bluuebunny/crossref_metadata_2025 huggingface dataset:
Salvicine Inactivates β1 Integrin and Inhibits Adhesion of MDA-MB-435 Cells to Fibronectin via Reactive Oxygen Species Signaling
Authors: Zhou Jin , Chen Yi , Lang Jing-Yu , Lu Jin-Jian , Ding Jian
Published: February 2008

Integrin-mediated adhesion to the extracellular matrix plays a fundamental role in tumor metastasis. Salvicine, a novel diterpenoid quinone compound identified as a nonintercalative topoisomerase II poison, possesses a broad range of antitumor and antimetastatic activity. Here, the mechanism underlying the antimetastatic capacity of salvicine was investigated by exploring the effect of salvicine on integrin-mediated cell adhesion. Salvicine inhibited the adhesion of human breast cancer MDA-MB-435 cells to fibronectin and collagen without affecting nonspecific adhesion to poly-l-lysine. The fibronectin-dependent formation of focal adhesions and actin stress fibers was also inhibited by salvicine, leading to a rounded cell morphology. Furthermore, salvicine down-regulated β1 integrin ligand affinity, clustering and signaling via dephosphorylation of focal adhesion kinase and paxillin. Conversely, salvicine induced extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) phosphorylation. The effect of salvicine on β1 integrin function and cell adhesion was reversed by U0126 and SB203580, inhibitors of MAPK/ERK kinase 1/2 and p38 MAPK, respectively. Salvicine also induced the production of reactive oxygen species (ROS) that was reversed by ROS scavenger N-acetyl-l-cysteine. N-acetyl-l-cysteine additionally reversed the salvicine-induced activation of ERK and p38 MAPK, thereby maintaining functional β1 integrin activity and restoring cell adhesion and spreading. Together, this study reveals that salvicine activates ERK and p38 MAPK by triggering the generation of ROS, which in turn inhibits β1 integrin ligand affinity. These findings contribute to a better understanding of the antimetastatic activity of salvicine and shed new light on the complex roles of ROS and downstream signaling molecules, particularly p38 MAPK, in the regulation of integrin function and cell adhesion. (Mol Cancer Res 2008;6(2):194–204)
MDM2 Gene Amplification Is Correlated to Tumor Progression but not to the Presence of SNP309 or TP53 Mutational Status in Primary Colorectal Cancers
Authors: Forslund Ann , Zeng Zhaoshi , Qin Li-Xuan , Rosenberg Shoshana , Ndubuisi MacKevin , Pincas Hanna , Gerald William , Notterman Daniel A. , Barany Francis , Paty Philip B.
Published: February 2008

Mdm2 is the main regulator of p53 and is amplified in ∼7% of all human cancers. MDM2 gene amplification as well as expression has been correlated to an increased tumorigenic potential. We have analyzed the prevalence of MDM2 gene amplifications and SNP309 in 284 colorectal tumors using a relatively new highly sensitive PCR/ligase detection reaction method in relation to TP53 mutational status and genomic instability. We found MDM2 to be amplified in 9% of the 284 colorectal cancers analyzed and a significantly higher proportion of tumors with high MDM2 gene amplification retained a wild-type p53 gene (P = 0.058). MDM2 gene amplification was significantly correlated to advanced tumor stage. Several small-molecule MDM2 antagonists have already been identified that either physically inhibit the p53-MDM2 binding or the E3 ligase function of MDM2. Our results suggest that MDM2 is a promising target for this type of cancer therapy in a substantial subgroup of colorectal cancers. (Mol Cancer Res 2008;6(2):205–11)
DNMT1 as a Molecular Target in a Multimodality-Resistant Phenotype in Tumor Cells
Authors: Mishra Mark V. , Bisht Kheem S. , Sun Lunching , Muldoon-Jacobs Kristi , Awwad Rania , Kaushal Aradhana , Nguyen Phuongmai , Huang Lei , Pennington J. Daniel , Markovina Stephanie , Bradbury C. Matthew , Gius David
Published: February 2008

We have previously shown that hydrogen peroxide–resistant permanent (OC-14) cells are resistant to the cytotoxicity of several exogenous oxidative and anticancer agents including H2O2, etoposide, and cisplatin; and we refer to this process as an oxidative multimodality-resistant phenotype (MMRP). Furthermore, OC-14 cells contain increased activator protein 1 activity, and inhibition of activator protein 1 reversed the MMRP. In this study, we show that permanent Rat-1 cell lines genetically altered to overexpress c-Fos also displayed a similar MMRP to H2O2, etoposide, and cisplatin as OC-14 cells. Gene expression analysis of the OC-14 cells and c-Fos–overexpressing cells showed increased DNMT1 expression. Where OC-14 and c-Fos–overexpressing cells were exposed to 5-aza-2′-deoxycytidine, which inhibits DNMT activity, a significant but incomplete reversal of the MMRP was observed. Thus, it seems logical to suggest that DNMT1 might be at least one target in the MMRP. Rat-1 cells genetically altered to overexpress DNMT1 were also shown to be resistant to the cytotoxicity of H2O2, etoposide, and cisplatin. Finally, somatic HCT116 knockout cells that do not express either DNMT1 (DNMT1−/−) or DNMT3B (DNMT3B−/−) were shown to be more sensitive to the cytotoxicity of H2O2, etoposide, and cisplatin compared with control HCT116 cells. This work is the first example of a role for the epigenome in tumor cell resistance to the cytotoxicity of exogenous oxidative (H2O2) or systemic (etoposide and cisplatin) agents and highlights a potential role for DNMT1 as a potential molecular target in cancer therapy. (Mol Cancer Res 2008;6(2):243–9)
Hyperglycemia and Acute Coronary Syndrome
Authors: Deedwania Prakash , Kosiborod Mikhail , Barrett Eugene , Ceriello Antonio , Isley William , Mazzone Theodore , Raskin Philip
Published: February 2008

