bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preclinical Analysis of the γ-Secretase Inhibitor PF-03084014 in Combination with Glucocorticoids in T-cell Acute Lymphoblastic Leukemia
Authors: Samon Jeremy B. , Castillo-Martin Mireia , Hadler Michael , Ambesi-Impiobato Alberto , Paietta Elisabeth , Racevskis Janis , Wiernik Peter H. , Rowe Jacob M. , Jakubczak John , Randolph Sophia , Cordon-Cardo Carlos , Ferrando Adolfo A. 
Published: April 2012

Abstract
T-cell acute lymphoblastic leukemias (T-ALL) and lymphomas are aggressive hematologic cancers frequently associated with activating mutations in NOTCH1. Early studies identified NOTCH1 as an attractive therapeutic target for the treatment of T-ALL through the use of γ-secretase inhibitors (GSI). Here, we characterized the interaction between PF-03084014, a clinically relevant GSI, and dexamethasone in preclinical models of glucocorticoid-resistant T-ALL. Combination treatment of the GSI PF-03084014 with glucocorticoids induced a synergistic antileukemic effect in human T-ALL cell lines and primary human T-ALL patient samples. Mechanistically PF-03084014 plus glucocorticoid treatment induced increased transcriptional upregulation of the glucocorticoid receptor and glucocorticoid target genes. Treatment with PF-03084014 and glucocorticoids in combination was highly efficacious in vivo, with enhanced reduction of tumor burden in a xenograft model of T-ALL. Finally, glucocorticoid treatment effectively reversed PF-03084014–induced gastrointestinal toxicity via inhibition of goblet cell metaplasia. These results warrant the analysis of PF-03084014 and glucocorticoids in combination for the treatment of glucocorticoid-resistant T-ALL. Mol Cancer Ther; 11(7); 1565–75. ©2012 AACR.
Environmental Estrogens Differentially Engage the Histone Methyltransferase EZH2 to Increase Risk of Uterine Tumorigenesis
Authors: Greathouse K. Leigh , Bredfeldt Tiffany , Everitt Jeffrey I. , Lin Kevin , Berry Tia , Kannan Kurunthachalam , Mittelstadt Megan L. , Ho Shuk-mei , Walker Cheryl L. 
Published: April 2012

Abstract
Environmental exposures during sensitive windows of development can reprogram normal physiologic responses and alter disease susceptibility later in life in a process known as developmental reprogramming. For example, exposure to the xenoestrogen diethylstilbestrol during reproductive tract development can reprogram estrogen-responsive gene expression in the myometrium, resulting in hyperresponsiveness to hormone in the adult uterus and promotion of hormone-dependent uterine leiomyoma. We show here that the environmental estrogens genistein, a soy phytoestrogen, and the plasticizer bisphenol A, differ in their pattern of developmental reprogramming and promotion of tumorigenesis (leiomyomas) in the uterus. Whereas both genistein and bisphenol A induce genomic estrogen receptor (ER) signaling in the developing uterus, only genistein induced phosphoinositide 3-kinase (PI3K)/AKT nongenomic ER signaling to the histone methyltransferase enhancer of zeste homolog 2 (EZH2). As a result, this pregenomic signaling phosphorylates and represses EZH2 and reduces levels of H3K27me3 repressive mark in chromatin. Furthermore, only genistein caused estrogen-responsive genes in the adult myometrium to become hyperresponsive to hormone; estrogen-responsive genes were repressed in bisphenol A–exposed uteri. Importantly, this pattern of EZH2 engagement to decrease versus increase H3K27 methylation correlated with the effect of these xenoestrogens on tumorigenesis. Developmental reprogramming by genistein promoted development of uterine leiomyomas, increasing tumor incidence and multiplicity, whereas bisphenol A did not. These data show that environmental estrogens have distinct nongenomic effects in the developing uterus that determines their ability to engage the epigenetic regulator EZH2, decrease levels of the repressive epigenetic histone H3K27 methyl mark in chromatin during developmental reprogramming, and promote uterine tumorigenesis. Mol Cancer Res; 10(4); 546–57. ©2012 AACR.
Resolvin D1 Limits Polymorphonuclear Leukocyte Recruitment to Inflammatory Loci
Authors: Norling Lucy V. , Dalli Jesmond , Flower Roderick J. , Serhan Charles N. , Perretti Mauro 
Published: April 2012

Objective—

Resolvin D1 (RvD1) limits neutrophil recruitment during acute inflammation and is derived from omega-3 docosahexaenoic acid to promote catabasis. The contribution of its specific receptors, the lipoxin A
4
/Annexin-A1 receptor formyl-peptide receptor 2 (FPR2/ALX) and the orphan receptor G-protein–coupled receptor 32 (GPR32) are of considerable interest.

