bluuebunny/crossref_metadata_2025 huggingface dataset:
Mature results of the M. D. Anderson Cancer Center risk-adapted transplantation strategy in mantle cell lymphoma
Authors: Tam Constantine S. , Bassett Roland , Ledesma Celina , Korbling Martin , Alousi Amin , Hosing Chitra , Kebraei Partow , Harrell Robyn , Rondon Gabriela , Giralt Sergio A. , Anderlini Paolo , Popat Uday , Pro Barbara , Samuels Barry , Hagemeister Frederick , Medeiros L. Jeffrey , Champlin Richard E. , Khouri Issa F.
Published: January 2009

In this study, we analyzed the long-term outcome of a risk-adapted transplantation strategy for mantle cell lymphoma in 121 patients enrolled in sequential transplantation protocols. Notable developments over the 17-year study period were the addition of rituximab to chemotherapy and preparative regimens and the advent of nonmyeloablative allogeneic stem cell transplantation (NST). In the autologous transplantation group (n = 86), rituximab resulted in a marked improvement in progression-free survival for patients who received a transplant in their first remission (where a plateau emerged at 3-8 years) but did not change the outcomes for patients who received a transplant beyond their first remission. In the NST group, composed entirely of patients who received a transplant beyond their first remission, durable remissions also emerged in progression-free survival at 5 to 9 years. The major determinants of disease control after NST were the use of a peripheral blood stem cell graft and donor chimerism of at least 95%, whereas the major determinant of death was immunosuppression for chronic graft-versus-host disease. Our results show that long-term disease-free survival in mantle cell lymphoma is possible after rituximab-containing autologous transplantation for patients in first remission and after NST for patients with relapsed or refractory disease.
Leukotriene B4release by human lung macrophagesviareceptor- not voltage-operated Ca2+channels
Authors: Finney-Hayward T. K. , Bahra P. , Li S. , Poll C. T. , Nicholson A. G. , Russell R. E. K. , Ford P. A. , Westwick J. , Fenwick P. S. , Barnes P. J. , Donnelly L. E.
Published: January 2009

Increased numbers of macrophages and neutrophils in the lung is a key feature of chronic obstructive pulmonary disease (COPD). The major neutrophil chemotactic agent in the airways of COPD patients is leukotriene (LT)B4and is released by macrophages. The present study examines the role and mechanism of Ca2+in platelet-activating factor (PAF)-stimulated LTB4release from human lung macrophages.

Macrophages were isolated from lung tissue of subjects undergoing lung resection surgery and monocyte-derived macrophages (MDM) were obtained from nonsmokers, smokers without obstruction and COPD patients. Cells were stimulated with PAF and LTB4release and [Ca2+]iwas measured.

Lung macrophages and MDM released LTB4following stimulation with PAF (mean effective concentration: 0.08±0.06 μM (n = 5)versus0.17±0.12 μM (n = 17), respectively). Compared with MDM, lung macrophages released approximately eight-fold more LTB4. Neither smoking nor COPD altered MDM responses. PAF-stimulated LTB4release was abrogated by ethylene glycol tetraacetic acid suggesting a role for extracellular Ca2+. This was substantiated by using store-operated channel blockers econazole, SK&F96365 and Gd3+. However, econazole and SK&F96365 were more effective in MDM than lung macrophages. Neither LOE908 nor nifedipine could attenuate this response.

These data suggest that platelet-activating factor-stimulated leukotriene B4release from human lung macrophages is mediated, in part, by Ca2+influx through receptor- but not voltage-operated Ca2+channels.
Role of lymphotoxin-α in cigarette smoke-induced inflammation and lymphoid neogenesis
Authors: Demoor T. , Bracke K. R. , Maes T. , Vandooren B. , Elewaut D. , Pilette C. , Joos G. F. , Brusselle G. G.
Published: January 2009

In chronic obstructive pulmonary disease (COPD), chronic inflammation is accompanied by peribronchial lymphoid aggregates. Lymphotoxin (LT)-α, crucial in secondary lymphoid organogenesis, may be involved in lymphoid neogenesis.

We examined cigarette smoke (CS)-induced pulmonary lymphoid neogenesis and inflammationin vivoin LTα knockout (LTα-/-) and wild-type (WT) mice and studied the expression of lymphoid chemokines by lung fibroblastsin vitro.

T-cell numbers (in bronchoalveolar lavage fluid (BALF) and lungs) and lymphoid aggregate numbers were significantly higher in air-exposed LTα-/-mice than in WT animals, and increased upon chronic CS exposure in both genotypes. In contrast, local immunoglobulin A responses upon chronic CS exposure were attenuated in LTα-/-mice. CXC chemokine ligand (CXCL) 13 and CC chemokine ligand (CCL) 19 mRNA in total lung and CXCL13 protein level in BALF increased upon CS exposure in WT, but not in LTα-/-mice.In vitrolymphotoxin-β receptor (LTβR) stimulation induced CXCL13 and CCL19 mRNA in WT lung fibroblasts. Furthermore,in vitroexposure to CS extract upregulated CXCL13 mRNA expression in WT, but not in LTβR-/-, lung fibroblasts.

