bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of mRNA Profiles after MEK1/2 Inhibition in Human Pancreatic Cancer Cell Lines Reveals Pathways Involved in Drug Sensitivity
Authors: Gysin Stephan , Paquette Jesse , McMahon Martin 
Published: July 2012

Abstract
Mutationally activated KRAS, detected in approximately 90% of pancreatic ductal adenocarcinomas (PDA), has proven an intractable pharmacologic target to date. Consequently, efforts to treat KRAS-mutated cancers are focused on targeting RAS-regulated signaling pathways. In mouse models, expression of BRAFV600E combined with dominant-negative TP53 elicits PDA, and pharmacologic blockade of mitogen-activated protein/extracellular signal–regulated kinase (MEK) inhibits proliferation of human PDA-derived cell lines. To better understand the role of RAF→MEK→ERK signaling on PDA cell proliferation, we assessed the consequences of MEK inhibition on global patterns of mRNA expression and tumor cell proliferation in a panel of human PDA-derived cell lines. This analysis revealed that RAF→MEK→ERK signaling regulates mRNAs involved in cell-cycle control as well as regulators of the immune system. Linear regression analysis of relative drug sensitivity and mRNA expression revealed mRNAs and pathways correlating with relative drug sensitivity of the cell lines. Mice carrying orthotopically implanted pancreas tumors that were treated with MEK inhibitor displayed reduced tumor growth, concomitant with a reduction of cells in S phase. Furthermore, analysis of tumor mRNA expression revealed PDA cell lines to display similar baseline and MEK inhibitor mRNA expression profiles in vitro and in vivo. Among the proteins subject to downregulation following MEK inhibition, we identified c-MYC as a key driver of cell proliferation downstream of RAF→MEK→ERK signaling. Indeed, in some PDA cell lines, RNA interference–mediated silencing of c-MYC expression had antiproliferative effects similar to that of MEK inhibition, thereby highlighting the importance of c-MYC in key aspects of pancreatic cancer cell maintenance. Mol Cancer Res; 10(12); 1607–19. ©2012 AACR.
Impact of Sex on Cardiovascular Outcome in Patients at High Cardiovascular Risk
Authors: Kappert Kai , Böhm Michael , Schmieder Roland , Schumacher Helmut , Teo Koon , Yusuf Salim , Sleight Peter , Unger Thomas 
Published: July 2012

Background—
Epidemiological data suggest that sex independently contributes to cardiovascular risk. Clinical trials are often hampered by the enrollment of few female patients.

Methods and Results—
The Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial (ONTARGET) and the parallel Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND) included a large proportion of female patients (9378 female versus 22 168 male patients). Differences in male and female patients enrolled in ONTARGET/TRANSCEND were analyzed for the primary 4-fold end point (composite of cardiovascular death, myocardial infarction, stroke, or admission to hospital for heart failure), a secondary 3-fold end point (cardiovascular death, myocardial infarction, stroke), and individual components of the primary composite. Baseline characteristics included age, ethnicity, body mass index, physical activity, tobacco use, alcohol consumption, formal education, clinical diagnosis for study entry, patient history, and concomitant medication. Patients were followed up until death or the end of the study (median, 56 months). Compared with male patients, female patients had a 19% significantly lower risk for the 4-fold end point and 21% for the 3-fold end point (after adjustment for study, treatment, and the above baseline values). Similarly, the adjusted risk for cardiovascular death (17%) and myocardial infarction (22%), but not for stroke and hospitalization for heart failure, was also significantly lower in women. Diabetic female patients were characterized by a higher risk for acute myocardial infarction compared with diabetic male patients, whereas alcohol consumption resulted in significantly lower risk in women.