Methods and Results—

RvD1 reduced human polymorphonuclear leukocytes recruitment to endothelial cells under shear conditions as quantified using a flow chamber system. Receptor-specific antibodies blocked these anti-inflammatory actions of RvD1, with low (1 nmol/L) concentrations sensitive to GPR32 blockade, while the higher (10 nmol/L) concentration appeared FPR2/ALX-specific. Interestingly, polymorphonuclear leukocytes surface expression of FPR2/ALX but not GPR32 increased following activation with pro-inflammatory stimuli, corresponding with secretory vesicle mobilization. Lipid mediator metabololipidomics carried out with 24-hour exudates revealed that RvD1 in vivo gave a significant reduction in the levels of a number of pro-inflammatory mediators including prostaglandins and leukotriene B
4
. These actions of RvD1 were abolished in
fpr2
null mice.

Conclusion—
Pro-resolving lipid mediators and their receptors, such as RvD1 and the 2 G-protein–coupled receptors, studied here regulate resolution and may provide new therapeutic strategies for diseases with a vascular inflammatory component.
Trabeculated (Noncompacted) and Compact Myocardium in Adults
Authors: Kawel Nadine , Nacif Marcelo , Arai Andrew E. , Gomes Antoinette S. , Hundley W. Gregory , Johnson W. Craig , Prince Martin R. , Stacey R. Brandon , Lima João A. C. , Bluemke David A. 
Published: April 2012

Background—
A high degree of noncompacted (trabeculated) myocardium in relationship to compact myocardium (trabeculated to compact myocardium [T/M] ratio >2.3) has been associated with a diagnosis of left ventricular noncompaction (LVNC). The purpose of this study was to determine the normal range of the T/M ratio in a large population-based study and to examine the relationship to demographic and clinical parameters.

Methods and Results—

The thickness of trabeculation and the compact myocardium were measured in 8 left ventricular regions on long axis cardiac MR steady-state free precession cine images in 1000 participants (551 women; 68.1±8.9 years) of the Multi-Ethnic Study of Atherosclerosis cohort. Of 323 participants without cardiac disease or hypertension and with all regions evaluable, 140 (43%) had a T/M ratio >2.3 in at least 1 region; in 20 of 323 (6%), T/M >2.3 was present in >2 regions. A multivariable linear regression model revealed no association of age, sex, ethnicity, height, and weight with maximum T/M ratio in participants without cardiac disease or hypertension (
P
>0.05). In the entire cohort (n=1000), left ventricular ejection fraction (β=−0.02/%;
P
=0.015), left ventricular end-diastolic volume (β=0.01/mL;
P
<0.0001), and left ventricular end-systolic volume (β=0.01/mL;
P
<0.001) were associated with maximum T/M ratio in adjusted models, whereas there was no association with hypertension or myocardial infarction (
P
>0.05). At the apical level, T/M ratios were significantly lower when obtained on short- compared with long-axis images (
P
=0.017).

Conclusions—
A ratio of T/M of >2.3 is common in a large population-based cohort. These results suggest re-evaluation of the current cardiac MR criteria for left ventricular noncompaction may be necessary.
Measuring Energy Expenditure After Stroke
Authors: Moore Sarah A. , Hallsworth Kate , Bluck Les J.C. , Ford Gary A. , Rochester Lynn , Trenell Michael I. 
Published: April 2012

Background and Purpose—
Current means of assessing physical activity and energy expenditure have restrictions in stroke, limiting our understanding of its role in therapeutic management. This study validates a portable multisensor array for measuring free-living total energy expenditure compared with a gold standard method (doubly labeled water) in individuals with stroke.

Methods—
Daily energy expenditure was measured in 9 participants with stroke (73±8 years) over a 10-day period with 2 techniques: a portable multisensor array and doubly labeled water.

Results—

Bland-Altman analysis revealed a mean difference of 94 kcal/day (3.8%) in total energy expenditure measures given by the multisensor array in comparison to doubly labeled water with lower and upper limits of agreement of −276 to 463.8 kcal/day (2473±468 versus 2380±551,
P
=0.167). There was strong agreement between the multisensor array and labeled water methods of capturing total daily energy expenditure (
r
=0.850,
P
=0.004).