In this murine model of COPD, CS induces pulmonary expression of lymphoid chemokines CXCL13 and CCL19 in a LTαβ–LTβR-dependent fashion. However, LTα is not required for CS-induced pulmonary lymphocyte accumulation and neogenesis of lymphoid aggregates.
A multiway analysis for identifying high integrity bovine BACs
Authors: Ratnakumar Abhirami , Barris Wesley , McWilliam Sean , Brauning Rudiger , McEwan John C , Snelling Warren M , Dalrymple Brian P
Published: January 2009

Background

In large genomics projects involving many different types of analyses of bacterial artificial chromosomes (BACs), such as fingerprinting, end sequencing (BES) and full BAC sequencing there are many opportunities for the identities of BACs to become confused. However, by comparing the results from the different analyses, inconsistencies can be identified and a set of high integrity BACs preferred for future research can be defined.

Results

The location of each bovine BAC in the BAC fingerprint-based genome map and in the genome assembly were compared based on the reported BESs, and for a smaller number of BACs the full sequence. BACs with consistent positions in all three datasets, or if the full sequence was not available, for both the fingerprint map and BES-based alignments, were deemed to be correctly positioned. BACs with consistent BES-based and fingerprint-based locations, but with conflicting locations based on the fully sequenced BAC, appeared to have been misidentified during sequencing, and included a number of apparently swapped BACs. Inconsistencies between BES-based and fingerprint map positions identified thirty one plates from the CHORI-240 library that appear to have suffered substantial systematic problems during the end-sequencing of the BACs. No systematic problems were identified in the fingerprinting of the BACs. Analysis of BACs overlapping in the assembly identified a small overrepresentation of clones with substantial overlap in the library and a substantial enrichment of highly overlapping BACs on the same plate in the CHORI-240 library. More than half of these BACs appear to have been present as duplicates on the original BAC-library plates and thus should be avoided in subsequent projects.

Conclusion

Our analysis shows that ~95% of the bovine CHORI-240 library clones with both a BAC fingerprint and two BESs mapping to the genome in the expected orientations (~27% of all BACs) have consistent locations in the BAC fingerprint map and the genome assembly. We have developed a broadly applicable methodology for checking the integrity of BAC-based datasets even where only incomplete and partially assembled genomic sequence is available.
Prevalence, evaluation and management of overactive bladder in primary care
Authors: Cheung Wellman W , Khan Nadia H , Choi Karmina K , Bluth Martin H , Vincent Miriam T
Published: January 2009

Background

Patients with overactive bladder (OAB) are under-diagnosed in the primary care setting. Primary care physicians (PCP) approach to the patient and appropriate patient disclosure may contribute to under-diagnosis.

Methods

An outpatient primary care setting was used to determine the prevalence and characteristics of OAB. Patients who visited the family medicine outpatient clinic were invited to answer a self-administered questionnaire. It included questions on evidence of lower urinary tract symptoms (modified Overactive Bladder-Validated 8-question Screener [OAB-V8]), relevant medical and surgical history, and demographic data. Relationship between OAB and other independent variables were analyzed using chi-square and risk ratio (RR) analysis.

Results

Of 325 questionnaires distributed, 311 were returned completed. Patients ranged from 18 to 97 years, the majority women (74.0%) and African American (74.3%). OAB was present in 60.5% of men and 48.3% of women (p = 0.058). OAB was significantly associated with obesity (BMI > = 30) in women (p = 0.018, RR = 1.72), specifically obese premenopausal women (age < 55 years) (p = 0.011, RR = 1.98).

Conclusion

OAB prevalence is more than double and higher in men than previously reported. The relative risk for OAB is significantly greater in obese premenopausal women.
Total laparoscopic hysterectomy versus abdominal hysterectomy in the treatment of patients with early stage endometrial cancer: A randomized multi center study
Authors: Bijen Claudia BM , Briët Justine M , de Bock Geertruida H , Arts Henriëtte JG , Bergsma-Kadijk Johanna A , Mourits Marian JE
Published: January 2009

Background

Traditionally standard treatment for patients with early stage endometrial cancer (EC) is total abdominal hysterectomy and bilateral salpingo oophorectomy (TAH+BSO) with or without lymph node dissection through a vertical midline incision. While TAH is an accepted effective treatment, it is highly invasive, visibly scarring and associated with morbidity. An alternative treatment is the same operation by laparoscopy. Though in several studies total laparoscopic hysterectomy (TLH+ BSO) seems a safe and feasible alternative approach in early stage endometrial cancer patients, there are no randomized data available yet. Furthermore, a randomized controlled trial with surgeons trained in laparoscopy is warranted in order to implement this technique in a safe manner. The aim of this study is to compare the treatment related morbidity, cost-effectiveness and quality of life in early stage endometrial cancer patients treated by laparoscopy versus the standard open approach.

Methods

A multi centre randomized clinical phase 3 trial, including 5 university hospitals and 15 regional hospitals in the Netherlands. Only gynecologists trained in performing a TLH are allowed to participate. Inclusion criteria: Patients with a clinical stage I endometrioid adenocarcinoma or complex atypical hyperplasia are randomized in a 2:1 allocation to receive TLH or TAH. The main outcome measure is the rate of major complications, as assessed by an independent clinical review board. In total, 275 patients are required to have 80% power at α-0.05 to detect a significant difference of 15% complication rate. Secondary outcome measures are 1) costs and cost-effectiveness, 2) minor complications, and 3) quality of life. All data from this multi center study are reported using case record forms. Data regarding quality of life, pain, body Image, sexuality and additional homecare are assessed with self reported questionnaires.