Hyperglycemia is common and associated with markedly increased mortality rates in patients hospitalized with acute coronary syndromes (ACS). Despite the fact that several studies have documented this association, hyperglycemia remains underappreciated as a risk factor, and it is frequently untreated in ACS patients. This is in large part due to limitations of prior studies, and the remaining critical gaps in our understanding of the relationship between hyperglycemia and poor outcomes. The main objective of the present statement is to summarize the current state of knowledge regarding the association between elevated glucose and patient outcomes in ACS and to outline the most important knowledge gaps in this field. These gaps include the need to specifically define hyperglycemia, develop optimal ways of measuring and tracking glucose values during ACS hospitalization, and better understand the physiological mechanisms responsible for poor outcomes associated with hyperglycemia. The most important issue, however, is whether elevated glucose is a direct mediator of adverse outcomes in ACS patients or just a marker of greater disease severity. Given the marked increase in short- and long-term mortality associated with hyperglycemia, there is an urgent need for definitive large randomized trials to determine whether treatment strategies aimed at glucose control will improve patient outcomes and to define specific glucose treatment targets. Although firm guidelines will need to await completion of these clinical trials, the present statement also provides consensus recommendations for hyperglycemia management in patients with ACS on the basis of the available data.
Immediate Mineralocorticoid Receptor Blockade Improves Myocardial Infarct Healing by Modulation of the Inflammatory Response
Authors: Fraccarollo Daniela , Galuppo Paolo , Schraut Susanne , Kneitz Susanne , van Rooijen Nico , Ertl Georg , Bauersachs Johann
Published: February 2008

Mineralocorticoid receptor (MR) blockade reduces morbidity and mortality after acute myocardial infarction; however, the underlying mechanisms are still under investigation. This study examined whether MR antagonism promotes healing of the infarcted myocardium. Starting immediately after coronary ligation, male Wistar rats were treated with the selective MR antagonist eplerenone (100 mg/kg per day by gavage) or placebo for 2 to 7 days. At 7 days, eplerenone therapy versus placebo significantly reduced thinning and dilatation of the infarcted wall, improved left ventricular function, and enhanced neovessel formation in the injured myocardium. At 2 days, eplerenone-treated rats displayed lower plasma corticosterone levels, higher circulating blood monocytes, and more macrophages infiltrating the infarcted myocardium. MR blockade led to a transient upregulation (at days 2 and 3 but not at day 7) of monocyte chemoattractant protein-1, tumor necrosis factor-α, interleukin-1β, interleukin-6, interleukin-10, and interleukin-4 and an increase in factor XIIIa protein expression in the healing myocardium. Prevention of macrophage accumulation into the infarct zone by treatment with liposome-encapsulated clodronate almost abrogated the protein expression of factor XIIIa and the beneficial effects of eplerenone on infarct expansion. In conclusion, selective MR blockade immediately after myocardial infarction accelerated macrophage infiltration and transiently increased the expression of healing promoting cytokines and factor XIIIa in the injured myocardium resulting in enhanced infarct neovascularization and reduced early LV dilation and dysfunction.
Sulh and the 18th Century Ottoman Courts of Üsküdar and Adana
Authors: Tamdoğan Işık
Published: February 2008

This article explores and compares cases of sulh (amicable agreement) that are documented in the records of two Ottoman courts—one in Üsküdar, the other in Adana—in the second half of the 18th century. As a dispute resolution practice, sulh draws on three normative systems: shari'a, kanun and 'örf. An abundance of references to sulh agreements in court records testifies not only to the importance of this social practice, but also to complex interrelations between the three normative systems. Sulh documents provide evidence of the interrelation between the shari'a court and other legal arenas. The judges in both Üsküdar and Adana viewed sulh agreements—even those concluded privately and outside of court—as valid and binding. There were, however, significant differences between the two courts regarding the sulh cases; these differences highlight the connection between the location of the court and its specific legal culture.
Notes on the Anomaly of the Shari'a Field in Israel
Authors: Ramadan Moussa Abou
Published: February 2008

