bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased CD8+ T-cell Function following Castration and Immunization Is Countered by Parallel Expansion of Regulatory T Cells
Authors: Tang Shuai , Moore Miranda L. , Grayson Jason M. , Dubey Purnima
Published: February 2012

Although androgen ablation therapy is effective in treating primary prostate cancers, a significant number of patients develop incurable castration-resistant disease. Recent studies have suggested a potential synergy between vaccination and androgen ablation, yet the enhanced T-cell function is transient. Using a defined tumor antigen model, UV-8101-RE, we found that concomitant castration significantly increased the frequency and function of antigen-specific CD8+ T cells early after the immunization of wild-type mice. However, at a late time point after immunization, effector function was reduced to the same level as noncastrated mice and was accompanied by a concomitant amplification in CD4+CD25+Foxp3+ regulatory T cells (Treg) following immunization. We investigated whether Treg expansion occurred following castration of prostate tumor–bearing mice. In the prostate-specific Pten−/− mouse model of prostate cancer, we observed an accelerated Treg expansion in mice bearing the castration-resistant endogenous prostate tumor, which prevented effector responses to UV-8101-RE. Treg depletion together with castration elicited a strong CD8+ T-cell response to UV-8101-RE in Pten−/− mice and rescued effector function in castrated and immunized wild-type mice. In addition, Treg expansion in Pten−/− mice was prevented by in vivo interleukin (IL)-2 blockade suggesting that increased IL-2 generated by castration and immunization promotes Treg expansion. Our findings therefore suggest that although effector responses are augmented by castration, the concomitant expansion of Tregs is one mechanism responsible for only transient immune potentiation after androgen ablation. Cancer Res; 72(8); 1975–85. ©2012 AACR.
Intragenic ATM Methylation in Peripheral Blood DNA as a Biomarker of Breast Cancer Risk
Authors: Brennan Kevin , Garcia-Closas Montserrat , Orr Nick , Fletcher Olivia , Jones Michael , Ashworth Alan , Swerdlow Anthony , Thorne Heather , Riboli Elio , Vineis Paolo , Dorronsoro Miren , Clavel-Chapelon Francoise , Panico Salvatore , Onland-Moret N. Charlotte , Trichopoulos Dimitrios , Kaaks Rudolf , Khaw Kay-Tee , Brown Robert , Flanagan James M.
Published: February 2012

Few studies have evaluated the association between DNA methylation in white blood cells (WBC) and the risk of breast cancer. The evaluation of WBC DNA methylation as a biomarker of cancer risk is of particular importance as peripheral blood is often available in prospective cohorts and easier to obtain than tumor or normal tissues. Here, we used prediagnostic blood samples from three studies to analyze WBC DNA methylation of two ATM intragenic loci (ATMmvp2a and ATMmvp2b) and genome-wide DNA methylation in long interspersed nuclear element-1 (LINE1) repetitive elements. Samples were from a case–control study derived from a cohort of high-risk breast cancer families (KConFab) and nested case–control studies in two prospective cohorts: Breakthrough Generations Study (BGS) and European Prospective Investigation into Cancer and Nutrition (EPIC). Bisulfite pyrosequencing was used to quantify methylation from 640 incident cases of invasive breast cancer and 741 controls. Quintile analyses for ATMmvp2a showed an increased risk of breast cancer limited to women in the highest quintile [OR, 1.89; 95% confidence interval (CI), 1.36–2.64; P = 1.64 × 10−4]. We found no significant differences in estimates across studies or in analyses stratified by family history or menopausal status. However, a more consistent association was observed in younger than in older women and individually significant in KConFab and BGS, but not EPIC. We observed no differences in LINE1 or ATMmvp2b methylation between cases and controls. Together, our findings indicate that WBC DNA methylation levels at ATM could be a marker of breast cancer risk and further support the pursuit of epigenome-wide association studies of peripheral blood DNA methylation. Cancer Res; 72(9); 2304–13. ©2012 AACR.
Densely Granulated Murine NK Cells Eradicate Large Solid Tumors
Authors: Liu Rebecca B. , Engels Boris , Arina Ainhoa , Schreiber Karin , Hyjek Elizabeth , Schietinger Andrea , Binder David C. , Butz Eric , Krausz Thomas , Rowley Donald A. , Jabri Bana , Schreiber Hans
Published: February 2012

Natural killer (NK) cells inhibit early stages of tumor formation, recurrence, and metastasis. Here, we show that NK cells can also eradicate large solid tumors. Eradication depended on the massive infiltration of proliferating NK cells due to interleukin 15 (IL-15) released and presented by the cancer cells in the tumor microenvironment. Infiltrating NK cells had the striking morphologic feature of being densely loaded with periodic acid-Schiff–positive, diastase-resistant granules, resembling uterine NK cells. Perforin-mediated killing by these densely granulated NK cells was essential for tumor eradication. Expression of the IL-15 receptor α on cancer cells was needed to efficiently induce granulated NK cells, and expression on host stromal cells was essential to prevent tumor relapse after near complete destruction. These results indicate that IL-15 released at the cancer site induces highly activated NK cells that lead to eradication of large solid tumors. Cancer Res; 72(8); 1964–74. ©2012 AACR.
Plasma Biomarkers as Predictors of Outcome in Patients with Advanced Hepatocellular Carcinoma
Authors: Llovet Josep M. , Peña Carol E.A. , Lathia Chetan D. , Shan Michael , Meinhardt Gerold , Bruix Jordi
Published: February 2012

Purpose: Validated biomarkers of prognosis and response to drug have not been identified for patients with hepatocellular carcinoma (HCC). One of the objectives of the phase III, randomized, controlled Sorafenib HCC Assessment Randomized Protocol (SHARP) trial was to explore the ability of plasma biomarkers to predict prognosis and therapeutic efficacy.

