bluuebunny/crossref_metadata_2025 huggingface dataset:
Possible involvement of caveolin in attenuation of cardioprotective effect of ischemic preconditioning in diabetic rat heart
Authors: Ajmani Preeti , Yadav Harlokesh N , Singh Manjeet , Sharma Pyare L
Published: July 2011

Background

Nitric oxide (NO) has been noted to produce ischemic preconditioning (IPC)-mediated cardioprotection. Caveolin is a negative regulator of NO, which inhibits endothelial nitric oxide synthase (eNOS) by making caveolin-eNOS complex. The expression of caveolin is increased during diabetes mellitus (DM). The present study was designed to investigate the involvement of caveolin in attenuation of the cardioprotective effect of IPC during DM in rat.

Methods

Experimental DM was induced by single dose of streptozotocin (50 mg/Kg, i.p,) and animals were used for experiments four weeks later. Isolated heart was mounted on Langendorff's apparatus, and was subjected to 30 min of global ischemia and 120 min of reperfusion. IPC was given by four cycles of 5 min of ischemia and 5 min of reperfusion with Kreb's-Henseleit solution (K-H). Extent of injury was measured in terms of infarct size by triphenyltetrazolium chloride (TTC) staining, and release of lactate dehydrogenase (LDH) and creatin kinase-MB (CK-MB) in coronary effluent. The cardiac release of NO was noted by measuring the level of nitrite in coronary effluent.

Results

IPC- induced cardioprotection and release of NO was significantly decreased in diabetic rat heart. Pre-treatment of diabetic rat with daidzein (DDZ) a caveolin inhibitor (0.2 mg/Kg/s.c), for one week, significantly increased the release of NO and restored the attenuated cardioprotective effect of IPC. Also perfusion of sodium nitrite (10 μM/L), a precursor of NO, significantly restored the lost effect of IPC, similar to daidzein in diabetic rat. Administration of 5-hydroxy deaconate (5-HD), a mito KATP channel blocker, significantly abolished the observed IPC-induced cardioprotection in normal rat or daidzein and sodium nitrite perfused diabetic rat heart alone or in combination.

Conclusions

Thus, it is suggested that attenuation of the cardioprotection in diabetic heart may be due to decrease the IPC mediated release of NO in the diabetic myocardium, which may be due to up -regulation of caveolin and subsequently decreased activity of eNOS.
The epidemiology of alcohol utilization during pregnancy: an analysis of the Canadian Maternity Experiences Survey (MES)
Authors: Walker Meghan J , Al-Sahab Ban , Islam Farah , Tamim Hala
Published: July 2011

Background

Maternal alcohol consumption during pregnancy may potentially constitute a major public health concern in Canada but despite this, the available epidemiological data on both rates and predictors of alcohol consumption during pregnancy is limited. The present study assessed the prevalence and predictors of maternal alcohol consumption during pregnancy of women living in Canada from 2005-2006 who had a singleton live birth and whose child remained in their care 5-9 months following birth. Prevalence of maternal alcohol consumption was examined across the Canadian provinces.

Methods

The analysis was based on the Maternity Experience Survey (MES), a population-based survey that assessed pregnancy, delivery and postnatal experiences of mothers and their children between November 2005 and May 2006. The main outcome variable assessed was ever drinking alcohol during pregnancy. The sample of mothers who drank during pregnancy consisted mainly of low to moderate level-alcohol drinkers (95.8%), while only 1.7% of the sample were heavy drinkers (>1 drink per day). Socio-economic factors, demographic factors, maternal characteristics, and pregnancy related factors that proved to be significant at the bivariate level were considered for a logistic regression analysis. Bootstrapping was performed to account for the complex sampling design.

Results

Analysis of 5882 mothers, weighted to represent 72,767 Canadian women, found that 10.8% of women drank alcohol at some point during their pregnancies. This mainly reflects prevalence of low to moderate maternal alcohol consumption. Prevalence of drinking alcohol during pregnancy was 13.8% in Eastern-Central provinces, 7.8% in Western Provinces-British Columbia, 4.1% in Eastern-Atlantic provinces and 4.0% in Western-Prairie Provinces. Utilizing alcohol during gestation was significantly associated with several important factors including marital status, smoking status, reaction to the pregnancy and immigrant status. While being an immigrant to Canada appeared to confer a protective effect, women who have partners (odds ratio (OR) = 2.00; 95% confidence interval (CI): 1.20, 3.31) and smoked during pregnancy (OR = 1.54; 95% CI: 1.12, 1.87) were significantly more likely to drink alcohol during their pregnancies. Perhaps most importantly, pregnant women who reported indifference or being unhappy/very unhappy in regards to their pregnancies exhibited 1.89- and 2.5-fold increased risk of drinking alcohol during their pregnancies, respectively.

Conclusion

A number of important factors associated with maternal alcohol utilization during pregnancy have been identified, indicating areas where increased focus may serve to reduce maternal and pediatric morbidity and mortality.
A study on trypsin, Aspergillus flavus and Bacillus sp. protease inhibitory activity in Cassia tora (L.) syn Senna tora (L.) Roxb. seed extract
Authors: Tripathi Vinayak R , Kumar Shailendra , Garg Satyendra K
Published: July 2011

Background

Proteases play an important role in virulence of many human, plant and insect pathogens. The proteinaceous protease inhibitors of plant origin have been reported widely from many plant species. The inhibitors may potentially be used for multiple therapeutic applications in viral, bacterial, fungal diseases and physiological disorders. In traditional Indian medicine system, Cassia tora (Senna tora) is reportedly effective in treatment of skin and gastrointestinal disorders. The present study explores the protease inhibitory activity of the above plant seeds against trypsin, Aspergillus flavus and Bacillus sp. proteases.