Conclusions—
In our analysis made up of 70.3% male and 29.7% female patients, an ≈20% lower risk for the combined cardiovascular end points in female patients was observed despite treatment with cardioprotective agents. This difference was driven primarily by a significantly lower incidence of myocardial infarction. Thus, we demonstrate in a large interventional trial that sex greatly affects the occurrence of cardiovascular events in patients with vascular disease or high-risk diabetes mellitus.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00153101.
Dissociation of Structural and Functional Phenotypes in Cardiac Myosin-Binding Protein C Conditional Knockout Mice
Authors: Chen Peter.P , Patel Jitandrakumar R. , Powers Patricia A. , Fitzsimons Daniel P. , Moss Richard L. 
Published: July 2012

Background—

Cardiac myosin-binding protein C (cMyBP-C) is a sarcomeric protein that dynamically regulates thick-filament structure and function. In constitutive cMyBP-C knockout (cMyBP-C
−/−
) mice, loss of cMyBP-C has been linked to left ventricular dilation, cardiac hypertrophy, and systolic and diastolic dysfunction, although the pathogenesis of these phenotypes remains unclear.

Methods and Results—
We generated cMyBP-C conditional knockout (cMyBP-C-cKO) mice expressing floxed cMyBP-C alleles and a tamoxifen-inducible Cre-recombinase fused to 2 mutated estrogen receptors to study the onset and progression of structural and functional phenotypes caused by the loss of cMyBP-C. In adult cMyBP-C-cKO mice, knockdown of cMyBP-C over a 2-month period resulted in a corresponding impairment of diastolic function and a concomitant abbreviation of systolic ejection, although contractile function was largely preserved. No significant changes in cardiac structure or morphology were immediately evident; however, mild hypertrophy developed after near-complete knockdown of cMyBP-C. In response to pressure overload induced by transaortic constriction, cMyBP-C-cKO mice treated with tamoxifen also developed greater cardiac hypertrophy, left ventricular dilation, and reduced contractile function.

Conclusions—

These results indicate that myocardial dysfunction is largely caused by the removal of cMyBP-C and occurs before the onset of cytoarchitectural remodeling in tamoxifen-treated cMyBP-C-cKO myocardium. Moreover, near ablation of cMyBP-C in adult myocardium primarily leads to the development of hypertrophic cardiomyopathy in contrast to the dilated phenotype evident in cMyBP-C
−/−
mice, which highlights the importance of additional factors such as loading stress in determining the expression and progression of cMyBP-C–associated cardiomyopathy.
The Status of Employment Discrimination Suits in Police and Fire Departments Across the United States
Authors: Riccucci Norma M. , Saldivar Karina 
Published: July 2012

Research indicates that women and people of color have made progress in gaining entry-level jobs in government, particularly at the federal level, but still lag behind in gaining positions at the upper levels. But, can the same be said for police and fire departments which have had perhaps the worst history of employment discrimination against women and people of color? This study seeks to answer this question by examining the extent to which race, gender or ethnic discrimination suits are being filed against city fire and police departments across the country, and at what level—entry or senior. The U.S. Supreme Court’s recent decision in Ricci v. DeStefano has renewed interest in this issue. Interestingly enough, while this study expected to find that lawsuits against police and fire departments are being filed by women and people of color in order to improve their representation in the uniformed services, it found just the opposite—the preponderance of the lawsuits filed against police and fire departments are “reverse discrimination” suits, filed by White men.
Defining indoor heat thresholds for health in the UK
Authors: Anderson Mindy , Carmichael Catriona , Murray Virginia , Dengel Andy , Swainson Michael 
Published: July 2012

Introduction: It has been recognised that as outdoor ambient temperatures increase past a particular threshold, so do mortality/morbidity rates. However, similar thresholds for indoor temperatures have not yet been identified. Due to a warming climate, the non-sustainability of air conditioning as a solution, and the desire for more energy-efficient airtight homes, thresholds for indoor temperature should be defined as a public health issue. Aims: The aim of this paper is to outline the need for indoor heat thresholds and to establish if they can be identified. Our objectives include: describing how indoor temperature is measured; highlighting threshold measurements and indices; describing adaptation to heat; summary of the risk of susceptible groups to heat; reviewing the current evidence on the link between sleep, heat and health; exploring current heat and health warning systems and thresholds; exploring the built environment and the risk of overheating; and identifying the gaps in current knowledge and research. Methods: A global literature search of key databases was conducted using a pre-defined set of keywords to retrieve peer-reviewed and grey literature. The paper will apply the findings to the context of the UK. Results: A summary of 96 articles, reports, government documents and textbooks were analysed and a gap analysis was conducted. Evidence on the effects of indoor heat on health implies that buildings are modifiers of the effect of climate on health outcomes. Personal exposure and place-based heat studies showed the most significant correlations between indoor heat and health outcomes. However, the data are sparse and inconclusive in terms of identifying evidence-based definitions for thresholds. Further research needs to be conducted in order to provide an evidence base for threshold determination. Conclusions: Indoor and outdoor heat are related but are different in terms of language and measurement. Future collaboration between the health and building sectors is needed to develop a common language and an index for indoor heat and health thresholds in a changing climate.
Gene therapy/bone marrow transplantation in ADA-deficient mice: roles of enzyme-replacement therapy and cytoreduction
Authors: Carbonaro Denise A. , Jin Xiangyang , Wang Xingchao , Yu Xiao-Jin , Rozengurt Nora , Kaufman Michael L. , Wang Xiaoyan , Gjertson David , Zhou Yang , Blackburn Michael R. , Kohn Donald B. 
Published: July 2012