Experimental Design: In SHARP, 602 patients with advanced HCC were randomized to receive either oral sorafenib 400 mg twice a day per os or matching placebo daily on a continuous basis. Ten plasma biomarkers implicated in the pathogenesis of HCC were measured in 491 patients at baseline and in 305 after 12 weeks of treatment. The candidate biomarkers were analyzed to identify correlates of prognosis or predictors of response to sorafenib.

Results: In both the entire patient population and the placebo cohort, baseline angiopoietin 2 (Ang2) and VEGF concentrations independently predicted survival. Clinical variables such as macroscopic vascular invasion, Eastern Cooperative Oncology Group (ECOG) performance status, and baseline α-fetoprotein and alkaline phosphatase concentrations also independently predicted survival in these groups. In the sorafenib cohort, trends toward enhanced survival benefit from sorafenib were observed in patients with high s-c-KIT or low hepatocyte growth factor concentration at baseline (P of interaction = 0.081 and 0.073, respectively).

Conclusions: The angiogenesis biomarkers Ang2 and VEGF were independent predictors of survival in patients with advanced HCC. In contrast, none of the biomarkers tested significantly predicted response to sorafenib. Clin Cancer Res; 18(8); 2290–300. ©2012 AACR.
Aurora A Inhibitor (MLN8237) plus Vincristine plus Rituximab Is Synthetic Lethal and a Potential Curative Therapy in Aggressive B-cell Non-Hodgkin Lymphoma
Authors: Mahadevan Daruka , Stejskal Amy , Cooke Laurence S. , Manziello Ann , Morales Carla , Persky Daniel O. , Fisher Richard I. , Miller Thomas P. , Qi Wenqing
Published: February 2012

Purpose: Aurora A and B are oncogenic serine/threonine kinases that regulate mitosis. Overexpression of Auroras promotes resistance to microtubule-targeted agents. We investigated mechanistic synergy by inhibiting the mitotic spindle apparatus in the presence of MLN8237 [M], an Aurora A inhibitor with either vincristine [MV] or docetaxel [MD] in aggressive B-cell non-Hodgkin lymphoma (B-NHL). The addition of rituximab [R] to MV or MD was evaluated for synthetic lethality.

Experimental Design: Aggressive B-NHL cell subtypes were evaluated in vitro and in vivo for target modulation and anti-NHL activity with single agents, doublets, and triplets by analyzing cell proliferation, apoptosis, tumor growth, survival, and mechanisms of response/relapse by gene expression profiling with protein validation.

Results: MV is synergistic whereas MD is additive for cell proliferation inhibition in B-NHL cell culture models. Addition of rituximab to MV is superior to MD, but both significantly induce apoptosis compared with doublet therapy. Mouse xenograft models of mantle cell lymphoma showed modest single-agent activity for MLN8237, rituximab, docetaxel, and vincristine with tumor growth inhibition (TGI) of approximately 10% to 15%. Of the doublets, MV caused tumor regression, whereas TGI was observed with MD (approximately 55%–60%) and MR (approximately 25%–50%), respectively. Although MV caused tumor regression, mice relapsed 20 days after stopping therapy. In contrast, MVR was curative, whereas MDR led to TGI of approximately 85%. Proliferation cell nuclear antigen, Aurora B, cyclin B1, cyclin D1, and Bcl-2 proteins of harvested tumors confirmed response and resistance to therapy.

Conclusions: Addition of rituximab to MV is a novel therapeutic strategy for aggressive B-NHL and warrants clinical trial evaluation. Clin Cancer Res; 18(8); 2210–9. ©2012 AACR.
cMET and Phospho-cMET Protein Levels in Breast Cancers and Survival Outcomes
Authors: Raghav Kanwal P. , Wang Wenting , Liu Shuying , Chavez-MacGregor Mariana , Meng Xiaolong , Hortobagyi Gabriel N. , Mills Gordon B. , Meric-Bernstam Funda , Blumenschein George R. , Gonzalez-Angulo Ana M.
Published: February 2012

Purpose: To evaluate cMET (mesenchymal–epithelial transition factor gene) and phospho-cMET (p-cMET) levels in breast cancer subtypes and its impact on survival outcomes.

Experimental Design: We measured protein levels of cMET and p-cMET in 257 breast cancers using reverse phase protein array. Regression tree method and Martingale residual plots were applied to find best cutoff point for high and low levels. Kaplan–Meier survival curves were used to estimate relapse-free (RFS) and overall (OS) survival. Cox proportional hazards models were fit to determine associations of cMET/p-cMET with outcomes after adjustment for other characteristics.