Methods

The crushed seeds of Cassia tora were washed thoroughly with acetone and hexane for depigmentation and defatting. The proteins were fractionated by ammonium sulphate (0-30, 30-60, 60-90%) followed by dialysis and size exclusion chromatography (SEC). The inhibitory potential of crude seed extract and most active dialyzed fraction against trypsin and proteases was established by spot test using unprocessed x-ray film and casein digestion methods, respectively. Electrophoretic analysis of most active fraction (30-60%) and SEC elutes were carried employing Sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) and Gelatin SDS-PAGE. Inhibition of fungal spore germination was studied in the presence of dialyzed active inhibitor fraction. Standard deviation (SD) and ANOVA were employed as statistical tools.

Results

The crude seeds' extract displayed strong antitryptic, bacterial and fungal protease inhibitory activity on x-ray film. The seed protein fraction 30-60% was found most active for trypsin inhibition in caseinolytic assay (P < 0.001). The inhibition of caseinolytic activity of the proteases increased with increasing ratio of seed extract. The residual activity of trypsin, Aspergillus flavus and Bacillus sp. proteases remained only 4, 7 and 3.1%, respectively when proteases were incubated with 3 mg ml-1 seed protein extract for 60 min. The inhibitory activity was evident in gelatin SDS-PAGE where a major band (~17-19 kD) of protease inhibitor (PI) was detected in dialyzed and SEC elute. The conidial germination of Aspergillus flavus was moderately inhibited (30%) by the dialyzed seed extract.

Conclusions

Cassia tora seed extract has strong protease inhibitory activity against trypsin, Aspergillus flavus and Bacillus sp. proteases. The inhibitor in Cassia tora may attenuate microbial proteases and also might be used as phytoprotecting agent.
Fabrication of ultrahigh-density nanowires by electrochemical nanolithography
Authors: Chen Feng , Jiang Hongquan , Kiefer Arnold M , Clausen Anna M , Ting Yuk-Hong , Wendt Amy E , Ding Bingjun , Lagally Max G
Published: July 2011

An approach has been developed to produce silver nanoparticles (AgNPs) rapidly on semiconductor wafers using electrochemical deposition. The closely packed AgNPs have a density of up to 1.4 × 1011 cm-2 with good size uniformity. AgNPs retain their shape and position on the substrate when used as nanomasks for producing ultrahigh-density vertical nanowire arrays with controllable size, making it a one-step nanolithography technique. We demonstrate this method on Si/SiGe multilayer superlattices using electrochemical nanopatterning and plasma etching to obtain high-density Si/SiGe multilayer superlattice nanowires.
PLGA-based gene delivering nanoparticle enhance suppression effect of miRNA in HePG2 cells
Authors: Liang Gao Feng , Zhu Yan Liang , Sun Bo , Hu Fei Hu , Tian Tian , Li Shu Chun , Xiao Zhong Dang
Published: July 2011

The biggest challenge in the field of gene therapy is how to effectively deliver target genes to special cells. This study aimed to develop a new type of poly(D,L-lactide-co-glycolide) (PLGA)-based nanoparticles for gene delivery, which are capable of overcoming the disadvantages of polyethylenimine (PEI)- or cationic liposome-based gene carrier, such as the cytotoxicity induced by excess positive charge, as well as the aggregation on the cell surface. The PLGA-based nanoparticles presented in this study were synthesized by emulsion evaporation method and characterized by transmission electron microscopy, dynamic light scattering, and energy dispersive spectroscopy. The size of PLGA/PEI nanoparticles in phosphate-buffered saline (PBS) was about 60 nm at the optimal charge ratio. Without observable aggregation, the nanoparticles showed a better monodispersity. The PLGA-based nanoparticles were used as vector carrier for miRNA transfection in HepG2 cells. It exhibited a higher transfection efficiency and lower cytotoxicity in HepG2 cells compared to the PEI/DNA complex. The N/P ratio (ratio of the polymer nitrogen to the DNA phosphate) 6 of the PLGA/PEI/DNA nanocomplex displays the best property among various N/P proportions, yielding similar transfection efficiency when compared to Lipofectamine/DNA lipoplexes. Moreover, nanocomplex shows better serum compatibility than commercial liposome. PLGA nanocomplexes obviously accumulate in tumor cells after transfection, which indicate that the complexes contribute to cellular uptake of pDNA and pronouncedly enhance the treatment effect of miR-26a by inducing cell cycle arrest. Therefore, these results demonstrate that PLGA/PEI nanoparticles are promising non-viral vectors for gene delivery.
Antibodies against outer-capsid proteins of grass carp reovirus expressed in E. coli are capable of neutralizing viral infectivity
Authors: Shao Ling , Sun Xiaoyun , Fang Qin
Published: July 2011

Background

Grass carp reovirus (GCRV), which causes severe infectious outbreaks of hemorrhagic disease in aquatic animals, is a highly pathogenic agent in the Aquareovirus genus of family Reoviridae. The outer capsid shell of GCRV, composed of the VP5-VP7 protein complex, is believed to be involved in cell entry. The objective of this study was to produce a major neutralization antibody for mitigating GCRV infection.

