improving some OA structural changes and reducing the synthesis of catabolic and inflammatory mediators.
The association between microvascular and macrovascular endothelial function in patients with rheumatoid arthritis: a cross-sectional study
Authors: Sandoo Aamer , Carroll Douglas , Metsios George S , Kitas George D , Veldhuijzen van Zanten Jet JCS
Published: June 2011

Introduction

Patients with rheumatoid arthritis (RA) are at an increased risk for cardiovascular disease (CVD). One of the earliest manifestations of CVD is endothelial dysfunction (ED). ED can occur in both the microcirculation and the macrocirculation, and these manifestations might be relatively independent of each other. Little is known about the association between endothelial function in the microcirculation and the macrocirculation in RA. The objectives of the present study were to examine the relationship between microvascular and macrovascular endothelial function in patients with RA.

Methods

Ninety-nine RA patients (72 females, mean age (± SD) 56 ± 12 years), underwent assessments of endothelial-dependent (acetylcholine) and endothelial-independent (sodium nitroprusside) microvascular vasodilatory function (laser Doppler imaging with iontophoresis), as well as endothelial-dependent (flow-mediated dilation) and endothelial-independent (glyceryl trinitrate-mediated dilation) macrovascular vasodilatory function. Vasodilatory function was calculated as the percentage increase after each stimulus was applied relative to baseline values.

Results

Pearson correlations showed that microvascular endothelial-dependent function was not associated with macrovascular endothelial-dependent function (r (90 patients) = 0.10, P = 0.34). Similarly, microvascular endothelial-independent function was not related to macrovascular endothelial-independent function (r (89 patients) = 0.00, P = 0.99).

Conclusions

Microvascular and macrovascular endothelial function were independent of each other in patients with RA, suggesting differential regulation of endothelial function in these two vascular beds. Assessments of both vascular beds may provide more meaningful clinical information on vascular risk in RA, but this hypothesis needs to be confirmed in long-term prospective studies.
Age of red blood cells and mortality in the critically ill
Authors: Pettilä Ville , Westbrook Andrew J , Nichol Alistair D , Bailey Michael J , Wood Erica M , Syres Gillian , Phillips Louise E , Street Alison , French Craig , Murray Lynnette , Orford Neil , Santamaria John D , Bellomo Rinaldo , Cooper David J ,   the Blood Observational Study Investigators for the ANZICS Clinical Trials Group
Published: June 2011

Introduction

In critically ill patients, it is uncertain whether exposure to older red blood cells (RBCs) may contribute to mortality. We therefore aimed to evaluate the association between the age of RBCs and outcome in a large unselected cohort of critically ill patients in Australia and New Zealand. We hypothesized that exposure to even a single unit of older RBCs may be associated with an increased risk of death.

Methods

We conducted a prospective, multicenter observational study in 47 ICUs during a 5-week period between August 2008 and September 2008. We included 757 critically ill adult patients receiving at least one unit of RBCs. To test our hypothesis we compared hospital mortality according to quartiles of exposure to maximum age of RBCs without and with adjustment for possible confounding factors.

Results

Compared with other quartiles (mean maximum red cell age 22.7 days; mortality 121/568 (21.3%)), patients treated with exposure to the lowest quartile of oldest RBCs (mean maximum red cell age 7.7 days; hospital mortality 25/189 (13.2%)) had an unadjusted absolute risk reduction in hospital mortality of 8.1% (95% confidence interval = 2.2 to 14.0%). After adjustment for Acute Physiology and Chronic Health Evaluation III score, other blood component transfusions, number of RBC transfusions, pretransfusion hemoglobin concentration, and cardiac surgery, the odds ratio for hospital mortality for patients exposed to the older three quartiles compared with the lowest quartile was 2.01 (95% confidence interval = 1.07 to 3.77).

Conclusions

In critically ill patients, in Australia and New Zealand, exposure to older RBCs is independently associated with an increased risk of death.
Prospective Multi-Institutional Study Evaluating the Performance of Prostate Cancer Risk Calculators
Authors: Nam Robert K. , Kattan Michael W. , Chin Joseph L. , Trachtenberg John , Singal Rajiv , Rendon Ricardo , Klotz Laurence H. , Sugar Linda , Sherman Christopher , Izawa Jonathan , Bell David , Stanimirovic Aleksandra , Venkateswaran Vasundara , Diamandis Eleftherios P. , Yu Changhong , Loblaw D. Andrew , Narod Steven A.
Published: June 2011

Purpose

Prostate cancer risk calculators incorporate many factors to evaluate an individual's risk for prostate cancer. We validated two common North American–based, prostate cancer risk calculators.