A close scrutiny of the Islamic religious field in Israel reveals that those responsible for the application of shari'a rules (i.e. judges presiding in shari'a courts), do not possess the "symbolic capital" that is required in order to distinguish them from laymen. Since shari'a judges in Israel enjoy unprecedented centrality within the Islamic religious field, the field itself is not well-distinguished from the secular legal field. This situation results not only from the fact that persons without proper shari'a training have been appointed to the office of shari'a judge (qadi), but also from the fact that the qadis are appointed by a non-Muslim authority and that the shari'a courts are subordinated to Israeli legislation. I argue that the Islamic religious field in Israel is an anomaly, characterized by lack of autonomy, ambiguous boundaries and lack of competition between actors (due to the monopolization of power by qadis).
Residential Segregation and Unemployment: The Case of Brussels
Authors: Dujardin Claire , Selod Harris , Thomas Isabelle
Published: February 2008

This paper investigates the causal effects of the spatial organisation of Brussels on unemployment propensities. Using census data at the individual level, the unemployment probability of young adults is estimated while taking into account personal, household and neighbourhood characteristics. The endogeneity of residential locations is solved by restricting the sample to young adults residing with their parents; the potential remaining bias is evaluated by conducting a sensitivity analysis. The results suggest that the neighbourhood of residence significantly increases a youngster's probability of being unemployed, a result which is quite robust to the presence of both observed and unobserved parental covariates.
Aboriginal Self-determination and Social Housing in Urban Canada: A Story of Convergence and Divergence
Authors: Walker Ryan
Published: February 2008

The right to adequate and affordable housing was pursued in Canadian policy during the 1970s and 1980s. The right of self-determination has been re-asserted by Aboriginal peoples since the 1970s, including in urban communities. The trajectories of social housing and Aboriginal self-determination were institutionalised together during the 1970s and 1980s. Such has not been the case since 1993. Self-determination in urban housing initiatives will not on its own rectify Aboriginal housing need, but must be paired with a common pursuit of adequate and affordable housing for all Canadians.
Perceived parental bonding, fear of failure and stress during class presentations
Authors: Sideridis Georgios D. , Kafetsios Konstantinos
Published: February 2008

The purpose of the present studies was to test the hypothesis that students' perceptions of parental bonding may be predictive of how individuals approach achievement situations. It was hypothesized that reports of parental overprotection would be predictive of elevated fears and subsequent stress and low achievement compared to perceived parental care. No hypotheses were specified regarding the gender of the parent. In Study 1 participants were 230 elementary school students who were assessed on motivation, stress and affect prior to a “high stakes testing”. Results indicated that paternal caring scores and, to a lesser degree, maternal caring scores were associated with lower levels of fear of failure, anxiety and depression. In Study 2, 58 college students were monitored (physiologically) during a class presentation in order to test the hypothesis that perceived parental rearing is predictive of stress through influencing fear of failure. Results from Multilevel Random Coefficient Modeling showed that perceived parental caring was associated with significantly lessened stress compared to perceived overprotection. Modeling the relationships using Structural Equation Modeling indicated that students reporting an overprotective parental style approached the task with significantly elevated fears, had elevated stress during the task, and lower task performance. Another salient finding was that students' perceptions of their fathers' parenting style was highly predictive of the stress response. The discussion reviews these findings and examines possible implications for enhancing achievement motivation in educational contexts.
Reduction of hemodilution in small adults undergoing open heart surgery: a prospective, randomized trial
Authors: Pappalardo F. , Corno C. , Franco A. , Giardina G. , Scandroglio A.M. , Landoni G. , Crescenzi G. , Zangrillo A.
Published: February 2008

Background. Given that there is an association between the degree of hemodilution during cardiopulmonary bypass (CPB) and postoperative complications, patients-outcome might be improved if the nadir hematocrit concentration is kept within an optimal range. Smaller patients are more likely to have a low hematocrit during CPB: this phenomenon may be related, at least partially, to the extreme hemodilution induced by a large fixed CPB priming volume. Methods. Forty patients with a body surface area (BSA) < 1.7 m2 undergoing open heart operations were randomized to either standard CPB with full prime volume (control group) or reduced prime extracorporeal circuit and vacuum-assisted venous drainage (VAVD) (study group). Results. There were no significant differences between the groups with respect to baseline characteristics, body surface area, hematologic profile and operative data. Clinical outcomes were similar. Nadir hematocrit and hemoglobin on bypass were significantly lower in the control group (22 ± 2.3 vs 24 ± 2.5%, p < 0.02 and 7.4 ± 0.7 vs 8 ± 0.9g/dl, p < 0.04, respectively).

Postoperative chest tube drainage was significantly higher in the control group (272 ± 253vs 139 ± 84ml, p < 0.04). There was no difference in blood transfusion in the two groups (0.5 ± 1.14 v 1.0 ± 1.77 units of packed red blood cells (PRBC), p = 0.29). Conclusions. Lowering CPB priming volume by means of using a small oxygenator and vacuum-assisted venous drainage (VAVD) resulted in a significant decrease of intraoperative hemodilution. This technique should be strongly considered for patients with a small BSA (<1.7 m2) undergoing open heart surgery. Perfusion (2007) 22, 317—322.
Influence of early re-infusion of autologous shed mediastinal blood on clinical outcome after cardiac surgery
Authors: Sirvinskas Edmundas , Veikutiene Audrone , Benetis Rimantas , Grybauskas Pranas , Andrejaitiene Judita , Veikutis Vincentas , Surkus Jonas
Published: February 2008

Various strategies have been proposed to decrease allogeneic blood transfusion requirements after cardiac surgery. The aim of the study was to evaluate the efficacy of collected and re-infused autologous shed mediastinal blood on a patient's postoperative course.