Discussion

A randomized multi center study in early stage endometrial cancer patients with inclusion criteria for patients and surgeons is designed and ongoing. Results will be presented at the end of 2009.

Trial Registration

Dutch trial register number NTR821.
EZH2 and BMI1 inversely correlate with prognosis and TP53 mutation in breast cancer
Authors: Pietersen Alexandra M , Horlings Hugo M , Hauptmann Michael , Langerød Anita , Ajouaou Abderrahim , Cornelissen-Steijger Paulien , Wessels Lodewijk F , Jonkers Jos , Vijver Marc J van de , van Lohuizen Maarten
Published: January 2009

Introduction

PolycombGroup (PcG) proteins maintain gene repression through histone modifications and have been implicated in stem cell regulation and cancer. EZH2 is part of Polycomb Repressive Complex 2 (PRC2) and trimethylates H3K27. This histone mark recruits the BMI1-containing PRC1 that silences the genes marked by PRC2. Based on their role in stem cells, EZH2 and BMI1 have been predicted to contribute to a poor outcome for cancer patients.

Methods

We have analysed the expression of EZH2 and BMI1 in a well-characterised dataset of 295 human breast cancer samples.

Results

Interestingly, although EZH2 overexpression correlates with a poor prognosis in breast cancer, BMI1 overexpression correlates with a good outcome. Although this may reflect transformation of different cell types, we also observed a functional difference. The PcG-target genes INK4A and ARF are not expressed in tumours with high BMI1, but they are expressed in tumours with EZH2 overexpression. ARF expression results in tumour protein P53 (TP53) activation, and we found a significantly higher proportion of TP53 mutations in tumours with high EZH2. This may explain why tumours with high EZH2 respond poorly to therapy, in contrast to tumours with high BMI1.

Conclusions

Overall, our data highlight that whereas EZH2 and BMI1 may function in a 'linear' pathway in normal development, their overexpression has different functional consequences for breast tumourigenesis.
1α,25-Dihydroxyvitamin D3 Reduces c-Myc Expression, Inhibiting Proliferation and Causing G1 Accumulation in C4-2 Prostate Cancer Cells
Authors: Rohan JoyAnn N. Phillips , Weigel Nancy L.
Published: January 2009

There is an inverse correlation between exposure to sunlight (the major source of vitamin D) and the risk for prostate cancer, the most common noncutaneous cancer and second most common cause of death from cancer in American men. The active metabolite of vitamin D, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] acting through the vitamin D receptor decreases prostate cancer cell growth and invasiveness. The precise mechanisms by which 1,25(OH)2D3 inhibits growth in prostate cancer have not been fully elucidated. Treatment with 1,25(OH)2D3 causes an accumulation in the G0/G1 phase of the cell cycle in several prostate cancer cell lines. One potential target known to regulate the G0/G1 to S phase transition is c-Myc, a transcription factor whose overexpression is associated with a number of cancers including prostate cancer. We find that 1,25(OH)2D3 reduces c-Myc expression in multiple prostate epithelial cell lines, including C4-2 cells, an androgen-independent prostate cancer cell line. Reducing c-Myc expression to the levels observed after 1,25(OH)2D3 treatment resulted in a comparable decrease in proliferation and G1 accumulation demonstrating that down-regulation of c-Myc is a major component in the growth-inhibitory actions of 1,25(OH)2D3. Treatment with 1,25(OH)2D3 resulted in a 50% decrease in c-Myc mRNA but a much more extensive reduction in c-Myc protein. Treatment with 1,25(OH)2D3 decreased c-Myc stability by increasing the proportion of c-Myc phosphorylated on T58, a glycogen synthase kinase-3β site that serves as a signal for ubiquitin-mediated proteolysis. Thus, 1,25(OH)2D3 reduces both c-Myc mRNA levels and c-Myc protein stability to inhibit growth of prostate cancer cells.
Loss of Betaglycan Contributes to the Malignant Properties of Human Granulosa Tumor Cells
Authors: Bilandzic Maree , Chu Simon , Farnworth Paul G. , Harrison Craig , Nicholls Peter , Wang Yao , Escalona Ruth M. , Fuller Peter J. , Findlay Jock K. , Stenvers Kaye L.
Published: January 2009

Betaglycan is a type III TGFβ receptor that modulates cellular sensitivity to inhibins and TGFβ. Previous studies have suggested that betaglycan acts as a tumor suppressor in certain human epithelial cancers. However, the roles of betaglycan in ovarian granulosa cell tumors (GCTs) are poorly understood. The objective of this study was to determine whether human GCTs exhibit betaglycan expression and, if so, what impact this receptor has on tumor biology. Real-time PCR was used to quantify betaglycan transcripts in human GCTs (n = 17) and normal premenopausal ovaries (n = 11). This analysis established that GCTs exhibited a significant 2-fold lower mean betaglycan mRNA level as compared with the normal ovary (P < 0.05). Similarly, two human GCT cell lines, KGN and COV434, exhibited low betaglycan expression and poor responsiveness to TGFβ and inhibin A in luciferase reporter assays, which was restored by stable transfection of wild-type betaglycan. Betaglycan significantly increased the adhesion of COV434 (P < 0.05) and KGN (P < 0.0001) cells, decreased cellular invasion through Matrigel, and inhibited wound healing. Expression of mutant forms of betaglycan that are defective in TGFβ and/or inhibin binding in each GCT cell line revealed that the inhibitory effects of betaglycan on wound healing were most strongly linked to the inhibin-binding region of betaglycan. Furthermore, knockdown of INHA mRNA expression abrogated the betaglycan-mediated inhibition of wound healing and invasion, whereas both INHA silencing and TGFβ neutralization abolished the betaglycan-mediated increase in adhesion to substrate. These data suggest that loss of betaglycan contributes to the pathogenesis of GCTs.
Epigenetic reprogramming and induced pluripotency
Authors: Hochedlinger Konrad , Plath Kathrin
Published: January 2009