Patients and Methods

We conducted a prospective, multi-institutional study of 2,130 patients who underwent a prostate biopsy for prostate cancer detection from five centers. We evaluated the performance of the Sunnybrook nomogram–based prostate cancer risk calculator (SRC) and the Prostate Cancer Prevention Trial (PCPT) –based risk calculator (PRC) to predict the presence of any cancer and high-grade cancer. We examined discrimination, calibration, and decision curve analysis techniques to evaluate the prediction models.

Results

Of the 2,130 patients, 867 men (40.7%) were found to have cancer, and 1,263 (59.3%) did not have cancer. Of the patients with cancer, 403 (46.5%) had a Gleason score of 7 or more. The area under the [concentration-time] curve (AUC) for the SRC was 0.67 (95% CI, 0.65 to 0.69); the AUC for the PRC was 0.61 (95% CI, 0.59 to 0.64). The AUC was higher for predicting aggressive disease from the SRC (0.72; 95% CI, 0.70 to 0.75) compared with that from the PRC (0.67; 95% CI, 0.64 to 0.70). Decision curve analyses showed that the SRC performed better than the PRC for risk thresholds of more than 30% for any cancer and more than 15% for aggressive cancer.

Conclusion

The SRC performed better than the PRC, but neither one added clinical benefit for risk thresholds of less than 30%. Further research is needed to improve the AUCs of the risk calculators, particularly for higher-grade cancer.
Levels of Symptom Burden During Chemotherapy for Advanced Lung Cancer: Differences Between Public Hospitals and a Tertiary Cancer Center
Authors: Cleeland Charles S. , Mendoza Tito R. , Wang Xin Shelley , Woodruff Jeanie F. , Palos Guadalupe R. , Richman Stephen P. , Nazario Arlene , Lynch Garrett R. , Liao Kai-Ping , Mobley Gary M. , Lu Charles
Published: June 2011

Purpose

We compared risk factors for high disease- and treatment-related symptom burden over 15 weeks of therapy in medically underserved patients with advanced non–small-cell lung cancer and in patients treated at a tertiary cancer center.

Patients and Methods

We monitored symptom severity weekly during chemotherapy. Patients were recruited from a tertiary cancer center (n=101) and three public hospitals treating the medically underserved (n=80). We used a composite symptom-severity score and group-based trajectory analysis to form two groups: one with consistently more severe symptoms and another with less severe symptoms. We examined predictors of group membership.

Results

Seventy percent of the sample (n=126) reported low symptom-severity levels that decreased during therapy; 30% (n=55) had consistently severe symptoms throughout the study. In multivariate analysis, patients with good performance status being treated in public hospitals were significantly more likely than patients treated at the tertiary cancer center to be in the high-symptom group (odds ratio, 5.6; 95% CI, 2.1 to 14.6; P =.001) and to report significantly higher symptom interference (P =.001). Other univariate predictors of high-symptom group membership included variables associated with being medically underserved (eg, having less education, being single, and being nonwhite). No group differences by ethnicity were observed in the public hospitals. Medically underserved patients were less likely to receive adequate pain management.

Conclusion

Patients with advanced lung cancer and good performance status treated at public hospitals were more likely than those treated at a tertiary cancer center to experience substantial symptoms during chemotherapy.
Phase I Study of Temsirolimus in Pediatric Patients With Recurrent/Refractory Solid Tumors
Authors: Spunt Sheri L. , Grupp Stephan A. , Vik Terry A. , Santana Victor M. , Greenblatt David J. , Clancy Jill , Berkenblit Anna , Krygowski Mizue , Ananthakrishnan Revathi , Boni Joseph P. , Gilbertson Richard J.
Published: June 2011

Purpose

To determine dose-limiting toxicities, maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of weekly intravenous temsirolimus, a mammalian target of rapamycin (mTOR) signaling pathway inhibitor, in pediatric patients with recurrent or refractory solid tumors.

Patients and Methods

Cohorts of three to six patients 1 to 21 years of age with recurrent or refractory solid tumors were treated with a 1-hour intravenous infusion of temsirolimus weekly for 3 weeks per course at one of four dose levels: 10, 25, 75, or 150 mg/m2. During the first two courses, pharmacokinetic and pharmacodynamic evaluations (phosphorylation of S6, AKT, and 4EBP1 in peripheral-blood mononuclear cells) were performed.