Ninety patients who underwent heart surgery with cardiopulmonary bypass (CPB) were studied. The patients were divided into two groups: Group 1 ( n = 41) received the centrifuged autologous shed mediastinal blood collected from the cardiotomy reservoir 4 hours after surgery; in Group 2 ( n = 49) all shed mediastinal blood was discarded (control group). Haemoglobin (Hb), haematocrit (Hct), C-reactive protein values, and leucocyte count were compared before surgery, at 4 h and 20 h after surgery, and on the fifth postoperative day. We have measured serum procalcitonin (PCT) concentration at 4 h and 20 h after CPB. We assessed drained blood loss within 20 postoperative hours.

Leucocyte count, Hb, Hct values, C-reactive protein, and procalcitonin concentration did not differ between the groups before and at 4 h after surgery. Hb, Hct level, and leucocyte count were similar at 20 hours and on the fifth day after surgery. At 20 hours after surgery, an increase of serum PCT concentration (>0.5—2 ng/mL) was more frequent in Group 2 (58.3% vs. 33.3%; p = 0.03). On the fifth postoperative day, C-reactive protein concentration was lower in Group 1 (71.74 ± 15.23; p < 0.01) compared to Group 2 (93.53 ± 20.3). Postoperative blood loss did not differ between the groups. Requirement for allogeneic blood transfusion was significantly lower in Group 1 (14.6% vs. 38.8%; p < 0.02). Patients in Group 1 developed less infective complications compared with Group 2 (2.4% and 16.3%, respectively; p < 0.05). The length of postoperative in-hospital stay was shorter in Group 1 compared with Group 2 (9.32 ± 2.55 and 16.45 ± 6.5, respectively; p < 0.05).

We conclude that postoperative re-infusion of autologous red blood cells processed from shed mediastinal blood did not increase bleeding tendency and systemic inflammatory response and was effective in reducing the requirement for allogeneic transfusion, the rate of infective complications and the length of postoperative in-hospital stay. Perfusion (2007) 22, 345—352.
Mathematical modeling of buffers used in myocardial preservation
Authors: Triana Jonathan R , Yanagihashi Mark , Larson Douglas F
Published: February 2008

Objective. Buffers added to myocardial preservation solutions are considered to be critical for resisting myocardium pH changes from the accumulation of protons (H +). Our hypothesis is that mathematical modeling of three clinically used buffers will define their individual buffering capacities under simulated clinical conditions. Methods. The buffers, tromethamine (THAM), sodium bicarbonate (HCO3-), and L-histidine, were compared in terms of their buffering capacity (β) under specific temperatures and concentrations, using a mathematical model. Results. At 37°C, the maximal beta (βmax) occurred at pH 7.75 for THAM, pH 6.10 for HCO3-, and pH 5.89 for L-histidine at equimolar concentrations. A decrease in temperature moved β max to a higher pH value for each buffer. At clinical concentrations, L-histidine provided the greatest buffering capacity followed by HCO 3- and THAM, respectively. Discussion. This model permitted comparison of the above buffers under simulated clinical conditions. The assumption was that the magnitude of βmax at a given temperature determines which buffer(s) could be most effective for myocardial preservation. Also, the assumption was taken that these buffers are used in a closed system — where there is no continuous blood flow — and that the buffering ability of THAM and L-histidine were not influenced by the accumulation of CO2 as is HCO3-. THAM and L-histidine were more effective at hypothermic temperatures compared with HCO3-; however, HCO3- provided buffering at normothermic temperatures. Through the theoretical considerations of this study, we propose that combining HCO3 - with THAM or L-histidine could be most efficacious for myocardial preservation during open heart surgery or organ transplantation. Perfusion (2007) 22, 353—362.
Mechanical Properties and Fracture Behavior of Short PET Fiber-Waste Polyethylene Composites
Authors: Satapathy Sukanya , Golok Bihari Nando  , Jose Jobin , Nag Ahin
Published: February 2008

Plastics used in the packaging industry, especially in the form of carry bags and pouches, manifest a formidable threat to the environment because of their non-biodegradable nature. Addition of both natural and synthetic fibers to these materials improves their performance, replacing the conventional materials like wood, metal, and ceramics in the majority of industrial applications. Short polyethylene terephthalate (PET) fiber-reinforced composites from waste high density polyethylene (WPE) such as carry bags/pouches collected from municipal solid waste and neat high density polyethylene (HDPE) were prepared in a Brabender Plasticorder using melt-mixing technique under optimum processing conditions. Physico-mechanical properties of these short PET fiber-reinforced WPE and neat HDPE composites were determined using standard procedures. It is observed that the mechanical strength is enhanced by increasing the fiber-loading up to 50% by weight. Maleic anhydride (MAH) grafting was done onto the WPE matrix and the resulting composites were evaluated for their mechanical properties. The thermal stability of the WPE-PET fiber composites also improves significantly with fiber-loading as well as upon grafting the WPE with MAH. Flexural strength exhibited an increase of 59% from 25.4 to 40.5 MPa, proving MAH-grafted WPE (MAH-g-WPE) to have good compatibilizing ability.
Practical Applications of Confidentiality Rules to Health Care Transition Instruction
Authors: Repetto Jeanne B. , Gibson Robert W. , Lubbers Joyce H. , Gritz Sheila , Reiss John
Published: February 2008

