bluuebunny/crossref_metadata_2025_split huggingface dataset:
TH‐D‐BRA‐03: Genetic Susceptibility Radiation Exposure and Risk of Second Primary Breast Cancer
Authors: Bernstein J 
Published: August 2010

Background: Deficiencies in cellular responses to DNA damage can predispose to cancer. Ionizing radiation induces double strand breaks (DSB). Upon activation by DSB‐inducing agents ATM (for ataxia‐telangiectasia (A‐T) mutated) phosphorylates a large number of downstream targets including the products of several known breast cancer susceptibility genes (e.g. BRCA1 BRCA2 Chek2 p53). In this study we examine whether defects in these breast cancer susceptibility factors are associated with radiation‐induced induced breast cancers. Methods: The WECARE Study is a case‐control study nested within 5 population‐based cancer registries in the US and in Denmark. The 708 cases were women with asynchronous bilateral breast cancer (CBC) and the 1399 controls were women with unilateral breast cancer (UBC) individually matched to cases on year of birth race geographic region and date of diagnosis (interval). All participants were interviewed medical records were comprehensively reviewed and full genetic screening was conducted. For women who received radiation therapy (RT) absorbed radiation doses to quadrants of the (CB) were estimated using dosimetry reconstruction. Rate ratios (RR) and 95% confidence intervals were calculated using multivariable‐adjusted conditional logistic regression models. Results: The mean dose to the specific quadrant of the CB tumor was 1.1 Gy. Women <40 years of age who received >1.0Gy and with >5 year follow‐up had a 3‐fold increased risk of CBC (95% CI‐1.1–1.8). The RR of CBC associated with carrying a BRCA1/2 mutation was 4.2 (95% CI=2.8–6.1); however among carriers radiation was not associated with risk. Among women carrying rare ATM missense mutations the risk of developing CBC was slightly increased but was significantly elevated among women treated with RT and strongest for mutations selected on their likelihood to disrupt structure. Conclusions: Risk of radiation‐associated CBC was inversely related to age at exposure and dose dependent. A subgroup of rare mutations may increase risk of CBC among women with early onset breast cancer treated with RT. However the fraction of CBC attributed to this is quite small suggesting that radiation contributes little to the already high risk of CBC associated with carrying these breast cancer susceptibility factors.Learning Objectives:1. Understand the role of DSB in CBC2. Understand the basic study design of the WECARE Study3. Understand the issues relating to genetic susceptibility and CBC risk
Poster — Thur Eve — 47: Automatic Comparison of Portal Images for the Detection of Radiotherapy Treatment Delivery Errors
Authors: Lee R , Tran M , McCurdy B , Pistorius S 
Published: August 2010

The goal of this project is to develop a real‐time automatic comparison tool to detect portal dose image errors and has two logical parts:1. A mechanism to detect the presence of a significant discrepancy.2. A set of components to identify the probable cause(s) of the discrepancy including geometrical positioning errors as well as machine specific delivery errors.Initially, we have only considered in‐plane rotations and translations. A total of ∼700 portal images of an anthropomorphic pelvic phantom were obtained using a Varian aS1000 EPID. The images contained combinations of three types of geometrical patient set‐up errors. The angle of rotation (about the axis perpendicular to the EPID) was varied from [−5, +5] degrees and the translational distance was varied from [−10, +10] mm. The majority of the images were acquired from the AP direction however ∼130 images were of a lateral view. The system was found to be sensitive to in‐plane rotations down to ∼ 2°, out of plane rotations greater than ∼4° and displacements 3mm. For the lateral views, the calculated rotation was correct to within 1/2° and translations to within 5mm 53% of the time. Considering only translations, the accuracy increases to ∼82%. The results are much better for the AP views. The in‐plane rotation was within ±1/2deg; for all cases and the displacement error was greater than 1.5 mm in only 1 case. The system was able to analyze an image pair in ∼10s, however, no effort was put toward optimization of the system.
Trypanocidal Activity of Aziridinyl Nitrobenzamide Prodrugs
Authors: Bot Chris , Hall Belinda S. , Bashir Noosheen , Taylor Martin C. , Helsby Nuala A. , Wilkinson Shane R. 
Published: August 2010