Results

Dose-limiting toxicity (grade 3 anorexia) occurred in one of 18 evaluable patients at the 150 mg/m2 level, which was determined to be tolerable, and an MTD was not identified. In 13 patients evaluable for response after two courses of therapy, one had complete response (CR; neuroblastoma) and five had stable disease (SD). Four patients (three SDs + one CR) remained on treatment for more than 4 months. The sum of temsirolimus and sirolimus areas under the concentration-time curve was comparable to values in adults. AKT and 4EBP1 phosphorylation were inhibited at all dose levels, particularly after two courses.

Conclusion

Weekly intravenous temsirolimus is well tolerated in children with recurrent solid tumors, demonstrates antitumor activity, has pharmacokinetics similar to those in adults, and inhibits the mTOR signaling pathway in peripheral-blood mononuclear cells. Further studies are needed to define the optimal dose for use in combination with other antineoplastic agents in pediatric patients.
Angiotensin Receptor Blockade and Risk of Cancer in Type 2 Diabetes Mellitus: A Nationwide Case-Control Study
Authors: Chang Chia-Hsuin , Lin Jou-Wei , Wu Li-Chiu , Lai Mei-Shu
Published: June 2011

Purpose

The objective of this case-control study was to evaluate the risk of malignancy in diabetic patients who received angiotensin receptor blockers (ARBs).

Patients and Methods

A total of 21,750 new diabetic patients who started antihypertensive treatment were identified from the Taiwan National Health Insurance claims database during the period from July 1, 2000, to December 31, 2000. As of December 31, 2007, patients with incident cancer were included as cases and up to four age- and sex-matched controls were selected by risk-set sampling. Logistic regression models were applied to estimate the odds ratios (ORs) and 95% CIs between ARB use and cancer incidence, adjusted for other types of antihypertensive drugs, insulin, oral hypoglycemic agents, statins, and underlying diseases.

Results

Among the 1,281 patients with incident cancer and 5,104 controls, 333 (26.0%) and 1,341 (26.3%), respectively, received ARBs (OR, 0.98; 95% CI, 0.85 to 1.14). There was no statistically significant association between the effect of ARBs as a class and cancer incidence after adjustment for covariates (OR, 0.94; 95% CI, 0.80 to 1.10). Among the individual ARBs, losartan decreased the risk (OR, 0.78; 95% CI, 0.63 to 0.97) and candesartan (OR, 1.79; 95% CI, 1.05 to 3.06) and telmisartan (OR, 1.54; 95% CI, 0.97 to 2.43) possibly increased the risk of occurrence of malignancy.

Conclusion

The results did not show an effect of ARBs as a class on increasing cancer incidence in patients with diabetes. However, there was a negative association of losartan but a positive one of candesartan and telmisartan with the overall occurrence of cancer. The underlying mechanism certainly requires further investigation.
Cost-Effectiveness of Contralateral Prophylactic Mastectomy Versus Routine Surveillance in Patients With Unilateral Breast Cancer
Authors: Zendejas Benjamin , Moriarty James P. , O'Byrne Jamie , Degnim Amy C. , Farley David R. , Boughey Judy C.
Published: June 2011

Purpose

Contralateral prophylactic mastectomy (CPM) rates in women with unilateral breast cancer are increasing despite controversy regarding survival advantage. Current scrutiny of the medical costs led us to evaluate the cost-effectiveness of CPM versus routine surveillance as an alternative contralateral breast cancer (CBC) risk management strategy.

Methods

Using a Markov model, we simulated patients with breast cancer from mastectomy to death. Model parameters were gathered from published literature or national databases. Base-case analysis focused on patients with average-risk breast cancer, 45 years of age at treatment. Outcomes were valued in quality-adjusted life-years (QALYs). Patients' age, risk level of breast cancer, and quality of life (QOL) were varied to assess their impact on results.

Results

Mean costs of treatment for women age 45 years are comparable: $36,594 for the CPM and $35,182 for surveillance. CPM provides 21.22 mean QALYs compared with 20.93 for surveillance, resulting in an incremental cost-effectiveness ratio (ICER) of $4,869/QALY gained for CPM. To prevent one CBC, six CPMs would be needed. CPM is no longer cost-effective for patients older than 70 years (ICER $62,750/QALY). For BRCA-positive patients, CPM is clearly cost-effective, providing more QALYs while being less costly. In non-BRCA patients, cost-effectiveness of CPM is highly dependent on assumptions regarding QOL for CPM versus surveillance strategy.