Results

Recombinant plasmids of GCRV outer capsid proteins VP5 and VP7 were constructed and expressed in prokaryotic cells in our previous work. In this study, we prepared GCRV Antibody (Ab), VP5Ab and VP7Ab generated from purified native GCRV, recombinant VP5 and VP7 respectively. Immunoblotting analysis showed that the prepared antibodies were specific to its antigens. In addition, combined plaque and cytopathic effect (CPE)-based TCID50 (50% tissue culture infective dose) assays showed that both VP5Ab and VP7Ab were capable of neutralizing viral infectivity. Particularly, the neutralizing activity of VP7Ab was 3 times higher than that of VP5Ab, suggesting that VP7 might be a dominating epitope. Moreover, the combination of VP5Ab and VP7Ab appeared to enhance GCRV neutralizing capacity.

Conclusions

The results presented in this study indicated that VP7 protein was the major epitope of GCRV. Furthermore, VP5Ab and VP7Ab in combination presented an enhanced capacity to neutralize the GCRV particle, suggesting that the VP5 and VP7 proteins may cooperate with each other during virus cell entry. The data can be used not only to further define the surface epitope domain of GCRV but may also be applicable in the designing of vaccines.
Dietary fructose and risk of metabolic syndrome in adults: Tehran Lipid and Glucose study
Authors: Hosseini-Esfahani Firoozeh , Bahadoran Zahra , Mirmiran Parvin , Hosseinpour-Niazi Somayeh , Hosseinpanah Farhad , Azizi Fereidoun
Published: July 2011

Background

Studies have shown that the excessive fructose intake may induce adverse metabolic effects. There is no direct evidence from epidemiological studies to clarify the association between usual amounts of fructose intake and the metabolic syndrome.

Objective

The aim this study was to determine the association of fructose intake and prevalence of metabolic syndrome (MetS) and its components in Tehranian adults.

Methods

This cross-sectional population based study was conducted on 2537 subjects (45% men) aged 19-70 y, participants of the Tehran Lipid and Glucose Study (2006-2008). Dietary data were collected using a validated 168 item semi-quantitative food frequency questionnaire. Dietary fructose intake was calculated by sum of natural fructose (NF) in fruits and vegetables and added fructose (AF) in commercial foods. MetS was defined according to the modified NCEP ATP III for Iranian adults.

Results

The mean ages of men and women were 40.5 ± 13.6 and 38.6 ± 12.8 years, respectively. Mean total dietary fructose intakes were 46.5 ± 24.5 (NF: 19.6 ± 10.7 and AF: 26.9 ± 13.9) and 37.3 ± 24.2 g/d (NF: 18.6 ± 10.5 and AF: 18.7 ± 13.6) in men and women, respectively. Compared with those in the lowest quartile of fructose intakes, men and women in the highest quartile, respectively, had 33% (95% CI, 1.15-1.47) and 20% (95% CI, 1.09-1.27) higher risk of the metabolic syndrome; 39% (CI, 1.16-1.63) and 20% (CI, 1.07-1.27) higher risk of abdominal obesity; 11% (CI, 1.02-1.17) and 9% (CI, 1.02-1.14) higher risk of hypertension; and 9% (CI, 1-1.15) and 9% (1.04-1.12) higher risk of impaired fasting glucose.

Conclusion

Higher consumption of dietary fructose may have adverse metabolic effects.
Primary growth hormone insensitivity (Laron syndrome) and acquired hypothyroidism: a case report
Authors: Cotta Oana R , Santarpia Libero , Curtò Lorenzo , Aimaretti Gianluca , Corneli Ginevra , Trimarchi Francesco , Cannavò Salvatore
Published: July 2011

Introduction

Primary growth hormone resistance or growth hormone insensitivity syndrome, also known as Laron syndrome, is a hereditary disease caused by deletions or different types of mutations in the growth hormone receptor gene or by post-receptor defects. This disorder is characterized by a clinical appearance of severe growth hormone deficiency with high levels of circulating growth hormone in contrast to low serum insulin-like growth factor 1 values.

Case presentation

We report the case of a 15-year-old Caucasian girl who was diagnosed with Silver-Russell syndrome at the age of four and a half years. Recombinant growth hormone was administered for 18 months without an appropriate increase in growth velocity. At the age of seven years, her serum growth hormone levels were high, and an insulin-like growth factor 1 generation test did not increase insulin-like growth factor 1 levels (baseline insulin-like growth factor 1 levels, 52 μg/L; reference range, 75 μg/L to 365 μg/L; and peak, 76 μg/L and 50 μg/L after 12 and 84 hours, respectively, from baseline). The genetic analysis showed that the patient was homozygous for the R217X mutation in the growth hormone receptor gene, which is characteristic of Laron syndrome. On the basis of these results, the diagnosis of primary growth hormone insensitivity syndrome was made, and recombinant insulin-like growth factor 1 therapy was initiated. The patient's treatment was well tolerated, but unexplained central hypothyroidism occurred at the age of 12.9 years. At the age of 15 years, when the patient's sexual development was almost completed and her menstrual cycle occurred irregularly, her height was 129.8 cm, which is 4.71 standard deviations below the median for normal girls her age.