The cloning of animals from adult cells has demonstrated that the developmental state of adult cells can be reprogrammed into that of embryonic cells by uncharacterized factors within the oocyte. More recently,transcription factors have been identified that can induce pluripotency in somatic cells without the use of oocytes, generating induced pluripotent stem(iPS) cells. iPS cells provide a unique platform to dissect the molecular mechanisms that underlie epigenetic reprogramming. Moreover, iPS cells can teach us about principles of normal development and disease, and might ultimately facilitate the treatment of patients by custom-tailored cell therapy.
Dual sex-specific functions ofDrosophilaUpstream of N-ras in the control of X chromosome dosage compensation
Authors: Patalano Solenn , Mihailovich Marija , Belacortu Yaiza , Paricio Nuria , Gebauer Fátima
Published: January 2009

Dosage compensation in Drosophila melanogaster involves the assembly of the MSL-2-containing dosage compensation complex (DCC) on the single X chromosome of male flies. Translational repression of msl-2mRNA blocks this process in females. Previous work indicated that the ubiquitous protein Upstream of N-ras (UNR) is a necessary co-factor for msl-2 repression in vitro. Here, we explore the function of UNR in vivo. Hypomorphic Unr mutant flies showed DCC assembly on high-affinity sites in the female X chromosomes, confirming that UNR inhibits dosage compensation in female flies. Unexpectedly, male mutant flies and UNR-depleted SL2 cells showed decreased DCC binding to the X chromosome,suggesting a role for UNR in DCC assembly or targeting. Consistent with this possibility, UNR overexpression resulted in moderate loss of DCC from the male X chromosome and predominant male lethality. Immunoprecipitation experiments revealed that UNR binds to roX1 and roX2, the non-coding RNA components of the DCC, providing possible targets for UNR function in males. These results uncover dual sex-specific functions of UNR in dosage compensation: to repress DCC formation in female flies and to promote DCC assembly on the male X chromosome.
Positive- and negative-feedback regulations coordinate the dynamic behavior of the Ras-Raf-MEK-ERK signal transduction pathway
Authors: Shin Sung-Young , Rath Oliver , Choo Sang-Mok , Fee Frances , McFerran Brian , Kolch Walter , Cho Kwang-Hyun
Published: January 2009

The Ras-Raf-MEK-ERK pathway (or ERK pathway) is an important signal transduction system involved in the control of cell proliferation, survival and differentiation. However, the dynamic regulation of the pathway by positive- and negative-feedback mechanisms, in particular the functional role of Raf kinase inhibitor protein (RKIP) are still incompletely understood. RKIP is a physiological endogenous inhibitor of MEK phosphorylation by Raf kinases, but also participates in a positive-feedback loop in which ERK can inactivate RKIP. The aim of this study was to elucidate the hidden dynamics of these feedback mechanisms and to identify the functional role of RKIP through combined efforts of biochemical experiments and in silico simulations based on an experimentally validated mathematical model. We show that the negative-feedback loop from ERK to SOS plays a crucial role in generating an oscillatory behavior of ERK activity. The positive-feedback loop in which ERK functionally inactivates RKIP also enhances the oscillatory activation pattern of ERK. However, RKIP itself has an important role in inducing a switch-like behavior of MEK activity. When overexpressed, RKIP also causes delayed and reduced responses of ERK. Thus, positive- and negative-feedback loops and RKIP work together to shape the response pattern and dynamical characteristics of the ERK pathway.
Incorporating uncertainty and multiple criteria in vessel selection
Authors: Yang Z L , Mastralis L , Bonsall S , Wang J
Published: January 2009

The selection of appropriate vessels to carry out shipping activities is crucial for many maritime stakeholders, including charterers, shipowners, brokers, surveyors, and safety engineers. The task is essentially a process of multiple criterion decision making under uncertainty, requiring analysts to derive rational decisions from uncertain and incomplete data contained in different quantitative and qualitative forms. The difficulty and complexity of such a task is obvious and thus stimulates the study of developing a novel decision-making technique under uncertainty with multiple criteria. The core of the method is the Dempster—Shafer theory, based on which the new function of fuzzy ‘evidential reasoning’ is investigated, analysed, and further applied to improve the vessel selection process of dealing with multiple criteria with insufficient and ambiguous information. A numerical case study of selecting an oil tanker based on a voyage charter party is presented to demonstrate the proposed method.
The effects of booking body mass index on obstetric and neonatal outcomes in an inner city UK tertiary referral centre
Authors: Chereshneva Maria , Hinkson Larry , Oteng-Ntim Eugene
Published: January 2009