Conclusions—
The multisensor array is a portable and accurate method of capturing daily energy expenditure and may assist in understanding how stroke influences free-living energy expenditure and aid in clinical management.
Perceived usefulness of learning strategies by children with Tourette syndrome plus, their parents and their teachers
Authors: Thomas Roger , Carroll Alan , Chomin Elizabeth , Williamson Tyler , Beran Tanya , Palacios-Derflingher Luz , Drummond Neil 
Published: April 2012

Objective: Children with Tourette syndrome and other co-morbidities (abbreviated hereafter to TS+) experience significant learning difficulties. We wished to identify educational strategies that these students, their parents and teachers considered useful. Design: An ‘educational toolkit’ was compiled of 84 strategies identified by teachers of TS+ children. Setting: Children attending the TS+ clinic of a university hospital in Edmonton, Alberta. Method: The educational toolkit was administered to 30 randomly selected TS+ children attending the clinic, their teachers, and their parents. Results: 13 strategies were endorsed by ≥ 50% of the students, 53 by ≥ 50% of parents, and 42 by ≥ 50% of teachers. The 10 strategies students most strongly endorsed were: (1) computers; (2) calculators; (3) spell-checkers; (4) extra time in class; (5) less homework; (6) information from the teacher; (7) feedback on how to improve work; (8) printed assignments; (9) TS+ explained to their teacher; and (10) not being punished or suspended because of TS+ behaviours. The 10 strategies most frequently endorsed by parents were: (1) the student paying attention and being informed; (2) computers; (3) the teacher telling the whole class ‘listen carefully’ when discussing important ideas; (4) providing ideas about organizing work; (5) providing printed assignments; (6) telling students when they are being helpful; (7) encouraging students for good behaviour and signaling incorrect behaviour; (8) checking students understand each idea the teacher presents; (9) outside experts explaining TS+ to the teacher; and (10) exchanging notes with the teacher. The 10 items most strongly endorsed by teachers were: (1) providing information and direction; (2) feedback on how to improve work; (3) checking students wrote down homework assignments; (4) helping students start work assignments; (5) computers; (6) spell-checkers; (7) monitoring time and work; (8) extra time; (9) feedback about the student’s behaviour and advice if misbehaving; and (10) the teacher explaining to the class how students can help students with learning challenges. Conclusions: There is considerable agreement among parents and teachers about how to help children with TS+ with their schoolwork and behaviours.
‘Letting go’: An auto-ethnography of higher degree supervision in music
Authors: Harrison Scott D. 
Published: April 2012

This paper examines my role as supervisor of research higher degree music students. Within this dyad, the pedagogical design has centred on conventional delivery, conceptualized in terms of the time-honoured top–down, supervisor–candidate interaction rather than exploration of a co-mentoring collaboration. Many doctoral candidates in music perceive this merely as an extension of the one-to-one instrumental or vocal tuition from their pre-tertiary and undergraduate learning experiences. This can serve to perpetuate over-reliance on the supervisor as master to provide the student as apprentice with technical work (researching and writing skills); repertoire (literature); and stylistic input (writing genre). Compared with undergraduate approaches, these aspects of learning may be often cobbled together in a haphazard fashion where an understanding of the overall project is somewhat fragmented. Consequently, the particular nature of pedagogy in research higher degrees in music remains under-developed and in need of reconceptualization or the development of an enlightened eye. This paper will review and explore this pedagogy, drawing on narratives presented from my perspectives as supervisor. My role is explored through an autoethnographic account of my experiences as a teacher of groups and individuals, and this is interwoven with references to the projects of candidates at various stages in their programme. In my self-study, I will consider some of my emerging themes, including confidence, project design and management, academic writing, teaching preparation and multi-exegetical formats.
H2M: a GP-focused multidisciplinary team for patients living with HIV and hepatitis C
Authors: Sternhell Peter , Landstra Jodie , Andersson-Noorgard Kurt 
Published: April 2012