Conclusion

The most important functional tests for the diagnosis of growth hormone insensitivity are the insulin-like growth factor 1 generation test and genetic analysis. Currently, the only effective treatment is daily administration of recombinant insulin-like growth factor 1 starting from early childhood. However, these patients show a dramatically impaired final height. In our case, unexplained central hypothyroidism occurred during treatment.
Prospective evaluation of serum tissue inhibitor of metalloproteinase 1 and carbonic anhydrase IX in correlation to circulating tumor cells in patients with metastatic breast cancer
Authors: Müller Volkmar , Riethdorf Sabine , Rack Brigitte , Janni Wolfgang , Fasching Peter A , Solomayer Erich , Aktas Bahriye , Kasimir-Bauer Sabine , Zeitz Julia , Pantel Klaus , Fehm Tanja ,   the DETECT study group
Published: July 2011

Introduction

Circulating tumor cells (CTCs) reflect aggressive tumor behavior by hematogenous tumor cell dissemination. The tissue inhibitor of metalloproteinase 1 (TIMP-1) plays a role in tissue invasion and is also involved in angiogenesis, abrogation of apoptosis and in chemoresistance. Carbonic anhydrase IX (CAIX) is a metalloenzyme involved in cell adhesion, growth and survival of tumor cells. The aim of the study was to investigate whether serum concentrations of TIMP-1 and CAIX are associated with the detection of CTC in metastatic breast cancer.

Methods

Blood was obtained in a prospective multicenter setting from 253 patients with metastatic breast cancer at the time of disease progression. Serum TIMP-1 and CAIX were determined using commercial ELISA-kits (Oncogene Science). CTC were detected with the CellSearch™ system (Veridex).

Results

Five or more CTCs were detected in 122 patients out of 245 evaluable patients (49.8%). Out of 253 metastatic patients 70 (28%) had serum TIMP-1 levels above 454 ng/mL. Serum CAIX was elevated above 506 ng/mL in 90 (35%) patients. Both serum markers had prognostic significance. Median progression free survival (PFS) was 7.2 months with elevated TIMP-1 vs. 11.4 months with non-elevated levels (p < 0.01). OS was 11.5 vs. 19.1 months (p < 0.01). Median PFS was 7.5 months with elevated CAIX vs. 11.7 months with non-elevated levels (p < 0.01), overall survival (OS) was 13.4 months vs. 19.1 months (p < 0.01). In patients with five or more CTCs, serum levels were above the cut-off for CAIX in 47% vs. 25% in those with less than five CTCs (p = 0.01). For TIMP-1, 37% patients with five or more CTCs had elevated serum levels and 17% of patients with less than five CTCs (p = 0.01). Including TIMP-1, CAIX, CTC and established prognostic factors in the multivariate analysis, the presence of CTCs, the therapy line and elevated CAIX remained independent predictors of OS.

Conclusions

Elevated serum levels of the invasion markers TIMP-1 and CAIX in metastatic breast cancer are prognostic markers and are associated with the presence of CTCs. Whether increased secretion of TIMP-1 and/or CAIX might directly contribute to tumor cell dissemination remains to be elucidated in further investigations.

Trial registration

Current Controlled Trials: ISRCTN59722891
Combining VTI and HTI anisotropy in prestack time migration: Workflow and data examples
Authors: Jenner Edward
Published: July 2011

Accounting for anisotropy in P-wave data processing is now recognized as an important step in improving the quality of seismic data. The quality of final migrated images, prestack gathers, and any attributes derived from the seismic data can all be improved. Commonly, two forms of anisotropy are considered. The first and most common is vertical transverse isotropy (VTI), or the closely associated tilted transverse isotropy (TTI). This anisotropy is often caused by fine layering of sediments, with the layering smaller in scale than the seismic wavelength. In the case of VTI the bedding planes are horizontal, while in TTI they are dipping.
Nomograms for Predicting Local Recurrence, Distant Metastases, and Overall Survival for Patients With Locally Advanced Rectal Cancer on the Basis of European Randomized Clinical Trials
Authors: Valentini Vincenzo , van Stiphout Ruud G.P.M. , Lammering Guido , Gambacorta Maria Antonietta , Barba Maria Cristina , Bebenek Marek , Bonnetain Franck , Bosset Jean-Francois , Bujko Krzysztof , Cionini Luca , Gerard Jean-Pierre , Rödel Claus , Sainato Aldo , Sauer Rolf , Minsky Bruce D. , Collette Laurence , Lambin Philippe
Published: July 2011

Purpose

The purpose of this study was to develop accurate models and nomograms to predict local recurrence, distant metastases, and survival for patients with locally advanced rectal cancer treated with long-course chemoradiotherapy (CRT) followed by surgery and to allow for a selection of patients who may benefit most from postoperative adjuvant chemotherapy and close follow-up.

Patients and Methods

All data (N = 2,795) from five major European clinical trials for rectal cancer were pooled and used to perform an extensive survival analysis and to develop multivariate nomograms based on Cox regression. Data from one trial was used as an external validation set. The variables used in the analysis were sex, age, clinical tumor stage stage, tumor location, radiotherapy dose, concurrent and adjuvant chemotherapy, surgery procedure, and pTNM stage. Model performance was evaluated by the concordance index (c-index). Risk group stratification was proposed for the nomograms.