The aim of the study was to investigate the effects of booking body mass index (BMI) on obstetric and neonatal outcomes in an inner city UK tertiary referral maternity centre. The Guy's and St Thomas' Maternity and Gynaecology (Terranova Healthware) Database was studied. All women that delivered at St Thomas' during 2005 with normal and high BMI were included in the study. Subjects were divided into three groups: BMI 19–24.9 (normal); 25–29.9 (overweight) and 30 or greater (obese). Groups were compared using Stata Statistical software. The study included 3642 patients: 2169 normal, 945 overweight and 528 obese. Both overweight and obese groups had a statistically significant association with gestational diabetes (odds ratio [OR] 5.7 and 11.6), hypertension in pregnancy (including preeclampsia [ORs 1.5 and 2.4], preterm rupture of membranes (ORs 3.7 and 5.0) and preterm delivery (ORs 1.4 and 1.6). The rate for caesarean delivery was increased in both overweight and obese women (ORs 1.4 and 1.7). Obesity is an independent risk factor for adverse obstetric outcomes and is significantly associated with caesarean section delivery.
External Learning Activities and Team Performance: A Multimethod Field Study
Authors: Bresman Henrik
Published: January 2009

This paper reports on a study of external team learning activities and their performance effects. It proposes and tests a model that consists of two sets of external learning activities: those that allow a team to learn from external experienced others about its task (vicarious learning activities) and those that allow a team to learn from external sources about its context (contextual learning activities). Qualitative data from six teams in one pharmaceutical firm are used to develop measures. Survey data from 62 additional teams in six other pharmaceutical firms are used, first to test the measurement model using structural equation modeling and second to test the relationships between external learning activities and team performance using random-effects regression models. Results show that vicarious learning activities are more strongly associated with performance when teams engage in more internal learning activities. Furthermore, vicarious learning activities in the absence of sufficient amounts of internal learning activities can hurt performance. The positive performance associated with contextual learning activities, by contrast, is unaffected by the level of internal learning activities. The paper contributes by distinguishing between two kinds of external learning activities and showing that they put different demands on teams to be effective. This is important because it helps us better understand how teams engage effectively in learning activities across their boundaries.
The development of asset-based welfare: the case of the Child Trust Fund in the UK
Authors: Prabhakar Rajiv
Published: January 2009

Asset-based welfare has recently attracted interest across the globe. This approach insists that the assets that a person owns are an important part of well-being. The UK's Child Trust Fund (CTF) is one of the most prominent examples of this approach. It provides a capital endowment to all new babies and the policy has generated international interest. However, the CTF does not command universal support in the UK. One of the main political parties is committed to abolishing it. This article examines the debate about the CTF in the UK. I suggest that criticisms of the Fund are part of wider concerns about the future direction of asset-based welfare. The article is important for highlighting some of the dilemmas associated with the new agenda on asset-based welfare.
Glutathione dysregulation and the etiology and progression of human diseases
Authors: Ballatori Nazzareno , Krance Suzanne M. , Notenboom Sylvia , Shi Shujie , Tieu Kim , Hammond Christine L.
Published: January 2009

Glutathione (GSH) plays an important role in a multitude of cellular processes, including cell differentiation, proliferation, and apoptosis, and as a result, disturbances in GSH homeostasis are implicated in the etiology and/or progression of a number of human diseases, including cancer, diseases of aging, cystic fibrosis, and cardiovascular, inflammatory, immune, metabolic, and neurodegenerative diseases. Owing to the pleiotropic effects of GSH on cell functions, it has been quite difficult to define the role of GSH in the onset and/or the expression of human diseases, although significant progress is being made. GSH levels, turnover rates, and/or oxidation state can be compromised by inherited or acquired defects in the enzymes, transporters, signaling molecules, or transcription factors that are involved in its homeostasis, or from exposure to reactive chemicals or metabolic intermediates. GSH deficiency or a decrease in the GSH/glutathione disulfide ratio manifests itself largely through an increased susceptibility to oxidative stress, and the resulting damage is thought to be involved in diseases, such as cancer, Parkinson's disease, and Alzheimer's disease. In addition, imbalances in GSH levels affect immune system function, and are thought to play a role in the aging process. Just as low intracellular GSH levels decrease cellular antioxidant capacity, elevated GSH levels generally increase antioxidant capacity and resistance to oxidative stress, and this is observed in many cancer cells. The higher GSH levels in some tumor cells are also typically associated with higher levels of GSH-related enzymes and transporters. Although neither the mechanism nor the implications of these changes are well defined, the high GSH content makes cancer cells chemoresistant, which is a major factor that limits drug treatment. The present report highlights and integrates the growing connections between imbalances in GSH homeostasis and a multitude of human diseases.
Two aspartic proteinases secreted by the pathogenic yeast Candida parapsilosis differ in expression pattern and catalytic properties
Authors: Hrušková-Heidingsfeldová Olga , Dostál Jiří , Majer Filip , Havlíková Jana , Hradilek Martin , Pichová Iva
Published: January 2009

Secreted aspartic proteinases (Sap) play a role in the virulence of pathogenic Candida spp. Candida parapsilosis possesses three genes encoding these enzymes: SAPP1, SAPP2, and SAPP3. We analyzed the expression of the SAPP1 and SAPP2 genes and the production of Sapp1p and Sapp2p proteinases in the presence of different nitrogen sources. While the SAPP2 transcript was present under all of the conditions tested, expression of SAPP1 was induced only by the presence of exogenous protein as the sole nitrogen source. The concentration of Sapp1p in the medium upon induction was at least one order of magnitude higher than the concentration of Sapp2p in all media tested in this study. Enzymological characterization of purified Sapp1p and Sapp2p demonstrated that Sapp2p has a more restricted substrate specificity and significantly lower catalytic activity than Sapp1p. Homology models of Sapp1p and Sapp2p revealed structural motifs that may be responsible for the differences between these two enzymes. Our results indicate that C. parapsilosis secretes a low level of Sapp2p proteinase with narrow substrate specificity and low proteolytic activity under most conditions, while expression and secretion of a higher amount of catalytically efficient Sapp1p enzymes is triggered in the presence of exogenous protein serving as a nitrogen source.
Central nervous system: cholesterol turnover, brain development and neurodegeneration
Authors: Dietschy John M.
Published: January 2009