Conclusion

CPM is cost-effective compared with surveillance for patients with breast cancer who are younger than 70 years. Results are sensitive to BRCA-positive status and assumptions of QOL differences between CPM and surveillance patients. This highlights the importance of tailoring treatment for individual patients.
Distinguished exchangeable coalescents and generalized Fleming-Viot processes with immigration
Authors: Foucart Clément
Published: June 2011

Coalescents with multiple collisions (also called Λ-coalescents or simple exchangeable coalescents) are used as models of genealogies. We study a new class of Markovian coalescent processes connected to a population model with immigration. Consider an infinite population with immigration labelled at each generation by N := {1, 2, …}. Some ancestral lineages cannot be followed backwards after some time because their ancestor is outside the population. The individuals with an immigrant ancestor constitute a distinguished family and we define exchangeable distinguished coalescent processes as a model for genealogy with immigration, focusing on simple distinguished coalescents, i.e. such that when a coagulation occurs all the blocks involved merge as a single block. These processes are characterized by two finite measures on [0, 1] denoted by M = (Λ0, Λ1). We call them M-coalescents. We show by martingale arguments that the condition of coming down from infinity for the M-coalescent coincides with that obtained by Schweinsberg for the Λ-coalescent. In the same vein as Bertoin and Le Gall, M-coalescents are associated with some stochastic flows. The superprocess embedded can be viewed as a generalized Fleming-Viot process with immigration. The measures Λ0 and Λ1 respectively specify the reproduction and the immigration. The coming down from infinity of the M-coalescent will be interpreted as the initial types extinction: after a certain time all individuals are immigrant children.
Approximation of bounds on mixed-level orthogonal arrays
Authors: Sezer Ali Devin , Özbudak Ferruh
Published: June 2011

Mixed-level orthogonal arrays are basic structures in experimental design. We develop three algorithms that compute Rao- and Gilbert-Varshamov-type bounds for mixed-level orthogonal arrays. The computational complexity of the terms involved in the original combinatorial representations of these bounds can grow fast as the parameters of the arrays increase and this justifies the construction of these algorithms. The first is a recursive algorithm that computes the bounds exactly, the second is based on an asymptotic analysis, and the third is a simulation algorithm. They are all based on the representation of the combinatorial expressions that appear in the bounds as expectations involving a symmetric random walk. The Markov property of the underlying random walk gives the recursive formula to compute the expectations. A large deviation (LD) analysis of the expectations provides the asymptotic algorithm. The asymptotically optimal importance sampling (IS) of the same expectation provides the simulation algorithm. Both the LD analysis and the construction of the IS algorithm use a representation of these problems as a sequence of stochastic optimal control problems converging to a limit calculus of a variations problem. The construction of the IS algorithm uses a recently discovered method of using subsolutions to the Hamilton-Jacobi-Bellman equations associated with the limit problem.
Hydrodynamic Limit for a Type of Exclusion Process with Slow Bonds in Dimension d ≥ 2
Authors: Franco Tertuliano , Neumann Adriana , Valle Glauco
Published: June 2011

Let Λ be a connected closed region with smooth boundary contained in the d-dimensional continuous torus Td. In the discrete torus N-1TdN, we consider a nearest-neighbor symmetric exclusion process where occupancies of neighboring sites are exchanged at rates depending on Λ in the following way: if both sites are in Λ or Λc, the exchange rate is 1; if one site is in Λ and the other site is in Λc, and the direction of the bond connecting the sites is ej, then the exchange rate is defined as N-1 times the absolute value of the inner product between ej and the normal exterior vector to ∂Λ. We show that this exclusion-type process has a nontrivial hydrodynamical behavior under diffusive scaling and, in the continuum limit, particles are not blocked or reflected by ∂Λ. Thus, the model represents a system of particles under hard-core interaction in the presence of a permeable membrane which slows down the passage of particles between two complementary regions.
Pricing the Zero-Coupon Bond and its Fair Premium Under a Structural Credit Risk Model with Jumps
Authors: Dong Yinghui , Wang Guojing , Wu Rong
Published: June 2011

In this paper we consider a structural form credit risk model with jumps. We investigate the credit spread, the price, and the fair premium of the zero-coupon bond for the proposed model. The price and the fair premium of the bond are associated with the Laplace transform of default time and the firm's expected present market value at default. We give sufficient conditions under which the Laplace transform and the expected present market value of a firm at default are twice continuously differentiable. We derive closed-form expressions for them when the jumps have a hyperexponential distribution. Using the closed-form expressions, we obtain numerical solutions for the default probability, the credit spread, and the fair premium of the bond.
A Stochastic Breakdown Model for an Unreliable Web Server System and an Optimal Admission Control Policy
Authors: Cha Ji Hwan , Lee Eui Yong
Published: June 2011