Results: Median age was 51 years. There were 140 (54.5%) hormone receptor (HR) positive, 53 (20.6%) HER2 positive, and 64 (24.9%) triple-negative tumors. Using selected cutoffs, 181 (70.4%) and 123 (47.9%) cancers had high levels of cMET and p-cMET, respectively. There were no significant differences in mean expression of cMET (P < 0.128) and p-cMET (P < 0.088) by breast cancer subtype. Dichotomized cMET and p-cMET level was a significant prognostic factor for RFS [HR: 2.44, 95% confidence interval (CI): 1.34–4.44, P = 0.003 and HR: 1.64, 95% CI: 1.04–2.60, P = 0.033] and OS (HR: 3.18, 95% CI: 1.43–7.11, P = 0.003 and HR: 1.92, 95% CI: 1.08–3.44, P = 0.025). Within breast cancer subtypes, high cMET levels were associated with worse RFS (P = 0.014) and OS (P = 0.006) in HR-positive tumors, and high p-cMET levels were associated with worse RFS (P = 0.019) and OS (P = 0.014) in HER2-positive breast cancers. In multivariable analysis, patients with high cMET had a significantly higher risk of recurrence (HR: 2.06, 95% CI: 1.08–3.94, P = 0.028) and death (HR: 2.81, 95% CI: 1.19–6.64, P = 0.019). High p-cMET level was associated with higher risk of recurrence (HR: 1.79, 95% CI: 1.08–2.95.77, P = 0.020).

Conclusions: High levels of cMET and p-cMET were seen in all breast cancer subtypes and correlated with poor prognosis. Clin Cancer Res; 18(8); 2269–77. ©2012 AACR.
nab-Paclitaxel Potentiates Gemcitabine Activity by Reducing Cytidine Deaminase Levels in a Mouse Model of Pancreatic Cancer
Authors: Frese Kristopher K. , Neesse Albrecht , Cook Natalie , Bapiro Tashinga E. , Lolkema Martijn P. , Jodrell Duncan I. , Tuveson David A.
Published: February 2012

Nanoparticle albumin-bound (nab)-paclitaxel, an albumin-stabilized paclitaxel formulation, demonstrates clinical activity when administered in combination with gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma (PDA). The limited availability of patient tissue and exquisite sensitivity of xenografts to chemotherapeutics have limited our ability to address the mechanistic basis of this treatment regimen. Here, we used a mouse model of PDA to show that the coadministration of nab-paclitaxel and gemcitabine uniquely demonstrates evidence of tumor regression. Combination treatment increases intratumoral gemcitabine levels attributable to a marked decrease in the primary gemcitabine metabolizing enzyme, cytidine deaminase. Correspondingly, paclitaxel reduced the levels of cytidine deaminase protein in cultured cells through reactive oxygen species–mediated degradation, resulting in the increased stabilization of gemcitabine. Our findings support the concept that suboptimal intratumoral concentrations of gemcitabine represent a crucial mechanism of therapeutic resistance in PDA and highlight the advantages of genetically engineered mouse models in preclinical therapeutic trials.

Significance: This study provides mechanistic insight into the clinical cooperation observed between gemcitabine and nab-paclitaxel in the treatment of pancreatic cancer. Cancer Discovery; 2(3); 260–9. ©2012 AACR.

Read the Commentary on this article by Clark, p. 208

This article is highlighted in the In This Issue feature, p. 193
First-Trimester Screening for Neural Tube Defects Using Alpha-Fetoprotein
Authors: Bredaki F.E. , Poon L.C. , Birdir C. , Escalante D. , Nicolaides K.H.
Published: February 2012

Objective: To assess the potential value of maternal serum alpha-fetoprotein (AFP) at 11–13 weeks’ gestation in early screening for fetal neural tube defects (NTDs). Methods: Maternal serum AFP at 11–13 weeks’ gestation was measured in 32 cases of fetal NTDs, including 18 cases of acrania and 14 cases of spina bifida, and 1,500 unaffected controls. The measured serum AFP was converted into multiple of the expected median (MoM) after adjustment for gestational age and maternal characteristics and Mann-Whitney test was used to determine the significance of difference in the mean MoM of serum AFP in the NTD group to that in the controls. Results: The mean AFP MoM in the NTD group (1.76, 95% CI 1.39–2.23) was significantly higher than in the controls (p < 0.0001). The mean AFP MoM was not significantly different between the cases of acrania and cases of spina bifida (1.78 vs. 1.75; p = 0.722). The detection rates of NTD in screening by serum AFP were 50.0% (95% CI 31.9–68.1) and 37.5% (95% CI 21.1–56.3) at fixed false-positive rates of 10 and 5%, respectively. Conclusion: Measurement ofmaternal serum AFP at 11–13 weeks’ gestation may be useful in screening for fetal NTDs.
Virotherapy of Neuroendocrine Tumors
Authors: Essand Magnus
Published: February 2012

Most patients with small intestinal neuroendocrine tumors (SI-NETs), also referred to as midgut carcinoids, present with systemic disease at the time of diagnosis with metastases primarily found in regional lymph nodes and the liver. Curative treatment is not available for these patients and there is a need for novel and specific therapies. Engineered oncolytic viruses may meet the need and play an important role in the future management of SI-NET liver metastases. This review focuses on adenovirus as the oncolytic anti-cancer agent and its potential curative role for SI-NET liver metastases, but it also summarizes the use of oncolytic viruses for NETs in general. It discusses how specific features of neuroendocrine cell biology can be used to engineer viruses to become selective for infection of NET cells and/or replication within NET cells. In addition, it points out the advantages and shortcomings of using replicating viruses in the treatment of cancer and addresses research fields that can increase the efficacy of virus-based therapy.
Effect of Neoadjuvant Chemotherapy in Hepatic Steatosis
Authors: Jiménez Raúl , Hijona Elizabeth , Emparanza José , Alústiza Jose M. , Hijona Lander , Macarulla Maria T. , Portillo Maria P. , Herreros-Villanueva Marta , Beguiristain Adolfo , Arenas Juan , Bujanda Luis
Published: February 2012