AbstractGene therapy (GT) for adenosine deaminase–deficient severe combined immune deficiency (ADA-SCID) can provide significant long-term benefit when patients are given nonmyeloablative conditioning and ADA enzyme-replacement therapy (ERT) is withheld before autologous transplantation of γ-retroviral vector-transduced BM CD34+ cells. To determine the contributions of conditioning and discontinuation of ERT to the therapeutic effects, we analyzed these factors in Ada gene knockout mice (Ada−/−). Mice were transplanted with ADA-deficient marrow transduced with an ADA-expressing γ-retroviral vector without preconditioning or after 200 cGy or 900 cGy total-body irradiation and evaluated after 4 months. In all tissues analyzed, vector copy numbers (VCNs) were 100- to 1000-fold greater in mice receiving 900 cGy compared with 200 cGy (P < .05). In mice receiving 200 cGy, VCN was similar whether ERT was stopped or given for 1 or 4 months after GT. In unconditioned mice, there was decreased survival with and without ERT, and VCN was very low to undetectable. When recipients were conditioned with 200 cGy and received transduced lineage-depleted marrow, only recipients receiving ERT (1 or 4 months) had detectable vector sequences in thymocytes. In conclusion, cytoreduction is important for the engraftment of gene-transduced HSC, and short-term ERT after GT did not diminish the capacity of gene-corrected cells to engraft and persist.
Molecular evolution of a-kinase anchoring protein (AKAP)-7: implications in comparative PKA compartmentalization
Authors: Johnson Keven R , Nicodemus-Johnson Jessie , Carnegie Graeme K , Danziger Robert S 
Published: July 2012

Abstract

Background
A-Kinase Anchoring Proteins (AKAPs) are molecular scaffolding proteins mediating the assembly of multi-protein complexes containing cAMP-dependent protein kinase A (PKA), directing the kinase in discrete subcellular locations. Splice variants from the AKAP7 gene (AKAP15/18) are vital components of neuronal and cardiac phosphatase complexes, ion channels, cardiac Ca2+ handling and renal water transport.

Results
Shown in evolutionary analyses, the formation of the AKAP7-RI/RII binding domain (required for AKAP/PKA-R interaction) corresponds to vertebrate-specific gene duplication events in the PKA-RI/RII subunits. Species analyses of AKAP7 splice variants shows the ancestral AKAP7 splice variant is AKAP7α, while the ancestral long form AKAP7 splice variant is AKAP7γ. Multi-species AKAP7 gene alignments, show the recent formation of AKAP7δ occurs with the loss of native AKAP7γ in rats and basal primates. AKAP7 gene alignments and two dimensional Western analyses indicate that AKAP7γ is produced from an internal translation-start site that is present in the AKAP7δ cDNA of mice and humans but absent in rats. Immunofluorescence analysis of AKAP7 protein localization in both rat and mouse heart suggests AKAP7γ replaces AKAP7δ at the cardiac sarcoplasmic reticulum in species other than rat. DNA sequencing identified Human AKAP7δ insertion-deletions (indels) that promote the production of AKAP7γ instead of AKAP7δ.