Results

The nomograms are able to predict events with a c-index for external validation of local recurrence (LR; 0.68), distant metastases (DM; 0.73), and overall survival (OS; 0.70). Pathologic staging is essential for accurate prediction of long-term outcome. Both preoperative CRT and adjuvant chemotherapy have an added value when predicting LR, DM, and OS rates. The stratification in risk groups allows significant distinction between Kaplan-Meier curves for outcome.

Conclusion

The easy-to-use nomograms can predict LR, DM, and OS over a 5-year period after surgery. They may be used as decision support tools in future trials by using the three defined risk groups to select patients for postoperative chemotherapy and close follow-up ( http://www.predictcancer.org ).
Impact of Treatment End Point Definitions on Perceived Differences in Long-Term Outcome With Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukemia
Authors: Kantarjian Hagop , O'Brien Susan , Jabbour Elias , Shan Jenny , Ravandi Farhad , Kadia Tapan , Faderl Stefan , Garcia-Manero Guillermo , Borthakur Gautam , Cortes Jorge
Published: July 2011

Purpose

Different definitions of progression-free survival (PFS) and event-free survival (EFS) may result in perceived differences in outcomes with tyrosine kinase inhibitor (TKI) therapies in chronic myelogenous leukemia (CML).

Patients and Methods

We analyzed the outcome of 435 patients with early chronic-phase, Philadelphia chromosome–positive CML treated with imatinib (n = 281), nilotinib (n = 78), and dasatinib (n = 76) using definitions of PFS and EFS used in the International Randomized Study of Interferon Versus STI571 (IRIS), Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients (ENEST-nd), Dasatinib Versus Imatinib Study in Treatment-Naïve CML Patients (DASISION), and MD Anderson Cancer Center (MDACC) trials. Definitions for EFS-IRIS, time without progression in ENEST-nd, PFS-DASISION, and EFS-MDACC were as previously reported. The EFS-MDACC considered an event any instance of toxicity or death from any cause on or off therapy (if not counted before death as progression/event).

Results

Of the 435 patients, 123 (28%) were taken off TKI therapy (resistance/loss of response, n = 33; blastic phase on TKI therapy, n = 6; intolerance/toxicity, n = 29; other causes, n = 55). Thirty-three patients (7.6%) have died; eight patients died on TKI therapy, two patients died within 60 days of being off TKIs, and 23 patients died after being off TKIs for more than 60 days. Of the 33 deaths, 19 deaths (eight deaths on TKI, two deaths within 60 days, and nine deaths off for resistance/relapse/transformation) would be counted as progression/events on the IRIS/ENEST-nd/DASISION studies, whereas 14 deaths would be censored at time off TKI. On the basis of the four definitions used by IRIS, ENEST-nd, DASISION, and MDACC trials, the corresponding 5-year PFS/EFS rates were 96%, 90%, 89%, and 81%.

Conclusion

Uniform definitions of PFS and EFS are needed to compare the long-term efficacy and potential use of different TKIs in CML.
Mutations and Deletions of the TP53 Gene Predict Nonresponse to Treatment and Poor Outcome in First Relapse of Childhood Acute Lymphoblastic Leukemia
Authors: Hof Jana , Krentz Stefanie , van Schewick Claudia , Körner Gabriele , Shalapour Shabnam , Rhein Peter , Karawajew Leonid , Ludwig Wolf-Dieter , Seeger Karl , Henze Günter , von Stackelberg Arend , Hagemeier Christian , Eckert Cornelia , Kirschner-Schwabe Renate
Published: July 2011

Purpose

In the clinical management of children with relapsed acute lymphoblastic leukemia (ALL), treatment resistance remains a major challenge. Alterations of the TP53 gene are frequently associated with resistance to chemotherapy, but their significance in relapsed childhood ALL has remained controversial because of small studies.

Patients and Methods

Therefore, we systematically studied 265 first-relapse patients enrolled in the German Acute Lymphoblastic Leukemia Relapse Berlin-Frankfurt-Mü nster 2002 (ALL-REZ BFM 2002) trial for sequence and copy number alterations of the TP53 gene by using direct sequencing and multiplex ligation-dependent probe amplification.

Results

We observed copy number and sequence alterations of TP53 in 12.4% (27 of 218) of patients with B-cell precursor ALL and 6.4% (three of 47) of patients with T-cell ALL relapse. Backtracking to initial ALL in 23 matched samples revealed that 54% of all TP53 alterations were gained at relapse. Within B-cell precursor ALL, TP53 alterations were consistently associated with nonresponse to chemotherapy (P < .001) and poor event-free survival (P < .001) and overall survival rates (P = .002). TP53 alterations also had a significant impact on survival within intermediate-risk (S2) and high-risk (S3/S4) relapse patients (P = .007 and P = .019, respectively). This prognostic significance of TP53 alterations was confirmed in multivariate analysis. Besides their clinical impact, TP53 alterations were associated with a higher fraction of leukemic cells in S/G2-M phase of the cell cycle at relapse diagnosis.