Chemotherapy drugs often produce side effects in the liver. In recent years, there has been speculation about the ability to produce hepatic steatosis in patients treated with 5-fluorouracil and oxaliplatin. This prospective study examines whether these drugs can produce steatosis in patients with neoadjuvant treatment who were operated on for liver tumors. Purpose: Our objective was to assess the effect of neoadjuvant chemotherapy (NAC) on the development of hepatic steatosis in the healthy liver. Patients and Methods: This was a prospective study based on 32 patients divided into two groups. The presence of steatosis was assessed using a histological score (Kleiner classification) and a biochemical method (Folch method) for patients from both groups. Results: A total of 14 patients (44%) had hepatic steatosis and half of these were in each group. The steatosis was moderate to severe (grades 2–3) in 4 patients (13%), 2 in each group. The mean levels of triglycerides in the liver were 33.38 and 29.94 mg/g in group I and group II, respectively, with the difference not being statistically significant. Conclusions: Almost half of the patients treated with NAC for liver neoplasia developed steatosis. Nevertheless, NAC does not seem to increase the risk of hepatic steatosis.
Tailoring Neoadjuvant Chemotherapy for Locally Advanced Breast Cancer: A Historical Prospective Study
Authors: Zer Alona , Rizel Shulamit , Braunstein Rony , Yerushalmi Rinat , Hendler Daniel , Neimann Victoria , Cioreuru Noa , Sulkes Aaron , Stemmer Salomon M.
Published: February 2012

Background: Despite the growing number of clinical trials assessing preoperative systemic chemotherapy (PST) for locally advanced breast cancer, the optimal regimen has still to be defined. Purpose: This was to evaluate the toxicity, operability rate, pathological response rate and disease-free and overall survival associated with a PST regimen consisting of the sequential administration of single agents according to the individual tumor response. Methods: Medical files were reviewed of 102 consecutive patients with breast cancer treated in 2000–2007 with a neoadjuvant sequential regimen of doxorubicin followed by taxane. The number of cycles and the addition of taxane were based on tumor response. Results: Seventy percent of the patients had inoperable disease at diagnosis and 29% were given preoperative therapy for breast conservation. All patients underwent surgery, 65% achieved breast conservation. An overall pathological complete response (breast and nodes) was achieved in 14% of the patients, and a complete nodal pathologic response in 34%. At a median follow-up of 54 months, the overall survival rate was 82% and the disease-free survival rate was 70%. There was no treatment-related mortality. Febrile neutropenia occurred in 19% of the patients. Conclusions: A neoadjuvant regimen of doxorubicin with or without a sequential taxane, in which the number of cycles and the sequential administration of taxane are determined according to clinical response, appears to be safe and effective for patients with locally advanced breast cancer and yields a high rate of breast conservation. Tailored PST can spare patients receiving unnecessary chemotherapy.
Antioxidant Therapies: A Potential Role in Perinatal Medicine
Authors: Miller S.L. , Wallace E.M. , Walker D.W.
Published: February 2012

Pregnancies complicated by impaired placentation, acute severe reductions in oxygen supply to the fetus, or intrauterine infection are associated with oxidative stress to the mother and developing baby. Such oxidative stress is characterized as an upregulation in the production of oxidative or nitrative free radicals and a concomitant decrease in the availability of antioxidant species, thereby creating a state of fetoplacental oxidative imbalance. Recently, there has been a good deal of interest in the potential for the use of antioxidant therapies in the perinatal period to protect the fetus, particularly the developing brain, against oxidative stress in complications of pregnancy and birth. This review will examine why the immature brain is particularly susceptible to oxidative imbalance and will provide discussion on antioxidant treatments currently receiving attention in the adult and perinatal literature – allopurinol, melatonin, α-lipoic acid, and vitamins C and E. In addition, we aim to address the interaction between oxidative stress and the fetal inflammatory response, an interaction that may be vital when proposing antioxidant or other neuroprotective strategies.
Literature-Based Genetic Risk Scores for Coronary Heart Disease
Authors: Vaarhorst Anika A.M. , Lu Yingchang , Heijmans Bastiaan T. , Dollé Martijn E.T. , Böhringer Stefan , Putter Hein , Imholz Sandra , Merry Audrey H.H. , van Greevenbroek Marleen M. , Jukema J. Wouter , Gorgels Anton P.M. , van den Brandt Piet A. , Müller Michael , Schouten Leo J. , Feskens Edith J.M. , Boer Jolanda M.A. , Slagboom P. Eline
Published: February 2012

Background—

Genome-wide association studies (GWAS) have identified many single-nucleotide polymorphisms (SNPs) associated with coronary heart disease (CHD) or CHD risk factors (RF). Using a case-cohort study within the prospective Cardiovascular Registry Maastricht (CAREMA) cohort, we tested if genetic risk scores (GRS) based on GWAS-identified SNPs are associated with and predictive for future CHD.