The increase in the number of students with disabilities and special health care needs and their need for health care transition (HCT) creates opportunity for education and health services professionals to work together. In response to this opportunity, the authors developed an HCT teaching module for 6th to 12th graders. A concern that surfaced during the project was the sharing of personal health information by students during health-related instructional activities. The authors' concern evolved into a review of the confidentiality guidelines found in the Individuals with Disabilities Education Improvement Act of 2004, Family Education Rights and Privacy Acts of 1974, and Health Information Portability and Accountability Act of 1996 and their relationship to educational activities. This article describes what the authors discovered and its application to HCT instruction.
Ethnicity and Risk for Symptoms of Posttraumatic Stress Following Intimate Partner Violence
Authors: Lilly Michelle M. , Graham-Bermann Sandra A.
Published: February 2008

The present study uses a feminist theoretical framework to explore risk factors for the development of posttraumatic stress symptoms following intimate partner violence, with a community sample of 120 low-income European American and African American women. Hierarchical regression analyses were used to examine demographic, violence, and mental health variables that predict posttraumatic stress symptoms. The data reveal that African American women report lower levels of posttraumatic stress symptoms than do their European American peers. This difference was observed despite the presence of more empirically identified risk factors for African American women. Regression analyses show that symptoms of depression increase risk for posttraumatic stress for both groups. However, a difference was observed such that past victimization increase risk for only European American women, whereas amount of psychological violence in the previous year increases risk for only African American women. Potential explanations for observed ethnic differences are offered.
Review Series: The Politics of TB: TB control services need tailoring for new arrivals, not vice versa
Authors: Wang Y. , Taegtmeyer M. , Squire S.B. , Theobald S.J.
Published: February 2008

High rates of TB amongst new arrivals to the UK require flexible, innovative responses that go beyond traditional biomedical models and take into account the needs of these heterogeneous groups. This article explores the merging of public health and human rights based approaches to TB control in response to the challenge of increasing rates of TB amongst new arrivals in the UK. Chronic Respiratory Disease 2008; 5: 49—51
The Parodic Sensibility and the Sophisticated Gaze
Authors: Thompson Ethan
Published: February 2008

The dramatic success of Playboy magazine in the 1950s paralleled the meteoric rise of television as both an industry and cultural form, but the magazine's relationship with the new electronic medium was an uneasy one. Television's status as a domestic, even feminine, medium posed particular challenges, even more so than the “masscult” critique. Rather than recommending specific programs for consumption as it did with books, albums, and movies, the magazine promoted parody as a “sophisticated” way to engage television. Parody was adopted as a form of interpretation that produced alternative pleasures and meaning, thereby making visual consumption practices a marker of cultural capital. The tensions between Playboy and television were especially apparent in Playboy's own syndicated program, Playboy's Penthouse (1959—1961). The urbane and varied performances of the program, and its distinctive televisual style, offered a version of sophisticated television production that supplemented the magazine's model of sophisticated television watching.
Clinician's Corner: The Metabolic Syndrome: A Lifestyle Medicine Foe Worthy of a Seek and Destroy Mission
Authors: Greenstone Clinton L.
Published: February 2008

The Metabolic syndrome (MetS) is comprised of dyslipidemia, elevated blood pressure, elevated plasma glucose, abdominal obesity and associated prothrombotic and proinflammatory states. It is accompanied by a life long twofold increased risk of cardiovascular disease and a fivefold increase risk for diabetes. Since cardiovascular disease and diabetes are predictable by modifiable risk factors, metabolic syndrome is a prime candidate for lifestyle modification utilizing the tools of Lifestyle Medicine (LM), (exercise, nutritional therapy and behavior modification). Such approaches can prevent the development of full blown Type II diabetes (5) and dramatically modify all of the components of the metabolic syndrome. This article discusses the definition and importance of MetS and how to screen for it and manage it using LM principles.
The recurrent SET-NUP214 fusion as a new HOXA activation mechanism in pediatric T-cell acute lymphoblastic leukemia
Authors: Van Vlierberghe Pieter , van Grotel Martine , Tchinda Joëlle , Lee Charles , Beverloo H. Berna , van der Spek Peter J. , Stubbs Andrew , Cools Jan , Nagata Kyosuke , Fornerod Maarten , Buijs-Gladdines Jessica , Horstmann Martin , van Wering Elisabeth R. , Soulier Jean , Pieters Rob , Meijerink Jules P. P.
Published: February 2008