Conclusion

Alterations of the TP53 gene are of particular importance in the relapse stage of childhood ALL, in which they independently predict high risk of treatment failure in a significant number of patients. Therefore, they will aid in future risk assessment of children with ALL relapse.
Fgf differentially controls cross-antagonism between cardiac and haemangioblast regulators
Authors: Simões Filipa Costa , Peterkin Tessa , Patient Roger
Published: July 2011

Fibroblast growth factor (Fgf) has been implicated in the control of heart size during development, although whether this is by controlling cell fate, survival or proliferation has not been clear. Here, we show that Fgf, without affecting survival or proliferation, acts during gastrulation to drive cardiac fate and restrict anterior haemangioblast fate in zebrafish embryos. The haemangioblast programme was thought to be activated before the cardiac programme and is repressive towards it, suggesting that activation by Fgf of the cardiac programme might be via suppression of the haemangioblast programme. However, we show that the cardiac regulator nkx2.5 can also repress the haemangioblast programme and, furthermore, that cardiac specification still requires Fgf signalling even when haemangioblast regulators are independently suppressed. We further show that nkx2.5 and the cloche candidate gene lycat are expressed during gastrulation and regulated by Fgf, and that nkx2.5 overexpression, together with loss of the lycat targets etsrp and scl can stably induce expansion of the heart. We conclude that Fgf controls cardiac and haemangioblast fates by the simultaneous regulation of haemangioblast and cardiac regulators. We propose that elevation of Fgf signalling in the anterior haemangioblast territory could have led to its recruitment into the heart field during evolution, increasing the size of the heart.
LATE MERISTEM IDENTITY2 acts together with LEAFY to activate APETALA1
Authors: Pastore Jennifer J. , Limpuangthip Andrea , Yamaguchi Nobutoshi , Wu Miin-Feng , Sang Yi , Han Soon-Ki , Malaspina Lauren , Chavdaroff Natasha , Yamaguchi Ayako , Wagner Doris
Published: July 2011

The switch from producing vegetative structures (branches and leaves) to producing reproductive structures (flowers) is a crucial developmental transition that significantly affects the reproductive success of flowering plants. In Arabidopsis, this transition is in large part controlled by the meristem identity regulator LEAFY (LFY). The molecular mechanisms by which LFY orchestrates a precise and robust switch to flower formation is not well understood. Here, we show that the direct LFY target LATE MERISTEM IDENTITY2 (LMI2) has a role in the meristem identity transition. Like LFY, LMI2 activates AP1 directly; moreover, LMI2 and LFY interact physically. LFY, LMI2 and AP1 are connected in a feed-forward and positive feedback loop network. We propose that these intricate regulatory interactions not only direct the precision of this crucial developmental transition in rapidly changing environmental conditions, but also contribute to its robustness and irreversibility.
Retrograde BMP signaling controls Drosophila behavior through regulation of a peptide hormone battery
Authors: Veverytsa Lyubov , Allan Douglas W.
Published: July 2011

Retrograde BMP signaling in neurons plays conserved roles in synaptic efficacy and subtype-specific gene expression. However, a role for retrograde BMP signaling in the behavioral output of neuronal networks has not been established. Insect development proceeds through a series of stages punctuated by ecdysis, a complex patterned behavior coordinated by a dedicated neuronal network. In Drosophila, larval ecdysis sheds the old cuticle between larval stages, and pupal ecdysis everts the head and appendages to their adult external position during metamorphosis. Here, we found that mutants of the type II BMP receptor wit exhibited a defect in the timing of larval ecdysis and in the completion of pupal ecdysis. These phenotypes largely recapitulate those previously observed upon ablation of CCAP neurons, an integral subset of the ecdysis neuronal network. Here, we establish that retrograde BMP signaling in only the efferent subset of CCAP neurons (CCAP-ENs) is required to cell-autonomously upregulate expression of the peptide hormones CCAP, Mip and Bursicon β. In wit mutants, restoration of wit exclusively in CCAP neurons significantly rescued peptide hormone expression and ecdysis phenotypes. Moreover, combinatorial restoration of peptide hormone expression in CCAP neurons in wit mutants also significantly rescued wit ecdysis phenotypes. Collectively, our data demonstrate a novel role for retrograde BMP signaling in maintaining the behavioral output of a neuronal network and uncover the underlying cellular and gene regulatory substrates.
RNA silencing in Monterey
Authors: Rissland Olivia S. , Lai Eric C.
Published: July 2011

The tenth annual Keystone Symposium on the Mechanism and Biology of Silencing convened in Monterey, California, in March 2011. Those seeking some West Coast sunshine were, unfortunately, met with incessant precipitation throughout the meeting. Nevertheless, attendees were brightened by enlightening and vigorous scientific discussions. Here, we summarize the results presented at the meeting, which inspire and push this expanding field into new territories.
Endodermal Hedgehog signals modulate Notch pathway activity in the developing digestive tract mesenchyme
Authors: Kim Tae-Hee , Kim Byeong-Moo , Mao Junhao , Rowan Sheldon , Shivdasani Ramesh A.
Published: July 2011