Methods and Results—

Incident cases (n=742), that is, participants who developed CHD during a median follow-up of 12.1 years (range, 0.0–16.9 years), were compared with a randomly selected subcohort of 2221 participants selected from the total cohort (n=21 148). We genotyped 179 SNPs previously associated with CHD or CHD RF in GWAS as published up to May 2, 2011. The allele-count GRS, composed of all SNPs, the 153 RF SNPs, or the 29 CHD SNPs were not associated with CHD independent of CHD RF. The weighted 29 CHD SNP GRS, with weights obtained from GWAS for every SNP, were associated with CHD independent of CHD RF (hazard ratio, 1.12 per weighted risk allele; 95% confidence interval, 1.04–1.21) and improved risk reclassification with 2.8% (
P
=0.031). As an exploratory approach to achieve weighting, we performed least absolute shrinkage and selection operator (LASSO) regression analysis on all SNPs and the CHD SNPs. The CHD LASSO GRS performed equal to the weighted CHD GRS, whereas the Overall LASSO GRS performed slightly better than the weighted CHD GRS.

Conclusions—

A GRS composed of CHD SNPs improves risk prediction when adjusted for the effect sizes of the SNPs. Alternatively LASSO regression analysis may be used to achieve weighting; however, validation in independent populations is required.
Novel Genetic Approach for In Vivo Vascular Imaging in Mice
Authors: Bartelle Benjamin B. , Berríos-Otero César A. , Rodriguez Joe J. , Friedland Anne E. , Aristizábal Orlando , Turnbull Daniel H.
Published: February 2012

Rationale:

The formation and maintenance of a functional vasculature is essential for normal embryonic development, and genetic changes that affect the vasculature underlie pathogenesis in many human diseases. In vivo imaging in mouse models is required to understand the full complexity of mammalian vascular formation, which is a dynamic and 3-dimensional process. Optical microscopy of genetically expressed fluorescent reporter proteins offers high resolution but limited depth of penetration in vivo. Conversely, there are a plethora of molecular probes for alternative in vivo vascular imaging modalities, but few options for genetic control of contrast enhancement.

Objective:

To develop a reporter system for multimodal imaging of genetic processes involved in mammalian vascular biology.

Methods and Results:

To approach this problem, we developed an optimal tagging system based on Biotag-BirA technology. In the resulting Biotag reporter system, coexpression of 2 interacting proteins results in biotin labeling of cell membranes, thus enabling multimodal imaging with “avidinated” probes. To assess this approach for in vivo imaging, we generated transgenic mice that expressed the Biotag-BirA transgene from a minimal
Tie2
promoter. A variety of imaging methods were used to show the utility of this approach for quantitative analysis in embryonic and adult models of vascular development, using intravascular injection of avidinated probes for near infrared, ultrasound, and magnetic resonance imaging.

Conclusions:

The present results demonstrate the versatility of the Biotag system for studies of vascular biology in genetically engineered mice, providing a robust approach for multimodal in vivo imaging of genetic processes in the vasculature.
A Human 3′ miR-499 Mutation Alters Cardiac mRNA Targeting and Function
Authors: Dorn Gerald W. , Matkovich Scot J. , Eschenbacher William H. , Zhang Yan
Published: February 2012

Rationale:

MyomiRs miR-499, miR-208a and miR-208b direct cardiac myosin gene expression. Sequence complementarity between miRs and their mRNA targets determines miR effects, but the functional consequences of human myomiR sequence variants are unknown.

Objective:

To identify and investigate mutations in human myomiRs in order to better understand how and to what extent naturally-occurring sequence variation can impact miR-mRNA targeting and end-organ function.

Methods and Results:

Screening of ≈2,600 individual DNAs for myomiR sequence variants identified a rare mutation of miR-499,
u
17
c
in the 3′ end, well outside the seed region thought to determine target recognition. In vitro luciferase reporter analysis showed that the 3′ miR-499 mutation altered suppression of a subset of artificial and natural mRNA targets. Cardiac-specific transgenic expression was used to compare consequences of wild-type and mutant miR-499. Both wild-type and mutant miR-499 induced heart failure in mice, but miR-499
c
17 misdirected recruitment of a subset of miR-499 target mRNAs to cardiomyocyte RNA-induced silencing complexes, altering steady-state cardiac mRNA and protein make-up and favorably impacting cardiac function. In vitro analysis of miR-499 target site mutations and modeling of binding energies revealed abnormal miR-mRNA duplex configurations induced by the
c
17 mutation.

Conclusions:

A naturally occurring miR-499 mutation outside the critical seed sequence modifies mRNA targeting and end-organ function. This first description of in vivo effects from a natural human miR mutation outside the seed sequence supports comprehensive studies of individual phenotypes or disease-modification conferred by miR mutations.
Global Fiscal Consolidation
Authors: McKibbin Warwick J. , Stoeckel Andrew B.
Published: February 2012

The buildup in government debt in response to the “great recession,” has raised a number of policy dilemmas for individual countries as well as the world as a whole. The recent need for a change of fiscal policy stance has fuelled debates about the impact of fiscal consolidation on domestic economies that are tightening, the flow-on effects to the world economy, and also about how much tightening there should be and how quickly it should happen. This paper explores these issues in a global framework focusing on the national and global consequences of coordinated fiscal consolidation. It explores the implications this fiscal adjustment might have on country risk premia and what happens if all countries coordinate their fiscal adjustment except the United States. A coordinated fiscal consolidation in the industrial world that is not accompanied by U.S. actions is likely to lead to a substantial worsening of trade imbalances globally as the release of capital in fiscally contracting economies flows into the U.S. economy, appreciates the U.S. dollar, and worsens the current account position of the United States. The scale of this change is likely to be sufficient to substantially increase the probability of a trade war between the United States and other economies. To avoid this outcome, a coordinated fiscal adjustment is clearly in the interest of the global economy.
Has electroconvulsive therapy use remained stable over time? A decade of electroconvulsive therapy service provision in Victoria, Australia
Authors: Plakiotis Chris , George Kuruvilla , O’Connor Daniel W
Published: February 2012