The average amount of cholesterol in the whole animal equals approximately 2100 mg/kg body weight, and 15% and 23% of this sterol in the mouse and human, respectively, is found in the central nervous system. There is no detectable uptake across the blood-brain barrier of cholesterol carried in lipoproteins in the plasma, even in the newborn. However, high rates of de novo cholesterol synthesis in the glia and neurons provide the sterol necessary for early brain development. Once a stable brain size is achieved in the adult, cholesterol synthesis continues, albeit at a much lower rate, and this synthesis is just balanced by the excretion of an equal amount of sterol, either as 24(S)-hydroxycholesterol or, presumably, as cholesterol itself.
Structure-function relationship of the human antimicrobial peptide LL-37 and LL-37 fragments in the modulation of TLR responses
Authors: Molhoek E. Margo , den Hertog Alice L. , de Vries Anne-Marij B.C. , Nazmi Kamran , Veerman Enno C.I. , Hartgers Franca C. , Yazdanbakhsh Maria , Bikker Floris J. , van der Kleij Desiree
Published: January 2009

Cathelicidins are effector molecules of the innate host defense system that establish an antimicrobial barrier at epithelial interfaces. The human cathelicidin LL-37, in addition to its antimicrobial activity, also exhibits immunomodulatory effects, such as inhibition of pro-inflammatory responses to bacterial LPS in human monocytic cells. In this report, we demonstrate that LL-37 almost completely prevents the pro-inflammatory cytokine release by human peripheral blood mononuclear cells (PBMCs) following stimulation with Toll-like receptor (TLR)4 and TLR2/1 agonists while leaving TLR2/6, TLR5, TLR7 and TLR8 responses unchanged. Modulation of the TLR response by LL-37 occurred at least partly through the MAP kinase pathway via inhibition of p38 phosphorylation. By using an LL-37 library with overlapping sequences, we identified the mid-region of LL-37, comprising amino acids 13–31, as the active domain for the modulation of TLR responses. The mechanism of immunomodulation of LL-37 and LL-37 fragments is lipopoly-saccharide binding. Correlations between the capacity of LL-37 fragments to modulate TLR responses and their physico-chemical properties revealed that cationicity and hydrophobicity are essential for the modulation of LL-37-mediated TLR responses.
The Impact of Time Pressure and Experience on Information Search and Decision-Making Processes
Authors: Khoo Yee-Len , Mosier Kathleen
Published: January 2009

The goal of this research was to examine the diagnosis and decision processes of pilots when dealing with conflicting information. The loose coupling between decision processes and an event outcome makes it hard for researchers to use data such as accident reports as reliable indicators of the quality of decisions, and one problem faced by researchers is determining the extent to which pilot decision processes during events are faulty. We examined pilot strategies in a Web-based automated cockpit scenario as a function of time pressure condition (present vs. absent) and experience with automated systems. Time pressure had an impact on time to diagnosis and information accessed for more experienced pilots only. Pilots who accessed more information were more likely to make accurate diagnoses but were less confident in them. Neither time pressure nor experience had a main effect on diagnosis accuracy or confidence. More experienced pilots tended to conduct a thorough information search when under no time pressure, but time pressure caused pilots of all experience levels to accelerate and filter their information search. Results highlight the importance of training for coherent information use under time pressure given the complexities of automated aircraft.
Improving Decision Making in Crisis Response through Critical Thinking Support
Authors: Schraagen Jan Maarten , van de Ven Josine G. M.
Published: January 2009

In this study, we describe how to use innovative techniques to improve the decision-making process in crisis response organizations. The focus was on building situation awareness of a crisis and overcoming pitfalls such as tunnel vision and information bias through using critical thinking. We started by observing typical difficulties in crisis management in a field study. The essential elements of concern were a deficit in sharing and communicating understanding and a patchy overview of the topics communicated, within as well as between teams. Communication frequently did not entail the reasoning behind a decision that was made. We therefore developed a critical thinking tool that made the reasoning process more explicit and at the same time more robust by tying it to specific hypotheses. We studied a candidate support tool in a controlled setting and found that people made better judgments, particularly in situations where they would be prone to decision biases. We subsequently extended the critical thinking tool to a team setting. We list a number of requirements that are essential for support systems that intend to limit tunnel vision and alleviate communication and coordination problems in crisis response organizations.
Ecological Interface Design for Military Command and Control
Authors: Bennett Kevin B. , Posey Shannon M. , Shattuck Lawrence G.
Published: January 2009