Conclusions
This AKAP7 molecular evolution study shows that these vital scaffolding proteins developed in ancestral vertebrates and that independent mutations in the AKAP7 genes of rodents and early primates has resulted in the recent formation of AKAP7δ, a splice variant of likely lesser importance in humans than currently described.
Prevalence and socio-behavioral influence of early childhood caries, ECC, and feeding habits among 6 – 36 months old children in Uganda and Tanzania
Authors: Masumo Ray , Bardsen Asgeir , Mashoto Kijakazi , Astrom Anne Nordrehaug 
Published: July 2012

AbstractBackgroundEarly childhood caries (ECC) is a serious problem that has remained unexplored in sub-Saharan Africa.This study aimed to identify possible socio-behavioral correlates of ECC focusing 6–36 months old children and their caretakers.MethodsCross sectional studies were conducted in a high fluoride rural area, Manyara, Tanzania and a low fluoride urban area, Kampala, Uganda. Totals of 1221 and 816 child - caretaker pairs attending health care facilities for growth monitoring were recruited in Manyara and Kampala, respectively. All caretakers completed face to face interviews at the health care facility. Children underwent oral clinical examination whereby ECC and Enamel hypoplasia were recorded using the dmft (WHO 1997) and the DDE index (FDI 1992).ResultsThe prevalence of ECC was 3.7% in Manyara and 17.6% in Kampala. According to multiple logistic regression analyses, received oral health information from health worker was the strongest determinant of ECC in Manyara, adjusted OR 0.3, 95% CI 0.09 – 0.93. In Kampala, visible plaque, high sugar intake and presence of enamel hypoplasia associated with ECC, adjusted ORs 2.8 (95% CI 1.61- 4.95), 3.0 (95% CI 1.39 – 6.34) and 2.3 (95% CI 1.36 - 3.95).ConclusionOral health education aimed at caretakers of 6–36 months, including health care workers’ information regarding the detrimental consequences for oral health of frequent sugar consumption and poor oral hygiene is important for prevention of ECC in Tanzania and Uganda.
The role of barrier membranes for guided bone regeneration and restoration of large bone defects: current experimental and clinical evidence
Authors: Dimitriou Rozalia , Mataliotakis George I , Calori Giorgio Maria , Giannoudis Peter V 
Published: July 2012

AbstractTreatment of large bone defects represents a great challenge in orthopedic and craniomaxillofacial surgery. Although there are several methods for bone reconstruction, they all have specific indications and limitations. The concept of using barrier membranes for restoration of bone defects has been developed in an effort to simplify their treatment by offering a sinlge-staged procedure. Research on this field of bone regeneration is ongoing, with evidence being mainly attained from preclinical studies. The purpose of this review is to summarize the current experimental and clinical evidence on the use of barrier membranes for restoration of bone defects in maxillofacial and orthopedic surgery. Although there are a few promising preliminary human studies, before clinical applications can be recommended, future research should aim to establish the 'ideal' barrier membrane and delineate the need for additional bone grafting materials aiming to 'mimic' or even accelerate the normal process of bone formation. Reproducible results and long-term observations with barrier membranes in animal studies, and particularly in large animal models, are required as well as well-designed clinical studies to evaluate their safety, efficacy and cost-effectiveness.
CTGC motifs within the HIV core promoter specify Tat-responsive pre-initiation complexes
Authors: Wilhelm Emmanuelle , Doyle Marie-Christine , Nzaramba Isaac , Magdzinski Alexandre , Dumais Nancy , Bell Brendan 
Published: July 2012

Abstract

Background
HIV latency is an obstacle for the eradication of HIV from infected individuals. Stable post-integration latency is controlled principally at the level of transcription. The HIV trans-activating protein, Tat, plays a key function in enhancing HIV transcriptional elongation. The HIV core promoter is specifically required for Tat-mediated trans-activation of HIV transcription. In addition, the HIV core promoter has been shown to be a potential anti-HIV drug target. Despite the pivotal role of the HIV core promoter in the control of HIV gene expression, the molecular mechanisms that couple Tat function specifically to the HIV core promoter remain unknown.