T-cell acute lymphoblastic leukemia (T-ALL) is mostly characterized by specific chromosomal abnormalities, some occurring in a mutually exclusive manner that possibly delineate specific T-ALL subgroups. One subgroup, including MLL-rearranged, CALM-AF10 or inv (7)(p15q34) patients, is characterized by elevated expression of HOXA genes. Using a gene expression–based clustering analysis of 67 T-ALL cases with recurrent molecular genetic abnormalities and 25 samples lacking apparent aberrations, we identified 5 new patients with elevated HOXA levels. Using microarray-based comparative genomic hybridization (array-CGH), a cryptic and recurrent deletion, del (9)(q34.11q34.13), was exclusively identified in 3 of these 5 patients. This deletion results in a conserved SET-NUP214 fusion product, which was also identified in the T-ALL cell line LOUCY. SET-NUP214 binds in the promoter regions of specific HOXA genes, where it interacts with CRM1 and DOT1L, which may transcriptionally activate specific members of the HOXA cluster. Targeted inhibition of SET-NUP214 by siRNA abolished expression of HOXA genes, inhibited proliferation, and induced differentiation in LOUCY but not in other T-ALL lines. We conclude that SET-NUP214 may contribute to the pathogenesis of T-ALL by enforcing T-cell differentiation arrest.
Mutations in the neutral sphingomyelinase gene SMPD3 implicate the ceramide pathway in human leukemias
Authors: Kim Woo Jae , Okimoto Ross A. , Purton Louise E. , Goodwin Meagan , Haserlat Sara M. , Dayyani Farshid , Sweetser David A. , McClatchey Andrea I. , Bernard Olivier A. , Look A. Thomas , Bell Daphne W. , Scadden David T. , Haber Daniel A.
Published: February 2008

Ceramide is a lipid second messenger derived from the hydrolysis of sphingomyelin by sphingomyelinases (SMases) and implicated in diverse cellular responses, including growth arrest, differentiation, and apoptosis. Defects in the neutral SMase (nSMase) gene Smpd3, the primary regulator of ceramide biosynthesis, are responsible for developmental defects of bone; regulation of ceramide levels have been implicated in macrophage differentiation, but this pathway has not been directly implicated in human cancer. In a genomic screen for gene copy losses contributing to tumorigenesis in a mouse osteosarcoma model, we identified a somatic homozygous deletion specifically targeting Smpd3. Reconstitution of SMPD3 expression in mouse tumor cells lacking the endogenous gene enhanced tumor necrosis factor (TNF)–induced reduction of cell viability. Nucleotide sequencing of the highly conserved SMPD3 gene in a large panel of human cancers revealed mutations in 5 (5%) of 92 acute myeloid leukemias (AMLs) and 8 (6%) of 131 acute lymphoid leukemias (ALLs), but not in other tumor types. In a subset of these mutations, functional analysis indicated defects in protein stability and localization. Taken together, these observations suggest that disruption of the ceramide pathway may contribute to a subset of human leukemias.
Human Pol II promoter recognition based on primary sequences and free energy of dinucleotides
Authors: Yang Jian-Yi , Zhou Yu , Yu Zu-Guo , Anh Vo , Zhou Li-Qian
Published: February 2008

Background

Promoter region plays an important role in determining where the transcription of a particular gene should be initiated. Computational prediction of eukaryotic Pol II promoter sequences is one of the most significant problems in sequence analysis. Existing promoter prediction methods are still far from being satisfactory.

Results

We attempt to recognize the human Pol II promoter sequences from the non-promoter sequences which are made up of exon and intron sequences. Four methods are used: two kinds of multifractal analysis performed on the numeric sequences obtained from the dinucleotide free energy, Z curve analysis and global descriptor of the promoter/non-promoter primary sequences. A total of 141 parameters are extracted from these methods and categorized into seven groups (methods). They are used to generate certain spaces and then each promoter/non-promoter sequence is represented by a point in the corresponding space. All the 120 possible combinations of the seven methods are tested. Based on Fisher's linear discriminant algorithm, with a relatively smaller number of parameters (96 and 117), we get satisfactory discriminant accuracies. Particularly, in the case of 117 parameters, the accuracies for the training and test sets reach 90.43% and 89.79%, respectively. A comparison with five other existing methods indicates that our methods have a better performance. Using the global descriptor method (36 parameters), 17 of the 18 experimentally verified promoter sequences of human chromosome 22 are correctly identified.

Conclusion

The high accuracies achieved suggest that the methods of this paper are useful for understanding the difficult problem of promoter prediction.
A mixture model approach to sample size estimation in two-sample comparative microarray experiments
Authors: Jørstad Tommy S , Midelfart Herman , Bones Atle M
Published: February 2008

Background

Choosing the appropriate sample size is an important step in the design of a microarray experiment, and recently methods have been proposed that estimate sample sizes for control of the False Discovery Rate (FDR). Many of these methods require knowledge of the distribution of effect sizes among the differentially expressed genes. If this distribution can be determined then accurate sample size requirements can be calculated.

Results

We present a mixture model approach to estimating the distribution of effect sizes in data from two-sample comparative studies. Specifically, we present a novel, closed form, algorithm for estimating the noncentrality parameters in the test statistic distributions of differentially expressed genes. We then show how our model can be used to estimate sample sizes that control the FDR together with other statistical measures like average power or the false nondiscovery rate. Method performance is evaluated through a comparison with existing methods for sample size estimation, and is found to be very good.