Objective: To describe the development and functioning of the HIV and hepatitis C mental health in primary care service (H2M), a multidisciplinary team that works with local general practitioners (GPs) and the St Vincent’s Hospital immunology clinic to meet the mental health needs of their patients living with HIV/AIDS and those undergoing interferon-based treatment for hepatitis C. Method: The authors describe and review the service, using information from a database of patient characteristics and from a GP satisfaction survey. Results: GP satisfaction with the service was high and participating GPs have increased their knowledge and understanding of their patients’ mental health problems. Conclusions: Over eight years, H2M has become a well utilized and valued specialty team with over 1,200 referrals in that time. Patients with other chronic health conditions, such as diabetes, cardiac and renal disease, could benefit from a similar service model.
Incidence, outcome and predictors of bleomycin pulmonary toxicity in a university hospital in Oman
Authors: Ahmed Bushra M , Al-Zakwani Ibrahim S 
Published: April 2012

Objectives: To determine the incidence and predictors of bleomycin pulmonary toxicity in a university hospital in Oman. Methods: This retrospective chart review consisted of 46 patients treated with bleomycin-containing regimes at Sultan Qaboos University Hospital in Oman between January 2007 and December 2010. Data regarding patient age, chemotherapy protocol, cumulative bleomycin dose, smoking history, renal function and concurrent use of granulocyte colony stimulating factor (GCSF) were collected from the hospital’s electronic database. Analyses were performed using univariate statistical techniques. Results: Of the 46 patients, 22% ( n = 10) experienced bleomycin pulmonary toxicity. There was an overall mortality of 4.3% ( n = 2; N = 46), with significantly more deaths in the bleomycin pulmonary toxicity group compared to the cohort that did not have bleomycin pulmonary toxicity (20% versus 0%; p = 0.043). The bleomycin pulmonary toxicity group was significantly older compared to the cohort that did not have bleomycin pulmonary toxicity (48 versus 34 years; p = 0.017). Furthermore, adriamycin, bleomycin, vinblastine, dacarbazine, as front-line chemotherapy, was found to have a trend towards increased risk of bleomycin pulmonary toxicity (90% versus 56%; p = 0.067; power = 31%). There did not seem to be significant differences in bleomycin dose (143 versus 149 units; p = 0.727), smoking status (10% versus 14%; p = 1.000) and systolic blood pressure (133 versus 131 mmHg; p = 0.746) between the two study groups. Conclusion: This study confirms a relatively high incidence of bleomycin pulmonary toxicity in a tertiary hospital in Oman. Older patients were significantly more likely to suffer bleomycin pulmonary toxicity compared to younger patients.
The diabetic patient has a higher benefit from infrapopliteal revascularization than the non-diabetic patient: A 10-year retrospective study
Authors: Oberhuber Alexander , Benecke Brigitte , Orend Karl-Heinz , Hutschenreiter Siegfried , Muehling Bernd M 
Published: April 2012

Objective: The objective of this article is to evaluate the limb salvage and patency rates after crural arterial revascularization, differences between graft material and co-morbidities. Patients and methods: All patients with crural artery bypasses were analysed retrospectively in a single centre (Department of Vascular Surgery, Thüringen Kliniken Saalfeld, Rudolstadt, Germany) over a 10-year period (1996–2006); 157 patients with 170 consecutive arterial reconstructions could be included. Results: Follow-up time was 55 months (6–119). Median age of the 56 women and the 101 men at the time of operation was 70 years (45.6–93.6). The five-year secondary patency rates were 71.5 ± 6.22% (vein), 44.3 ± 10.8% (composite; p = 0.0011), 52.6 ± 13.4% (prosthetic graft with distal vein cuff/patch; p = 0.00953) and 42 ± 12% (prosthetic graft without distal vein cuff/patch; p = 0.00443). Limb salvage rates after five years were 79.5 ± 5.8%, 61.6 ± 10.3%, 77.9 ± 11.3% and 70.1 ± 14.7%, respectively. Cumulative limb salvage rate was significantly higher in diabetic patients (78.9 ± 4.9%), than in non-diabetic patients (66.6 ± 6.8); p = 0.023. Conclusion: Crural reconstruction is a suitable method for peripheral arterial occlusive disease to prevent amputation, particularly in diabetics.
Comparative cost efficiency across the European G5 countries of originators and a biosimilar erythropoiesis-stimulating agent to manage chemotherapy-induced anemia in patients with cancer
Authors: Aapro Matti , Cornes Paul , Sun Diana , Abraham Ivo 
Published: April 2012