Results
Using electrophoretic mobility shift assays (EMSAs), the TATA box and adjacent sequences of HIV essential for Tat trans-activation were shown to form specific complexes with nuclear extracts from peripheral blood mononuclear cells, as well as from HeLa cells. These complexes, termed pre-initiation complexes of HIV (PICH), were distinct in composition and DNA binding specificity from those of prototypical eukaryotic TATA box regions such as Adenovirus major late promoter (AdMLP) or the hsp70 promoter. PICH contained basal transcription factors including TATA-binding protein and TFIIA. A mutational analysis revealed that CTGC motifs flanking the HIV TATA box are required for Tat trans-activation in living cells and correct PICH formation in vitro. The binding of known core promoter binding proteins AP-4 and USF-1 was found to be dispensable for Tat function. TAR RNA prevented stable binding of PICH-2, a complex that contains the general transcription factor TFIIA, to the HIV core promoter. The impact of TAR on PICH-2 specifically required its bulge sequence that is also known to interact with Tat.

Conclusion
Our data reveal that CTGC DNA motifs flanking the HIV TATA box are required for correct formation of specific pre-initiation complexes in vitro and that these motifs are also required for Tat trans-activation in living cells. The impact of TAR RNA on PICH-2 stability provides a mechanistic link by which pre-initiation complex dynamics could be coupled to the formation of the nascent transcript by the elongating transcription complex. Together, these findings shed new light on the mechanisms by which the HIV core promoter specifically responds to Tat to activate HIV gene expression.
Condor-COPASI: high-throughput computing for biochemical networks
Authors: Kent Edward , Hoops Stefan , Mendes Pedro 
Published: July 2012

Abstract

Background
Mathematical modelling has become a standard technique to improve our understanding of complex biological systems. As models become larger and more complex, simulations and analyses require increasing amounts of computational power. Clusters of computers in a high-throughput computing environment can help to provide the resources required for computationally expensive model analysis. However, exploiting such a system can be difficult for users without the necessary expertise.

Results
We present Condor-COPASI, a server-based software tool that integrates COPASI, a biological pathway simulation tool, with Condor, a high-throughput computing environment. Condor-COPASI provides a web-based interface, which makes it extremely easy for a user to run a number of model simulation and analysis tasks in parallel. Tasks are transparently split into smaller parts, and submitted for execution on a Condor pool. Result output is presented to the user in a number of formats, including tables and interactive graphical displays.

Conclusions
Condor-COPASI can effectively use a Condor high-throughput computing environment to provide significant gains in performance for a number of model simulation and analysis tasks. Condor-COPASI is free, open source software, released under the Artistic License 2.0, and is suitable for use by any institution with access to a Condor pool. Source code is freely available for download athttp://code.google.com/p/condor-copasi/, along with full instructions on deployment and usage.
Haloperidol augmentation of fluvoxamine in skin picking disorder: a case report
Authors: Luca Maria , Vecchio Costanza , Luca Antonina , Calandra Carmela 
Published: July 2012

Abstract

Introduction
Compulsive skin picking, being part of the broader category of impulse control disorders, is considered a residual diagnosis in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. It is characterized by excessive scratching or picking of normal skin, or skin with minor surface irregularities, and occurs in 2% of patients attending dermatology clinics. Despite the clinical relevance of this disorder, no clear guidelines are available yet; clinical management is, therefore, compromised and the day-to-day clinical practice is burdened by difficulties. Studies on selective serotonin reuptake inhibitors and anti-epileptic drugs have provided limited results. The association between anti-depressants and anti-epileptics has been found to be beneficial in some impulse control disorders, but in skin picking no previous studies have been conducted on this pharmacological approach. There are very few reports on the efficacy of anti-psychotics in skin picking.

Case presentation
The therapeutic path described in this case report produced good results for a 59-year-old Caucasian woman. The first therapeutic approach, with fluvoxamine and oxcarbazepine was partially effective; then, the suspension of oxcarbazepine and haloperidol augmentation of fluvoxamine were adopted. After 10 weeks, a significant improvement of the disease was observed: the clinical picture and the associated symptoms were nearly solved.

Conclusions
To the best of our knowledge, this is the first article reporting the association of fluvoxamine and haloperidol in skin picking disorder. It might be useful to perform further research regarding the treatment of skin picking disorder: in clinical practice, several variables might limit the choice of certain drugs. Therefore, it would be useful for the clinician to be aware of other therapeutic options.