Conclusion

A novel method for estimating the appropriate sample size for a two-sample comparative microarray study is presented. The method is shown to perform very well when compared to existing methods.
Exon level integration of proteomics and microarray data
Authors: Bitton Danny A , Okoniewski Michał J , Connolly Yvonne , Miller Crispin J
Published: February 2008

Background

Previous studies comparing quantitative proteomics and microarray data have generally found poor correspondence between the two. We hypothesised that this might in part be because the different assays were targeting different parts of the expressed genome and might therefore be subjected to confounding effects from processes such as alternative splicing.

Results

Using a genome database as a platform for integration, we combined quantitative protein mass spectrometry with Affymetrix Exon array data at the level of individual exons. We found significantly higher degrees of correlation than have been previously observed (r = 0.808). The study was performed using cell lines in equilibrium in order to reduce a major potential source of biological variation, thus allowing the analysis to focus on the data integration methods in order to establish their performance.

Conclusion

We conclude that part of the variation observed when integrating microarray and proteomics data may occur as a consequence both of the data analysis and of the high granularity to which studies have until recently been limited. The approach opens up the possibility for the first time of considering combined microarray and proteomics datasets at the level of individual exons and isoforms, important given the high proportion of alternative splicing observed in the human genome.
Hey2 functions in parallel with Hes1 and Hes5 for mammalian auditory sensory organ development
Authors: Li Shuangding , Mark Sharayne , Radde-Gallwitz Kristen , Schlisner Rebecca , Chin Michael T , Chen Ping
Published: February 2008

Background

During mouse development, the precursor cells that give rise to the auditory sensory organ, the organ of Corti, are specified prior to embryonic day 14.5 (E14.5). Subsequently, the sensory domain is patterned precisely into one row of inner and three rows of outer sensory hair cells interdigitated with supporting cells. Both the restriction of the sensory domain and the patterning of the sensory mosaic of the organ of Corti involve Notch-mediated lateral inhibition and cellular rearrangement characteristic of convergent extension. This study explores the expression and function of a putative Notch target gene.

Results

We report that a putative Notch target gene, hairy-related basic helix-loop-helix (bHLH) transcriptional factor Hey2, is expressed in the cochlear epithelium prior to terminal differentiation. Its expression is subsequently restricted to supporting cells, overlapping with the expression domains of two known Notch target genes, Hairy and enhancer of split homolog genes Hes1 and Hes5. In combination with the loss of Hes1 or Hes5, genetic inactivation of Hey2 leads to increased numbers of mis-patterned inner or outer hair cells, respectively. Surprisingly, the ectopic hair cells in Hey2 mutants are accompanied by ectopic supporting cells. Furthermore, Hey2
-/-
;Hes1
-/- and Hey2
-/-
;Hes1
+/- mutants show a complete penetrance of early embryonic lethality.

Conclusion

Our results indicate that Hey2 functions in parallel with Hes1 and Hes5 in patterning the organ of Corti, and interacts genetically with Hes1 for early embryonic development and survival. Our data implicates expansion of the progenitor pool and/or the boundaries of the developing sensory organ to account for patterning defects observed in Hey2 mutants.
New miRNAs cloned from neuroblastoma
Authors: Afanasyeva Elena A , Hotz-Wagenblatt Agnes , Glatting Karl-Heinz , Westermann Frank
Published: February 2008

Background

MicroRNAs (miRNAs) are a novel class of gene expression regulators implicated in cancer biology. Neuroblastoma (NB) is an embryonal tumour consisting of neural crest-derived undifferentiated cells and is characterised by variable clinical courses ranging from spontaneous regression to therapy-resistant progression. Recent advances identified a subset of miRNAs with putative function in NB biology. However, the full repertoire of miRNAs expressed in NBs is not available.

Results

We describe miRNA profiles of 13 NB specimens and 2 NB cell lines as determined by miRNA cloning. A total of 3153 sequences were sequenced and analysed by a miRNA prediction tool (miRpredict). Our library covered 27% miRNAs known to date. 39 reads corresponding to 25 individual sequences were classified as novel miRNAs, including miRNA* species of 10 known miRNAs. Expression of 5 new miRNA* forms and 8 individual sequences was supported by Northern blotting. Most of the novel miRNA genes are not related to each other and do not share homology with the annotated sequences in the public miRNA database, but they are conserved within mammals or have close homologues in primates genomes.

Conclusion

We provide evidence for 29 new miRNA and miRNA-like sequences (24 novel sequences and 5 miRNAs discovered initially in other species). Some of these newly identified sequences reside within frequently altered chromosomal regions in NB tumours and may play a role in NB biology.
A genome-wide SNP panel for mapping and association studies in the rat
Authors: Nijman Isaäc J , Kuipers Sylvia , Verheul Mark , Guryev Victor , Cuppen Edwin
Published: February 2008

Background

The laboratory rat (Rattus norvegicus) is an important model for human disease, and is extensively used for studying complex traits for example in the physiological and pharmacological fields. To facilitate genetic studies like QTL mapping, genetic makers that can be easily typed, like SNPs, are essential.