The authors use the cognitive systems engineering framework to design and evaluate an interface for military command and control. They discuss analytic tools and principles of this framework and provide concrete examples (e.g., work domain analyses for U.S. Army tactical operations at the battalion level). They also discuss principles of ecological interface design, including direct perception, direct manipulation, and the perception-action loop. The translation between work domain analyses and the specific characteristics of the interface are made explicit. The authors describe the potential for this interface to support effective decision making and problem solving, including links with naturalistic decision-making approaches. Evaluations of the interface have been positive and are described briefly. Actual or potential applications of this research include both specific interface design strategies for military command and control and general interface design principles for this category of work domain.
In PWR Comprehensive Study of High Burn-Up Corrosion and Growth Behavior of M5® and Recrystallized Low-Tin Zircaloy-4
Authors: Bossis Philippe , Verhaeghe Bénédicte , Doriot Sylvie , Gilbon Didier , Chabretou Valérie , Dalmais Agnès , Mardon Jean-Paul , Blat Martine , Miquet Alain
Published: January 2009

This paper is dealing with the corrosion and growth behavior of M5® and recrystallized low tin Zircaloy-4 irradiated as stress-free tubes in conditions representative of grids and guide-tubes of PWR fuel assemblies. The low-tin Zircaloy-4 tubes have reached equivalent burn-ups up to 93 GWd/tU (corresponding to a fluence of 21.0×1025 n⋅m−2, E>1 MeV), and the M5® tubes have reached equivalent burn-ups up to 79 GWd/tU (corresponding to a fluence of 17.1×1025 n⋅m−2). Postirradiation growth was measured by comparing the distances between holes regularly distributed along the rod to the initial measurements. Postirradiation outer diameter oxide thicknesses were measured by eddy currents. Detailed characterizations of oxide layers have been realized through optical microscopy and scanning electron microscopy. Hydrogen uptake has been obtained through global hydrogen content measurements and metallographic examination of hydrides. Finally, the irradiation-induced microstructure of the metallic matrix has been observed by transmission electron microscopy. On these tubes, the free growth reached 1.9 % at 93 GWd/tU on Zircaloy-4 and 0.3 % at 79 GWd/tU on M5®. The external oxide thicknesses are far greater on Zircaloy-4 (∼60 μm at 93 GWd/tU) than on M5® (∼7.5 μm at 79 GWd/tU), and the oxidation rate is eight times higher on Zircaloy-4 than on M5®. Very high hydrogen content is achieved on Zircaloy-4, up to ∼1600 ppm (due to the low wall thickness and two-sided corrosion), whereas the maximum value on M5® is ∼100 ppm (despite the same geometry and corrosion conditions). On both alloys, the hydrogen pickup fraction is of the same order for these experimental empty rods as for previously analyzed fuel rod claddings, which may indicate the absence of a heat flux effect on the hydrogen uptake. Finally, potential correlation between growth, corrosion and hydrogen uptake will be discussed. Taking account of the results obtained on both experimental tubes and fuel rods, the effects of the presence or absence of heat flux through the wall thickness and of hydride rim at the metal/oxide interface are discussed, especially concerning the high burn-up corrosion acceleration on Zircaloy-4.
Contaminants in Used Oils and Their Behavior
Authors: Sasaki Akira
Published: January 2009

Either particle count or gravimetric analysis is commonly used for assessing oil cleanliness. These analytical methods are useful and practical. However, the former provides the particle number of defined size groups and the latter the gross weight of the contaminants in a certain volume of oil, but they cannot inform us of the characteristics of contamination. To solve hydraulic and lubrication problems due to oil contamination, it is imperative to know the characteristics of contamination. Solvent extraction methods have been used to separate contaminants from used oils. Solvent extraction analysis showed that the majority of contaminants in used oils were polymerized oil oxidation products, which were not soluble in oil. Recently, problems of varnish formation in gas turbines has been of great interest. Varnish is the polymerized oil oxidation product. Such polymerized oil oxidation products have polarity, although base mineral oils are non-polar. Polar and non-polar materials are basically incompatible with each other. Polar materials behave independently in oils. The molecular weight of oil oxidation products was determined by GPC, and it was found that they were good for lubrication when they were soluble in oil but harmful when they became insoluble. However, contaminants must be considered on the level of molecular size in order to solve hydraulic and lubrication problems. This paper discusses the behavior of oil oxidation products in oils.
F-Actin and Myosin II Accelerate Catecholamine Release from Chromaffin Granules
Authors: Berberian Khajak , Torres Alexis J. , Fang Qinghua , Kisler Kassandra , Lindau Manfred
Published: January 2009

The roles of nonmuscle myosin II and cortical actin filaments in chromaffin granule exocytosis were studied by confocal fluorescence microscopy, amperometry, and cell-attached capacitance measurements. Fluorescence imaging indicated decreased mobility of granules near the plasma membrane following inhibition of myosin II function with blebbistatin. Slower fusion pore expansion rates and longer fusion pore lifetimes were observed after inhibition of actin polymerization using cytochalasin D. Amperometric recordings revealed increased amperometric spike half-widths without change in quantal size after either myosin II inhibition or actin disruption. These results suggest that actin and myosin II facilitate release from individual chromaffin granules by accelerating dissociation of catecholamines from the intragranular matrix possibly through generation of mechanical forces.
Protein Synthesis in Distal Axons Is Not Required for Growth Cone Responses to Guidance Cues
Authors: Roche Florence K. , Marsick Bonnie M. , Letourneau Paul C.
Published: January 2009