Objectives: To evaluate the comparative cost efficiency across the European Union G5 countries of the erythropoiesis-stimulating agents (ESAs) epoetin α (originator [Eprex®] and biosimilar [Binocrit®]; once weekly), epoetin β (NeoRecormon®; once weekly), and darbepoetin α (Aranesp®; once weekly or once every 3 weeks) under different scenarios of fixed and weight-based dosing in the management of chemotherapy-induced anemia. Methods: Direct costs of ESA treatment were calculated for one patient with cancer undergoing chemotherapy (six cycles at 3-week intervals) with ESA initiated at week 4 and continued for 15 weeks. Five scenarios were developed under fixed and weight-based dosing: continuous standard dose for 15 weeks; sustained dose escalation to 1.5× or double the standard dose at week 7, continued for 12 weeks; and discontinued dose escalation to 1.5× or double the standard dose at week 7 for a 3-week period, then 9 weeks of standard dose. Results: Under fixed dosing, the average cost of biosimilar epoetin α treatment across scenarios was €4643 (30,000 IU) or €6178 (40,000 IU). Corresponding estimates were €7168 for originator epoetin α, €7389 for epoetin β, €8299 for darbepoetin α once weekly, and €9221 for darbepoetin α once every 3 weeks. Under weight-based dosing, the average cost of biosimilar epoetin α treatment across scenarios was €4726. Corresponding estimates were €5484 for originator epoetin α, €5652 for epoetin β, and €8465 for both darbepoetin α once weekly and once every three weeks. Conclusion: Managing chemotherapy-induced anemia with biosimilar epoetin α is consistently cost efficient over treatment with originator epoetin α, epoetin β, and darbepoetin α under both fixed and weight-based dosing scenarios.
PU.1 is linking the glycolytic enzyme HK3 in neutrophil differentiation and survival of APL cells
Authors: Federzoni Elena A. , Valk Peter J. M. , Torbett Bruce E. , Haferlach Torsten , Löwenberg Bob , Fey Martin F. , Tschan Mario P. 
Published: April 2012

Abstract
The transcription factor PU.1 is a master regulator of myeloid differentiation and function. On the other hand, only scarce information is available on PU.1-regulated genes involved in cell survival. We now identified the glycolytic enzyme hexokinase 3 (HK3), a gene with cytoprotective functions, as transcriptional target of PU.1. Interestingly, HK3 expression is highly associated with the myeloid lineage and was significantly decreased in acute myeloid leukemia patients compared with normal granulocytes. Moreover, HK3 expression was significantly lower in acute promyelocytic leukemia (APL) compared with non-APL patient samples. In line with the observations in primary APL patient samples, we observed significantly higher HK3 expression during neutrophil differentiation of APL cell lines. Moreover, knocking down PU.1 impaired HK3 induction during neutrophil differentiation. In vivo binding of PU.1 and PML-RARA to the HK3 promoter was found, and PML-RARA attenuated PU.1 activation of the HK3 promoter. Next, inhibiting HK3 in APL cell lines resulted in significantly reduced neutrophil differentiation and viability compared with control cells. Our findings strongly suggest that HK3 is: (1) directly activated by PU.1, (2) repressed by PML-RARA, and (3) functionally involved in neutrophil differentiation and cell viability of APL cells.
Allogeneic stem cell transplantation for elderly patients with myelodysplastic syndrome
Authors: Kröger Nicolaus 
Published: April 2012

Abstract
Allogeneic hematopoietic stem cell transplantation (SCT) is well accepted as a curative treatment approach for younger patients with myelodysplastic syndrome (MDS) and has become one of the most frequent indications for allogeneic SCT as reported to the Center for International Blood and Marrow Transplant Research. However, MDS patients are usually elderly with a median age of approximately 75 years at diagnosis. Large register studies have confirmed the feasibility of the procedure in elderly MDS patients; and in the register of the European Group for Blood and Marrow Transplantation, one-third of the allogeneic transplant procedures for MDS were performed in 2010 in patients older than 60 years. Despite its curative potential, its role in the treatment of elderly MDS patients is less defined. Because of the inherent complications of the transplantation leading to treatment-related mortality and the risk of relapse, a careful calculation of the benefit for each patient is mandatory, taking into account comorbidities, disease status, donor selection, and effective nontransplant therapies. Prospective multicenter studies are needed to define optimal intensity of the conditioning regimen, timing of transplantation within a treatment algorithm, including drug-based therapies, and posttransplant strategies to reduce the risk of relapse.