Objective: Despite the long history of electroconvulsive therapy (ECT) as a psychiatric treatment modality in Australia, existing literature regarding ECT use and practices in Australia is limited. In this unique study, we report ECT provision in Victoria to adults aged 25 years and over from 1998 to 2007, based on complete data from all public and private treatment settings within the State; compare our results to previous literature in the field; and offer possible explanations for these findings as a basis for future research.

Method: Analysis of statutory ECT service provision data collected by the Office of the Chief Psychiatrist of Victoria.

Results: ECT use declined overall from 2001 onward, followed by a small increase in use in 2007. Eighty per cent of patients received ECT for depression and 14% for psychosis. Sixty-two per cent of ECT recipients were women. Although patients aged 65 years and over were small in number, age adjustment of data was indicative of a higher utilisation rate in this group. With increasing age, the percentage of ECT recipients treated for depression increased, whereas the percentage treated for psychosis decreased. Sixty per cent of patients were treated in the public sector. Public-private sector ECT use did not differ greatly for depression, but more patients were treated in the public sector for psychosis. The majority of patients with depression received treatment voluntarily, but the converse was true for patients with psychosis. Unilateral electrode placement predominated.

Conclusions: While utilisation rates gradually declined over the decade studied, patients continued receiving ECT in significant numbers, suggesting its role in treating severe mental illness is far from superceded. The present, population-level research cannot explain the causative factors underlying the patterns observed, but raises interesting questions for further investigation. Ongoing collection of statutory ECT data in a manner making it amenable to research applications is recommended.
An efficient version of inverse boosting for classification
Authors: Gao Jingyang , Chen Chenglizhao , Zhen Dantong , Zhu Qunxiong
Published: February 2012

This paper gives a survey of the inverse boosting algorithm which employs an inverse error vector to produce new sample distributions. The experimental result shows that the inverse boosting can outperform normal boosting in some cases. Further experiments on several benchmark real-world data sets available from the UCI repository are taken to get a better insight into the inverse boosting algorithm, and then we find that the performance of the ensemble is determined by the performance of its base classifiers. This distinctive feature of inverse boosting indicates that traditional ways to improve the performance of an ensemble through enhancing the diversity between the base classifier are invalid here. Therefore, this paper proposes a method with pertinence to improve the performance of inverse boosting.
Alliances and arguments: A case study of a child with persisting speech difficulties in peer play
Authors: Tempest Alison , Wells Bill
Published: February 2012

The ability to argue and to create alliances with peers are important social competencies for all children, including those who have speech, language and communication needs. In this study, we investigated the management of arguments and alliances by a group of 5-year-old male friends, one of whom has a persisting speech difficulty (PSD). Twelve argument episodes that arose naturally during video-recorded free play at school were analysed, using Conversation Analysis. Overall the data show that the child with PSD was just as likely as one of his friends to be included in, or excluded from, play alliances. Detailed analysis of two episodes reveals that the child with PSD competently used a range of linguistic devices in and around arguments and that his speech difficulties apparently did not impact on his ability to form alliances. This study highlights the need for those of us who work with children to take account of peer interactions and to consider the linguistic strategies that children employ when participating in peer talk and play: the social world in which inclusion and exclusion are accomplished. The study also illustrates the value of qualitative micro-interactional analysis as a research tool for investigating social inclusion and exclusion.
Peer acceptance of children with language and communication impairments in a mainstream primary school: Associations with type of language difficulty, problem behaviours and a change in placement organization
Authors: Laws Glynis , Bates Geraldine , Feuerstein Maike , Mason-Apps Emily , White Catherine
Published: February 2012

This research investigated peer acceptance of children with language and communication impairments attending a language resource base attached to a mainstream school. Compared to other children in their mainstream peer groups, peer acceptance was poor. Peer rejection was more common for children with profiles consistent with an autistic spectrum disorder than for children with specific language impairment, and peer acceptance was significantly associated with social communication abilities. Children with clearer speech and more mature syntax also had more positive peer relationships. Language and communication appeared to be more important for peer acceptance than classroom behaviour. Changing children’s principal placements from the language resource base to the mainstream classes had some beneficial effect; peer rejection was reduced and most children were more tolerated.
Risk Factors for Suicidal Ideation Among African American and European American College Women
Authors: Lamis Dorian A. , Lester David
Published: February 2012