Recent evidence suggests that growth cone responses to guidance cues require local protein synthesis. Using chick neurons, we investigated whether protein synthesis is required for growth cones of several types to respond to guidance cues. First, we found that global inhibition of protein synthesis stops axonal elongation after 2 h. When protein synthesis inhibitors were added 15 min before adding guidance cues, we found no changes in the typical responses of retinal, sensory, and sympathetic growth cones. In the presence of cycloheximide or anisomycin, ephrin-A2, slit-3, and semaphorin3A still induced growth cone collapse and loss of actin filaments, nerve growth factor (NGF) and neurotrophin-3 still induced growth cone protrusion and increased filamentous actin, and sensory growth cones turned toward an NGF source. In compartmented chambers that separated perikarya from axons, axons grew for 24–48 h in the presence of cycloheximide and responded to negative and positive cues. Our results indicate that protein synthesis is not strictly required in the mechanisms for growth cone responses to many guidance cues. Differences between our results and other studies may exist because of different cellular metabolic levels inin vitroconditions and a difference in when axonal functions become dependent on local protein synthesis.
E449X mutation in the thyroid hormone receptor β associated with autoimmune thyroid disease and severe neuropsychomotor involvement
Authors: Gurgel Maria Helane Costa , Montenegro Junior Renan M. , Magalhaes Rejane Araujo , Lima Grayce Ellen da C. Paiva , Montenegro Renan Magalhães , Magalhães Patricia Kunzle Ribeiro , Maciel Lea Maria Zanini
Published: January 2009

OBJECTIVE: To report the clinical and molecular aspects of a patient with a diagnosis of Resistance to Thyroid Hormone (RTH) harboring the E449X mutation associated with autoimmune thyroid disease and severe neuropsychomotor retardation. METHODS: We present a case report including clinical and laboratory findings, and molecular analysis of a Brazilian patient with RTH. RESULTS: A 23-year old male presented hyperactivity disorder, attention deficit, delayed neuropsychomotor development, and goiter. Since the age of 1 year and 8 months, his mother had sought medical care for her son for the investigation of delayed neuropsychomotor development associated with irritability, aggressiveness, recurrent headache, profuse sudoresis, intermittent diarrhea, polyphagia, goiter, and low weight. Laboratory tests revealed normal TSH, increased T3, T4, antithyroglobulin and antimicrosomal antibody titers. Increasing doses of levothyroxine were prescribed, reaching 200 µg/day, without significant changes in his clinical-laboratory picture. Increasing doses of tiratricol were introduced, with a clear clinical improvement of aggressiveness, hyperactivity, tremor of the extremities, and greater weight gain. Molecular study revealed a nonsense mutation in exon 10, in which a substitution of a guanine to tyrosine in nucleotide 1345 (codon 449) generates the stop codon TAA, confirming the diagnosis of RTH. CONCLUSION: This patient has severe neuropsychomotor retardation not observed in a single previous report with the same mutation. This may reflect the lack of a genotype-phenotype correlation in affected cases with this syndrome, suggesting that genetic variability of factors other than β receptor of thyroid hormone (TRβ) might modulate the phenotype of RTH.
HNF1α mutations are present in half of clinically defined MODY patients in South-Brazilian individuals
Authors: Maraschin Jorge de Faria , Kannengiesser Caroline , Murussi Nádia , Campagnolo Nicole , Canani Luís Henrique , Gross Jorge Luiz , Velho Gilberto , Grandchamp Bernard , Silveiro Sandra Pinho
Published: January 2009

Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes mellitus characterized by autosomal dominant inheritance, early age of onset, and pancreatic beta cell dysfunction. Heterozygous mutations in at least seven genes can cause MODY. In the present study we investigated the relative prevalence of GCK (glucokinase) and HNF1α (hepatocyte nuclear factor 1α) mutations, the more frequent causes of MODY, in 13 South-Brazilian families with multiple cases of diabetes consistent with MODY. Heterozygous variants in GCK and HNF1α genes were observed respectively in one (7.7%), and six (46.2%) families. The six HNF1α variants are likely to cause diabetes in the families where they were observed. However, we could not ascertain whether the GCK Gly117Ser variant found in one family is a causal mutation. In conclusion, we have confirmed in a South-Brazilian population that HNF1α mutations are a common cause of monogenic diabetes in adults selected with strict clinical diagnostic criteria.
Possible association between Carney complex and multiple endocrine neoplasia type 1 phenotypes
Authors: Nunes Vania S. , Chang Cláudia V. , Mazeto Gláucia M. F. S. , Marques Mariângela E. A. , Castro Ana Valéria B. , Nogueira Célia R.
Published: January 2009

Carney Complex (CNC) and Multiple Endocrine Neoplasia type 1 (MEN1) are forms of multiple endocrine neoplasia of dominant autosomal inheritance. Diagnosis of CNC occurs when two major criteria (lentiginoses, primary pigmented nodular adrenocortical disease, cardiac and cutaneous myxomas, acromegaly, testicular neoplasias, thyroid cancer) are observed and/or a major criterion associated with a supplementary criterion (affected relative, PRKAR1A gene mutation) occurs. On the other hand, diagnosis for MEN1 occurs through detection of two or more tumors located at the pituitary gland, parathyroid and/or pancreatic cells. The present case describes a 55 year-old male patient, diagnosed with acromegaly, primary hyperparathyroidism and papillary thyroid cancer, exhibiting components that meet the diagnostic criteria of both conditions described. Despite the occurrence of only one sporadic association or the acromegaly per se being responsible for the papillary cancer, new molecular mechanisms may not be ruled out.