Web servers have to be protected against overload since overload can lead to a server breakdown, which in turn causes high response times and low throughput. In this paper, a stochastic model for breakdowns of server systems due to overload is proposed and an admission control policy which protects Web servers by controlling the amount and rate of work entering the system is studied. Requests from the clients arrive at the server following a nonhomogeneous Poisson process and each requested job takes a random time to be completed. It is assumed that the breakdown rate of the server depends on the number of jobs which are currently being performed by the server. Based on the proposed model, the reliability function and the breakdown rate function of the server system are derived. Furthermore, the long-run expected number of jobs completed per unit time is derived as the efficiency measure, and the optimal admission control policy which maximizes the efficiency will be discussed.
Conditionally Independent Increment Point Processes
Authors: Vélez Ibarrola Ricardo , Prieto-Rumeau Tomás
Published: June 2011

In this paper we introduce conditionally independent increment point processes, that is, processes that are conditionally independent inside and outside a bounded setAgivenN(A), the number of points inA. We show that these point processes can be characterized by means of the avoidance function of a multinomial ‘support process’, the solution of a suitably defined linear system of equations, and, finally, the infinitesimal matrix of a continuous-time Markov chain.
Asymptotic Properties of a Leader Election Algorithm
Authors: Kalpathy Ravi , Mahmoud Hosam M. , Ward Mark Daniel
Published: June 2011

We consider a serialized coin-tossing leader election algorithm that proceeds in rounds until a winner is chosen, or all contestants are eliminated. The analysis allows for either biased or fair coins. We find the exact distribution for the duration of any fixed contestant; asymptotically, it turns out to be a geometric distribution. Rice's method (an analytic technique) shows that the moments of the duration contain oscillations, which we give explicitly for the mean and variance. We also use convergence in the Wasserstein metric space to show that the distribution of the total number of coin flips (among all participants), suitably normalized, approaches a normal limiting random variable.
Neuropilin-2 promotes branching morphogenesis in the mouse mammary gland
Authors: Goel Hira Lal , Bae Donggoo , Pursell Bryan , Gouvin Lindsey M. , Lu Shaolei , Mercurio Arthur M.
Published: June 2011

Although the neuropilins were characterized as semaphorin receptors that regulate axon guidance, they also function as vascular endothelial growth factor (VEGF) receptors and contribute to the development of other tissues. Here, we assessed the role of NRP2 in mouse mammary gland development based on our observation that NRP2 is expressed preferentially in the terminal end buds of developing glands. A floxed NRP2 mouse was bred with an MMTV-Cre strain to generate a mammary gland-specific knockout of NRP2. MMTV-Cre;NRP2loxP/loxP mice exhibited significant defects in branching morphogenesis and ductal outgrowth compared with either littermate MMTV-Cre;NRP2+/loxP or MMTV-Cre mice. Mechanistic insight into this morphological defect was obtained from a mouse mammary cell line in which we observed that VEGF165, an NRP2 ligand, induces branching morphogenesis in 3D cultures and that branching is dependent upon NRP2 as shown using shRNAs and a function-blocking antibody. Epithelial cells in the mouse mammary gland express VEGF, supporting the hypothesis that this NRP2 ligand contributes to mammary gland morphogenesis. Importantly, we demonstrate that VEGF and NRP2 activate focal adhesion kinase (FAK) and promote FAK-dependent branching morphogenesis in vitro. The significance of this mechanism is substantiated by our finding that FAK activation is diminished significantly in developing MMTV-Cre;NRP2loxP/loxP mammary glands compared with control glands. Together, our data reveal a VEGF/NRP2/FAK signaling axis that is important for branching morphogenesis and mammary gland development. In a broader context, our data support an emerging hypothesis that directional outgrowth and branching morphogenesis in a variety of tissues are influenced by signals that were identified initially for their role in axon guidance.
Rac1 mediates morphogenetic responses to intercellular signals in the gastrulating mouse embryo
Authors: Migeotte Isabelle , Grego-Bessa Joaquim , Anderson Kathryn V.
Published: June 2011