The digestive tract epithelium and its adjoining mesenchyme undergo coordinated patterning and growth during development. The signals they exchange in the process are not fully characterized but include ligands of the Hedgehog (Hh) family, which originate in the epithelium and are necessary for mesenchymal cells to expand in number and drive elongation of the developing gut tube. The Notch signaling pathway has known requirements in fetal and adult intestinal epithelial progenitors. We detected Notch pathway activity in the embryonic gut mesenchyme and used conditional knockout mice to study its function. Selective disruption of the Notch effector gene RBP-Jκ (Rbpj) in the mesenchyme caused progressive loss of subepithelial fibroblasts and abbreviated gut length, revealing an unexpected requirement in this compartment. Surprisingly, constitutive Notch activity also induced rapid mesenchymal cell loss and impaired organogenesis, probably resulting from increased cell death and suggesting the need for a delicate balance in Notch signaling. Because digestive tract anomalies in mouse embryos with excess Notch activity phenocopy the absence of Hh signaling, we postulated that endodermal Hh restrains mesenchymal Notch pathway activity. Indeed, Hh-deficient embryos showed Notch overactivity in their defective gut mesenchyme and exposure to recombinant sonic hedgehog could override Notch-induced death of cultured fetal gut mesenchymal cells. These results reveal unexpected interactions between prominent signals in gastrointestinal development and provide a coherent explanation for Hh requirements in mesenchymal cell survival and organ growth.
A-MYB (MYBL1) transcription factor is a master regulator of male meiosis
Authors: Bolcun-Filas Ewelina , Bannister Laura A. , Barash Alex , Schimenti Kerry J. , Hartford Suzanne A. , Eppig John J. , Handel Mary Ann , Shen Lishuang , Schimenti John C.
Published: July 2011

The transcriptional regulation of mammalian meiosis is poorly characterized, owing to few genetic and ex vivo models. From a genetic screen, we identify the transcription factor MYBL1 as a male-specific master regulator of several crucial meiotic processes. Spermatocytes bearing a novel separation-of-function allele (Mybl1repro9) had subtle defects in autosome synapsis in pachynema, a high incidence of unsynapsed sex chromosomes, incomplete double-strand break repair on synapsed pachytene chromosomes and a lack of crossing over. MYBL1 protein appears in pachynema, and its mutation caused specific alterations in expression of diverse genes, including some translated postmeiotically. These data, coupled with chromatin immunoprecipitation (ChIP-chip) experiments and bioinformatic analysis of promoters, identified direct targets of MYBL1 regulation. The results reveal that MYBL1 is a master regulator of meiotic genes that are involved in multiple processes in spermatocytes, particularly those required for cell cycle progression through pachynema.
Designing New Electoral Districts for the City of Edmonton
Authors: Bozkaya Burcin , Erkut Erhan , Haight Dan , Laporte Gilbert
Published: July 2011

Every few years, the city of Edmonton, Canada must review and evaluate changes to its electoral district boundaries. The review process that was completed in 2009 resulted in modifying the district plan from a six-ward system with two council members in each to a single-member 12-ward system. The authors of this paper designed the redistricting plan. This paper describes the algorithm we applied to solve the problem and the decision support system we used. The algorithm is based on a multicriteria mathematical model, which is solved by a tabu search heuristic embedded within a geographic information system (GIS)-based decision support system. The resulting district plan meets districting criteria, including population balance, contiguity, compactness, respect for natural boundaries, growth areas, and integrity of communities of interest. This plan was formally approved as a city bylaw and used in the municipal elections in 2010.
Evaluating OR/MS Journals via PageRank
Authors: Xu Zhou , Cheang Brenda , Lim Andrew , Wen Qi
Published: July 2011

Scholars, practitioners, and students in operations research and management science (OR/MS) often hesitate to use traditional approaches to evaluate journal quality because of the inconsistency of these approaches to perceptions and other associated biases. We introduce an alternative approach, which is based on Google's PageRank, to evaluate 31 OR/MS journals. This approach enhances the impact factor method by considering both citation quantity and quality. When we apply our method to OR/MS journals, the results match survey opinions and significantly outperform rankings based on impact factors. In addition, we provide an extensive discussion of other methods that have been used to assess journal quality. Compared to these methods, our method is better able to discern quality differences for journals that are perceived to be of relatively higher quality. Most importantly, we integrate our method into a Web-based journal-ranking system.
Student Reactions to the Field Consulting Capstone Course in Operations Management at the University of Dayton
Authors: Gorman Michael F.
Published: July 2011

The University of Dayton's operations management major offers a unique capstone opportunity for students to apply theory in a live consulting project that addresses real problems of live clients. Projects require students to apply a broad spectrum of skills learned in the major, including, but not limited to, optimization, simulation, and statistical analysis, and apply techniques from business improvement programs such as lean, Six Sigma, and reengineering. As a result, students gain valuable experience applying technical skills in a live environment. This paper, a companion to The University of Dayton Operations Management Capstone Course: Undergraduate Student Field Consulting Applies Theory to Practice, which explores client reactions, presents the student perspectives on the risks and benefits of a course based on field consulting projects. Quantitative and qualitative student reaction to the course are reported from three sources: course evaluations at the time it was taken, a retrospective of the four-year experience upon graduation, and a survey that captures graduate reflections on the course up to seven years after completion of the course. Despite the inherent risks of offering a capstone based on field work, students find the experience both of tremendous practical value and of high academic rigor.
Accounting for Parameter Uncertainty in Large-Scale Stochastic Simulations with Correlated Inputs
Authors: Biller Bahar , Corlu Canan G.
Published: July 2011