Given that suicide is the second leading cause of death among college students, it is important to identify risk factors that may contribute to college students’ suicide. Our study examined the differences in risk factors of suicidal ideation between 99 African American and 529 European American college women (18–24 years old). The only significant difference that was reported between the two groups of women was on hopelessness, with African American women having lower hopelessness scores. In hierarchical regression analyses, reports of hopelessness, depression, and perceived burdensomeness, but not thwarted belongingness, significantly predicted suicidal ideation in college women. Furthermore, race moderated the relationship between hopelessness and suicidal ideation such that hopelessness was a stronger predictor for African American women than it was for European American women. Race also moderated the depression–suicidal ideation association, with depression emerging as a stronger predictor of suicidal ideation for European American than for African American women. When assessing risk for suicide, our results suggest that practitioners may need to focus more on hopelessness in African American women and more on depression in European American women while also considering perceived burdensomeness in college women regardless of race. In addition to assessment, prevention programs which target these identified risk factors for suicidality should be developed specifically for African American and European American college women.
Modern special collections cataloguing: A University of London case study
Authors: Attar KE
Published: February 2012

Recent years have seen a growing emphasis on modern special collections (in themselves no new phenomenon), with a dichotomy between guidance for detailed cataloguing in Descriptive Cataloging of Rare Materials (Books) (DCRM(B), 2007) and the value of clearing cataloguing backlogs expeditiously. This article describes the De la Mare Family Archive of Walter de la Mare’s Printed Oeuvre at Senate House Library, University of London, as an example of a modern author collection in an institutional library. It sets out the particular cataloguing challenges faced, looking at both general and copy-specific features and discussing the relation between bibliography and catalogue when no comprehensive bibliography exists. It confirms the adequacy of the Anglo American Cataloging Rules (AACR2, 1998) for general cataloguing purposes, while noting the benefit of DCRM(B)’s more expansive copy-specific instructions.
Loss of faith in the origins of information literacy in e-environments: Proposal of a holistic approach
Authors: Nazari Maryam , Webber Sheila
Published: February 2012

The original concept of information literacy (IL) identifies it as an enabler for lifelong learning and learning-to-learn, adaptable and transferable in any learning environment and context. However, practices of IL in electronic information and learning environments (e-environments) tend to question the origins, and workability, of IL on the grounds that the generic models of IL are inadequate for the complex and evolving context of e-environments. Conducting an analytical review of the literature on the approaches taken to adapt IL in e-environments, we discuss how a failure in understanding the dynamic context and components of e-environments and IL have resulted in the emergence of a marginalised way of viewing and practicing IL in these environments. Drawing on Nazari’s (2011) contextual study of IL in an online distance learning programme, we propose a holistic way of viewing and practicing IL in EL environments which is aligned with IL origins; it enables the e-learner to conceptualise IL and customise it to their actual learning style and needs. This study can be of value to IL scholars and practitioners who are interested in the concept and practice of IL in e-environments.
Public perceptions of incompatibility between “science and religion”
Authors: Baker Joseph O.
Published: February 2012

Narratives of conflict regarding the connections between science and religion receive considerable attention in multiple forums of public discourse. These discussions tend to focus on philosophical, abstract, and/or polemical, rather than empirical issues. Data from a 2007 national survey indicate that a relatively small proportion of American adults perceive incompatibility between science and religion. Those who do are divided evenly into groups privileging science and privileging religion. These groups are markedly different with regard to sociodemographic and religious characteristics. Overall, I advocate a theoretical perspective on “science and religion” that is culturally constructionist, but methodologically empiricist.
Forming an ‘Activism Bubble’ in Tourism: Peace Guiding at Okinawa’s Battle Ruins
Authors: Suzuki Taku
Published: February 2012

Peace activists in Okinawa, Japan, serve as tour guides, or ‘peace guides’, for school excursion tour groups from Japan’s main islands. Their purpose is to encourage the students to learn about the devastating Battle of Okinawa in 1945 and engage in current issues of war and peace. By historically contextualizing the emergence of school excursion and peace guides in Okinawa, and ethnographically portraying the peace guides’ narrative and performative tactics in a natural cave and at a war memorial, the essay demonstrates that the guides attempt to form a spatiotemporal bubble within which the students develop an active learning community with a critical awareness of militarized realities of the past and present.
Physical Webbing: Collaborative kinesthetic three-dimensional Mind Maps®
Authors: Williams Marian H.
Published: February 2012

Mind Mapping has predominantly been used by individuals or collaboratively in groups as a paper-based or computer-generated learning strategy. In an effort to make Mind Mapping kinesthetic, collaborative, and three-dimensional, an innovative pedagogical strategy, termed Physical Webbing, was devised. In the Physical Web activity, groups collaboratively build concrete (physical) representations of content using kinesthetic or participatory manipulatives. The theoretical underpinnings of the Physical Web include the scientific findings on the physicality of learning and Papert’s constructionist theory. A case study example of the implementation of the Physical Webbing process delineates a specific application and provides procedures for replication and expansion of the strategy. Qualitative analysis of the attitudinal surveys following the activity provided data regarding students’ preference for the Physical Webbing activity over the traditional lecture, acceptance of participatory manipulatives, perceived learning and attitudes towards collaborative kinesthetic three-dimensional Mind Mapping.
Examining NIARA
Authors: Nickels Ashley , Kowalski-Braun Marlene
Published: February 2012

The Problem.

Higher education and human resource development (HRD) personnel are constantly seeking ways to enhance the job satisfaction and leadership development of women of color, which is often challenged by resources and cultural climate.

The Solution.

As organizations seek to address improvements within these areas, HRD practitioners and higher education administrators may find value in the documented experiences of mentorship. This interpretive qualitative study explores how NIARA, an innovative mentoring program designed for women of color in higher education, influenced the personal and professional satisfaction of four African American women staff mentors involved in the program.