The establishment of the mammalian body plan depends on signal-regulated cell migration and adhesion, processes that are controlled by the Rho family of GTPases. Here we use a conditional allele of Rac1, the only Rac gene expressed early in development, to define its roles in the gastrulating mouse embryo. Embryos that lack Rac1 in the epiblast (Rac1Δepi) initiate development normally: the signaling pathways required for gastrulation are active, definitive endoderm and all classes of mesoderm are specified, and the neural plate is formed. After the initiation of gastrulation, Rac1Δepi embryos have an enlarged primitive streak, make only a small amount of paraxial mesoderm, and the lateral anlage of the heart do not fuse at the midline. Because these phenotypes are also seen in Nap1 mutants, we conclude that Rac1 acts upstream of the Nap1/WAVE complex to promote migration of the nascent mesoderm. In addition to migration phenotypes, Rac1Δepi cells fail to adhere to matrix, which leads to extensive cell death. Cell death is largely rescued in Rac1Δepi mutants that are heterozygous for a null mutation in Pten, providing evidence that Rac1 is required to link signals from the basement membrane to activation of the PI3K-Akt pathway in vivo. Surprisingly, the frequency of apoptosis is greater in the anterior half of the embryo, suggesting that cell survival can be promoted either by matrix adhesion or by signals from the posterior primitive streak. Rac1 also has essential roles in morphogenesis of the posterior notochordal plate (the node) and the midline.
How to make stripes: deciphering the transition from non-periodic to periodic patterns inDrosophilasegmentation
Authors: Schroeder Mark D. , Greer Christina , Gaul Ulrike
Published: June 2011

The generation of metameric body plans is a key process in development. In Drosophila segmentation, periodicity is established rapidly through the complex transcriptional regulation of the pair-rule genes. The ‘primary’ pair-rule genes generate their 7-stripe expression through stripe-specific cis-regulatory elements controlled by the preceding non-periodic maternal and gap gene patterns, whereas ‘secondary’ pair-rule genes are thought to rely on 7-stripe elements that read off the already periodic primary pair-rule patterns. Using a combination of computational and experimental approaches, we have conducted a comprehensive systems-level examination of the regulatory architecture underlying pair-rule stripe formation. We find that runt (run), fushi tarazu (ftz) and odd skipped (odd) establish most of their pattern through stripe-specific elements, arguing for a reclassification of ftz and odd as primary pair-rule genes. In the case of run, we observe long-range cis-regulation across multiple intervening genes. The 7-stripe elements of run, ftz and odd are active concurrently with the stripe-specific elements, indicating that maternal/gap-mediated control and pair-rule gene cross-regulation are closely integrated. Stripe-specific elements fall into three distinct classes based on their principal repressive gap factor input; stripe positions along the gap gradients correlate with the strength of predicted input. The prevalence of cis-elements that generate two stripes and their genomic organization suggest that single-stripe elements arose by splitting and subfunctionalization of ancestral dual-stripe elements. Overall, our study provides a greatly improved understanding of how periodic patterns are established in the Drosophila embryo.
Msx genes define a population of mural cell precursors required for head blood vessel maturation
Authors: Lopes Miguel , Goupille Olivier , Cloment Cécile Saint , Lallemand Yvan , Cumano Ana , Robert Benoît
Published: June 2011

Vessels are primarily formed from an inner endothelial layer that is secondarily covered by mural cells, namely vascular smooth muscle cells (VSMCs) in arteries and veins and pericytes in capillaries and veinules. We previously showed that, in the mouse embryo, Msx1lacZ and Msx2lacZ are expressed in mural cells and in a few endothelial cells. To unravel the role of Msx genes in vascular development, we have inactivated the two Msx genes specifically in mural cells by combining the Msx1lacZ, Msx2lox and Sm22α-Cre alleles. Optical projection tomography demonstrated abnormal branching of the cephalic vessels in E11.5 mutant embryos. The carotid and vertebral arteries showed an increase in caliber that was related to reduced vascular smooth muscle coverage. Taking advantage of a newly constructed Msx1CreERT2 allele, we demonstrated by lineage tracing that the primary defect lies in a population of VSMC precursors. The abnormal phenotype that ensues is a consequence of impaired BMP signaling in the VSMC precursors that leads to downregulation of the metalloprotease 2 (Mmp2) and Mmp9 genes, which are essential for cell migration and integration into the mural layer. Improper coverage by VSMCs secondarily leads to incomplete maturation of the endothelial layer. Our results demonstrate that both Msx1 and Msx2 are required for the recruitment of a population of neural crest-derived VSMCs.