This paper considers large-scale stochastic simulations with correlated inputs having normal-to-anything (NORTA) distributions with arbitrary continuous marginal distributions. Examples of correlated inputs include processing times of workpieces across several workcenters in manufacturing facilities and product demands and exchange rates in global supply chains. Our goal is to obtain mean performance measures and confidence intervals for simulations with such correlated inputs by accounting for the uncertainty around the NORTA distribution parameters estimated from finite historical input data. This type of uncertainty is known as the parameter uncertainty in the discrete-event stochastic simulation literature. We demonstrate how to capture parameter uncertainty with a Bayesian model that uses Sklar's marginal-copula representation and Cooke's copula-vine specification for sampling the parameters of the NORTA distribution. The development of such a Bayesian model well suited for handling many correlated inputs is the primary contribution of this paper. We incorporate the Bayesian model into the simulation replication algorithm for the joint representation of stochastic uncertainty and parameter uncertainty in the mean performance estimate and the confidence interval. We show that our model improves both the consistency of the mean line-item fill-rate estimates and the coverage of the confidence intervals in multiproduct inventory simulations with correlated demands.
Economic and Emissions Implications of Load-Based, Source-Based, and First-Seller Emissions Trading Programs Under California AB32
Authors: Chen Yihsu , Liu Andrew L. , Hobbs Benjamin F.
Published: July 2011

In response to Assembly Bill 32, the state of California considered three types of carbon emissions trading programs for the electric power sector: load-based, source-based, and first-seller. They differed in terms of their point of regulation and in whether in-state-to-out-of-state and out-of-state-to-in-state electricity sales are regulated. In this paper, we formulate a market equilibrium model for each of the three approaches, considering power markets, transmission limitations, and emissions trading, and making the simplifying assumption of pure bilateral markets. We analyze the properties of their solutions and show the equivalence of load-based, first-seller, and source-based approaches when in-state-to-out-of-state sales are regulated under the cap. A numeric example illustrates the emissions and economic implications of the models. In the simulated cases, “leakage” eliminates most of the emissions reductions that the regulations attempt to impose. Furthermore, “contract reshuffling” occurs to such an extent that all the apparent emissions reductions resulting from changes in sources of imported power are illusory.

In reality, the three systems would not be equivalent because there will also be pool-type markets, and the three systems provide different incentives for participating in those markets. However, the equivalence results under our simplifying assumptions show that load-based trading has no inherent advantage compared to other systems in terms of costs to consumers, contrary to claims elsewhere.
Mixed 0-1 Linear Programs Under Objective Uncertainty: A Completely Positive Representation
Authors: Natarajan Karthik , Teo Chung Piaw , Zheng Zhichao
Published: July 2011

In this paper, we analyze mixed 0-1 linear programs under objective uncertainty. The mean vector and the second-moment matrix of the nonnegative objective coefficients are assumed to be known, but the exact form of the distribution is unknown. Our main result shows that computing a tight upper bound on the expected value of a mixed 0-1 linear program in maximization form with random objective is a completely positive program. This naturally leads to semidefinite programming relaxations that are solvable in polynomial time but provide weaker bounds. The result can be extended to deal with uncertainty in the moments and more complicated objective functions. Examples from order statistics and project networks highlight the applications of the model. Our belief is that the model will open an interesting direction for future research in discrete and linear optimization under uncertainty.
Charlemagne's Challenge: The Periodic Latency Problem
Authors: Coene Sofie , Spieksma Frits C. R. , Woeginger Gerhard J.
Published: July 2011

Latency problems are characterized by their focus on minimizing the waiting time for all clients. We study periodic latency problems, a nontrivial extension of standard latency problems. In a periodic latency problem each client has to be visited regularly: there is a server traveling at unit speed, and there is a set of n clients with given positions. The server must visit the clients over and over again, subject to the constraint that successive visits to client i are at most qi time units away from each other.

We investigate two main problems. In problem PLPP the goal is to find a repeatable route for the server visiting as many clients as possible without violating their qis. In problem PLP the goal is to minimize the number of servers needed to serve all clients. Depending on the topology of the underlying network, we derive polynomial-time algorithms or hardness results for these two problems. Our results draw sharp separation lines between easy and hard cases.
High Folate Intake Is Related to Better Academic Achievement in Swedish Adolescents
Authors: Nilsson Torbjörn K. , Yngve Agneta , Böttiger Anna K. , Hurtig-Wennlöf Anita , Sjöström Michael
Published: July 2011

BACKGROUND:

Adolescents are vulnerable to increased plasma total homocysteine (tHcy) and to insufficient folate status. Folate status and Hcy metabolism are linked to cognitive functions, but academic achievement by adolescents has not been studied in this respect.

OBJECTIVE:

To assess a possible link between academic achievement in adolescents and tHcy and its determinants, dietary folate intake, MTHFR 677 TT homozygosity, and socioeconomic status (SES).

SUBJECTS AND METHODS:

A study of 386 Swedish adolescents aged 15 years in whom plasma tHcy and MTHFR 677C →T genotype were assayed. The sum of school grades in 10 core subjects obtained in the final semester of compulsory 9 years of schooling was used as outcome measure of academic achievement. Lifestyle and SES data were obtained from questionnaires.

RESULTS:

Academic achievement was strongly correlated to tertiles of tHcy (negatively; P = .023) and to tertiles of folate intake (positively; P < .001). Other significant predictors were gender, smoking, and SES (proxied by school, mother's education, and father's income). When these were controlled for, tertiles of folate intake (P < .002) but not tertiles of tHcy (P = .523) or MTHFR genotype remained significantly related to academic achievement.

CONCLUSION:

Folate intake had a positive association with academic achievement in the 15-year-olds, which was not attenuated by SES or MTHFR 677 TT homozygosity. These results provide new information that points to the importance of keeping a closer watch on folate status in childhood and adolescence. They may also have direct implications for school meal provisions, school teaching programs, and information to parents.