ABSTRACT

The trypanocidal agents nifurtimox and benznidazole both function as prodrugs and must undergo enzyme-mediated activation, a reaction catalyzed by type I nitroreductase (NTR). In the search for new parasitic therapies, we have utilized this finding to investigate whether aziridinyl nitrobenzamide derivatives have activity against bloodstream-form
Trypanosoma brucei
and
Trypanosoma cruzi
amastigotes, parasite stages that replicate in the mammalian host. For
T. cruzi
drug screening, we generated trypanosomes that expressed the luciferase reporter gene and optimized a mammalian infection model in a 96-well plate format. A subset of compounds having a 5-(aziridin-1-yl)-2,4-dinitrobenzyl structure was shown to be metabolized by purified
T. brucei
NTR and when screened against both parasite life cycle stages displayed significant growth-inhibitory properties: the most potent compounds generated 50% inhibitory concentrations of <1 μM. The trypanocidal activity was shown to be NTR specific, since parasites overexpressing this enzyme were hypersensitive to the aziridinyl dinitrobenzyl agents. We conclude that members of the aziridinyl nitrobenzamide class of nitroheterocycles provide new lead structures that have the potential to treat trypanosomal infections.
The impact of tobacco control policies in Albania
Authors: Zaloshnja Eduard , Ross Hana , Levy David T 
Published: August 2010

ObjectiveTo assess the impact of a tobacco control law adopted in Albania in 2007 and to estimate the share of illicit cigarettes on the market.DesignComparative analysis of two waves of a nationally representative household survey, one conducted before the new law went into effect and the other after 2 years. Official sales data were contrasted with the consumption estimate based on the survey.Main outcome measuresSmoking prevalence, quit attempts, exposure to cigarette advertising, exposure to second-hand smoke, total cigarette consumption, share of illicit packs among packs possessed by smokers.ResultsDespite the adoption of strong smoke-free policies and adverting restrictions, smoking prevalence in Albania has risen. The increase in prevalence has been driven by higher smoking rates among females (18.9% in 2007 vs 29.3% in 2009) and young adults (23.2% in 2007 vs 38.5% in 2009 among 18–19 year olds). Self-reported exposure to second-hand smoke and cigarette advertising have been reduced since 2007. The majority of respondents are still exposed to second-hand smoke and more than half are exposed to tobacco advertising. Nevertheless, there are signs that the consumption of illicit cigarettes is declining.ConclusionsThe impacts of smoke-free policies and an advertising ban have been limited due to lack of enforcement and failure to adopt a comprehensive set of tobacco control measures. These measures should include sizeable and regular tobacco tax increases in excess of the general level of inflation and income growth. The decline in the share of illicit cigarettes should improve the effectiveness of the cigarette tax policy.
Gene genealogies indicates abundant gene conversions and independent evolutionary histories of the mating-type chromosomes in the evolutionary history of Neurospora tetrasperma
Authors: Menkis Audrius , Whittle Carrie A , Johannesson Hanna 
Published: August 2010

Abstract

Background
The self-fertile filamentous ascomycete Neurospora tetrasperma contains a large (~7 Mbp) and young (< 6 MYA) region of suppressed recombination within its mating-type (mat) chromosomes. The objective of the present study is to reveal the evolutionary history, including key genomic events, associated with the various regions of the mat chromosomes among ten strains representing all the nine known species (lineages) contained within the N. tetrasperma species complex.

Results
Comparative analysis of sequence divergence among alleles of 24 mat-linked genes (mat A and mat a) indicates that a large region of suppressed recombination exists within the mat chromosome for each of nine lineages of N. tetrasperma sensu latu. The recombinationally suppressed region varies in size and gene composition among lineages, and is flanked on both ends by normally recombining regions. Genealogical analyses among lineages reveals that eight gene conversion events have occurred between homologous mat A and mat a-linked alleles of genes located within the region of restricted recombination during the evolutionary history of N. tetrasperma.