The Stakeholders.

This article is relevant to HRD professionals and higher education administrators who are developing and assessing mentoring opportunities for faculty, staff, and students. Implications for HRD and the advancement of opportunities for women of color in higher education are also examined.
The simulation for a new nanomagnetic setback generator
Authors: Fu Yue , Lou Wen-zhong , Zhang Long-fei
Published: February 2012

Applications of nanomaterials will become the leading technology during the next decades of this century. The composite nanomagnet, which has better features, lower cost and is less demanding of rare earth elements, is a new type of permanent magnetic material. It has become one of the important developments of the nanomagnet generator. In this paper, we apply this nanomagnet in a magnetic setback generator and simulate its electromotive force using COMSOL Multiphysic, comparing it with traditional generators. We find it is better than the traditional option in performance, with obvious advantage in respect of cost.
New treatments in hemophilia: insights for the clinician
Authors: Knobe Karin , Berntorp Erik
Published: February 2012

Hemophilia has evolved from an often fatal hereditary bleeding disorder to a disorder for which safe and effective treatment is available. However, there are several challenges remaining in the treatment of hemophilia. Prophylaxis to prevent bleeding is costly and requires frequent intravenous injections, which are cumbersome for patients. Venous access is often difficult to achieve, especially in small children where central venous lines may need to be implanted. Development of inhibitory antibodies makes treatment of acute bleeds difficult and prophylaxis in patients with inhibitors must also be better addressed. In order to improve treatment, new products are being developed, some of which are already in clinical trials. There are several approaches to prolonging half-lives such as PEGylation, Fc fusion and albumin fusion. Increased activity has been demonstrated in preclinical trials for factor IX and in a human trial with factor VII where the activity of the molecules has been increased by manipulation of the molecular composition. Additional approaches, including blockage of inhibitors of clotting, are also under investigation. Factor VIII and factor IX gene therapy have become a tangible possibility since phase I data recently have been published. Results are promising and there is hope that in the near future substantial progress will be made, perhaps making hemophilia the first genetic condition to be cured.
The FLT3ITD mRNA level has a high prognostic impact in NPM1 mutated, but not in NPM1 unmutated, AML with a normal karyotype
Authors: Schneider Friederike , Hoster Eva , Unterhalt Michael , Schneider Stephanie , Dufour Annika , Benthaus Tobias , Mellert Gudrun , Zellmeier Evelyn , Kakadia Purvi M. , Bohlander Stefan K. , Feuring-Buske Michaela , Buske Christian , Braess Jan , Heinecke Achim , Sauerland Maria C. , Berdel Wolfgang E. , Büchner Thomas , Wörmann Bernhard J. , Hiddemann Wolfgang , Spiekermann Karsten
Published: February 2012

The impact of a FLT3-internal tandem duplication (FLT3ITD) on prognosis of patients with acute myeloid leukemia (AML) is dependent on the ratio of mutated to wild-type allele. In 648 normal karyotype (NK) AML patients, we found a significant independent effect of the quantitative FLT3ITD mRNA level—measured as (FLT3ITD/wtFLT3)/(FLT3ITD/wtFLT3 + 1)—on outcome. Moreover, this effect was clearly seen in 329 patients with a mutated NPM1 gene (NPM1+), but not in 319 patients without a NPM1 mutation (wtNPM1). In a multivariate Cox regression model, the quantitative FLT3ITD mRNA level showed an independent prognostic impact on overall survival (OS) and relapse-free survival (RFS) only in the NPM1+ subgroup (OS: hazard ratio, 5.9; [95% confidence interval [CI]: 3.1-11.2]; RFS: hazard ratio, 7.5 [95% CI: 3.4-16.5]). The FLT3ITD mRNA level contributes to relapse risk stratification and might help to guide postremission therapy in NPM1-mutated AML.
An acute negative bystander effect of γ-irradiated recipients on transplanted hematopoietic stem cells
Authors: Shen Hongmei , Yu Hui , Liang Paulina H. , Cheng Haizi , XuFeng Richard , Yuan Youzhong , Zhang Peng , Smith Clayton A. , Cheng Tao
Published: February 2012

Ultimate success of hematopoietic stem cell transplantation (HSCT) depends not only on donor HSCs themselves but also on the host environment. Total body irradiation is a component in various host conditioning regimens for HSCT. It is known that ionizing radiation exerts “bystander effects” on nontargeted cells and that HSCs transplanted into irradiated recipients undergo proliferative exhaustion. However, whether irradiated recipients pose a proliferation-independent bystander effect on transplanted HSCs is unclear. In this study, we found that irradiated mouse recipients significantly impaired the long-term repopulating ability of transplanted mouse HSCs shortly (∼ 17 hours) after exposure to irradiated hosts and before the cells began to divide. There was an increase of acute cell death associated with accelerated proliferation of the bystander hematopoietic cells. This effect was marked by dramatic down-regulation of c-Kit, apparently because of elevated reactive oxygen species. Administration of an antioxidant chemical, N-acetylcysteine, or ectopically overexpressing a reactive oxygen species scavenging enzyme, catalase, improved the function of transplanted HSCs in irradiated hosts. Together, this study provides evidence for an acute negative, yet proliferation-independent, bystander effect of irradiated recipients on transplanted HSCs, thereby having implications for HSCT in both experimental and clinical scenarios in which total body irradiation is involved.