Results

A genome-wide set of 820 SNP assays was designed for the KASPar genotyping platform, which uses a technique based on allele specific oligo extension and energy transfer-based detection. SNPs were chosen to be equally spread along all chromosomes except Y and to be polymorphic between Brown Norway and SS or Wistar rat strains based on data from the rat HapMap EU project. This panel was tested on 38 rats of 34 different strains and 3 wild rats to determine the level of polymorphism and to generate a phylogenetic network to show their genetic relationships. As a proof of principle we used this panel to map an obesity trait in Zucker rats and confirmed significant linkage (LOD 122) to chromosome 5: 119–129 Mb, where the leptin receptor gene (Lepr) is located (chr5: 122 Mb).

Conclusion

We provide a fast and cost-effective platform for genome-wide SNP typing, which can be used for first-pass genetic mapping and association studies in a wide variety of rat strains.
Coral life history and symbiosis: Functional genomic resources for two reef building Caribbean corals, Acropora palmata and Montastraea faveolata
Authors: Schwarz Jodi A , Brokstein Peter B , Voolstra Christian , Terry Astrid Y , Miller David J , Szmant Alina M , Coffroth Mary Alice , Medina Mónica
Published: February 2008

Background

Scleractinian corals are the foundation of reef ecosystems in tropical marine environments. Their great success is due to interactions with endosymbiotic dinoflagellates (Symbiodinium spp.), with which they are obligately symbiotic. To develop a foundation for studying coral biology and coral symbiosis, we have constructed a set of cDNA libraries and generated and annotated ESTs from two species of corals, Acropora palmata and Montastraea faveolata.

Results

We generated 14,588 (Ap) and 3,854 (Mf) high quality ESTs from five life history/symbiosis stages (spawned eggs, early-stage planula larvae, late-stage planula larvae either infected with symbionts or uninfected, and adult coral). The ESTs assembled into a set of primarily stage-specific clusters, producing 4,980 (Ap), and 1,732 (Mf) unigenes. The egg stage library, relative to the other developmental stages, was enriched in genes functioning in cell division and proliferation, transcription, signal transduction, and regulation of protein function. Fifteen unigenes were identified as candidate symbiosis-related genes as they were expressed in all libraries constructed from the symbiotic stages and were absent from all of the non symbiotic stages. These include several DNA interacting proteins, and one highly expressed unigene (containing 17 cDNAs) with no significant protein-coding region. A significant number of unigenes (25) encode potential pattern recognition receptors (lectins, scavenger receptors, and others), as well as genes that may function in signaling pathways involved in innate immune responses (toll-like signaling, NFkB p105, and MAP kinases). Comparison between the A. palmata and an A. millepora EST dataset identified ferritin as a highly expressed gene in both datasets that appears to be undergoing adaptive evolution. Five unigenes appear to be restricted to the Scleractinia, as they had no homology to any sequences in the nr databases nor to the non-scleractinian cnidarians Nematostella vectensis and Hydra magnipapillata.

Conclusion

Partial sequencing of 5 cDNA libraries each for A. palmata and M. faveolata has produced a rich set of candidate genes (4,980 genes from A. palmata, and 1,732 genes from M. faveolata) that we can use as a starting point for examining the life history and symbiosis of these two species, as well as to further expand the dataset of cnidarian genes for comparative genomics and evolutionary studies.
Association between variations in the TLR4gene and incident type 2 diabetes is modified by the ratio of total cholesterol to HDL-cholesterol
Authors: Kolz Melanie , Baumert Jens , Müller Martina , Khuseyinova Natalie , Klopp Norman , Thorand Barbara , Meisinger Christine , Herder Christian , Koenig Wolfgang , Illig Thomas
Published: February 2008

Background

Toll-like receptor 4 (TLR4), the signaling receptor for lipopolysaccharides, is an important member of the innate immunity system. Since several studies have suggested that type 2 diabetes might be associated with changes in the innate immune response, we sought to investigate the association between genetic variants in the TLR4 gene and incident type 2 diabetes.

Methods

A case-cohort study was conducted in initially healthy, middle-aged subjects from the MONICA/KORA Augsburg studies including 498 individuals with incident type 2 diabetes and 1,569 non-cases. Seven SNPs were systematically selected in the TLR4 gene and haplotypes were reconstructed.

Results

The effect of TLR4 SNPs on incident type 2 diabetes was modified by the ratio of total cholesterol to high-density lipoprotein cholesterol (TC/HDL-C). In men, four out of seven TLR4 variants showed significant interaction with TC/HDL-C after correction for multiple testing (p < 0.01). The influence of the minor alleles of those variants on the incidence of type 2 diabetes was observed particularly for male patients with high values of TC/HDL-C. Consistent with these findings, haplotype-based analyses also revealed that the effect of two haplotypes on incident type 2 diabetes was modified by TC/HDL-C in men (p < 10-3). However, none of the investigated variants or haplotypes was associated with type 2 diabetes in main effect models without assessment of effect modifications.

Conclusion

We conclude that minor alleles of several TLR4 variants, although not directly associated with type 2 diabetes might increase the risk for type 2 diabetes in subjects with high TC/HDL-C. Additionally, our results confirm previous studies reporting sex-related dissimilarities in the development of type 2 diabetes.