Conclusions
We conclude that the region of suppressed recombination in the mat chromosomes has likely been subjected to independent contraction and/or expansion during the evolutionary history of the N. tetrasperma species complex. Furthermore, we infer that gene conversion events are likely a common phenomenon within this recombinationally suppressed genomic region. We argue that gene conversions might provide an efficient mechanism of adaptive editing of functional genes, including the removal of deleterious mutations, within the young recombinationally suppressed region of the mat chromosomes.
A new family of phosphoinositide phosphatases in microorganisms: identification and biochemical analysis
Authors: Beresford Nicola J , Saville Charis , Bennett Hayley J , Roberts Ian S , Tabernero Lydia 
Published: August 2010

Abstract

Background
Phosphoinositide metabolism is essential to membrane dynamics and impinges on many cellular processes, including phagocytosis. Modulation of phosphoinositide metabolism is important for pathogenicity and virulence of many human pathogens, allowing them to survive and replicate in the host cells. Phosphoinositide phosphatases from bacterial pathogens are therefore key players in this modulation and constitute attractive targets for chemotherapy. MptpB, a virulence factor from Mycobacterium tuberculosis, has phosphoinositide phosphatase activity and a distinct active site P-loop signature HCXXGKDR that shares characteristics with eukaryotic lipid phosphatases and protein tyrosine phosphatases. We used this P-loop signature as a "diagnostic motif" to identify related putative phosphatases with phosphoinositide activity in other organisms.

Results
We found more than 200 uncharacterised putative phosphatase sequences with the conserved signature in bacteria, with some related examples in fungi and protozoa. Many of the sequences identified belong to recognised human pathogens. Interestingly, no homologues were found in any other organisms including Archaea, plants, or animals. Phylogenetic analysis revealed that these proteins are unrelated to classic eukaryotic lipid phosphatases. However, biochemical characterisation of those from Listeria monocytogenes and Leishmania major, demonstrated that, like MptpB, they have phosphatase activity towards phosphoinositides. Mutagenesis studies established that the conserved Asp and Lys in the P-loop signature (HCXXGKD R) are important in catalysis and substrate binding respectively. Furthermore, we provide experimental evidence that the number of basic residues in the P-loop is critical in determining activity towards poly-phosphoinositides.

Conclusion
This new family of enzymes in microorganisms shows distinct sequence and biochemical characteristics to classic eukaryotic lipid phosphatases and they have no homologues in humans. This study provides a foundation for examining the biological role of this new family of phosphatases and their potential as pharmaceutical targets against infectious diseases.
Dynamics of dendritic cell maturation are identified through a novel filtering strategy applied to biological time-course microarray replicates
Authors: Olex Amy L , Hiltbold Elizabeth M , Leng Xiaoyan , Fetrow Jacquelyn S 
Published: August 2010

Abstract

Background
Dendritic cells (DC) play a central role in primary immune responses and become potent stimulators of the adaptive immune response after undergoing the critical process of maturation. Understanding the dynamics of DC maturation would provide key insights into this important process. Time course microarray experiments can provide unique insights into DC maturation dynamics. Replicate experiments are necessary to address the issues of experimental and biological variability. Statistical methods and averaging are often used to identify significant signals. Here a novel strategy for filtering of replicate time course microarray data, which identifies consistent signals between the replicates, is presented and applied to a DC time course microarray experiment.

Results
The temporal dynamics of DC maturation were studied by stimulating DC with poly(I:C) and following gene expression at 5 time points from 1 to 24 hours. The novel filtering strategy uses standard statistical and fold change techniques, along with the consistency of replicate temporal profiles, to identify those differentially expressed genes that were consistent in two biological replicate experiments. To address the issue of cluster reproducibility a consensus clustering method, which identifies clusters of genes whose expression varies consistently between replicates, was also developed and applied. Analysis of the resulting clusters revealed many known and novel characteristics of DC maturation, such as the up-regulation of specific immune response pathways. Intriguingly, more genes were down-regulated than up-regulated. Results identify a more comprehensive program of down-regulation, including many genes involved in protein synthesis, metabolism, and housekeeping needed for maintenance of cellular integrity and metabolism.

Conclusions
The new filtering strategy emphasizes the importance of consistent and reproducible results when analyzing microarray data and utilizes consistency between replicate experiments as a criterion in both feature selection and clustering, without averaging or otherwise combining replicate data. Observation of a significant down-regulation program during DC maturation indicates that DC are preparing for cell death and provides a path to better understand the process. This new filtering strategy can be adapted for use in analyzing other large-scale time course data sets with replicates.
Voltage dependent anion channel-1 regulates death receptor mediated apoptosis by enabling cleavage of caspase-8
Authors: Chacko Alex D , Liberante Fabio , Paul Ian , Longley Daniel B , Fennell Dean A 
Published: August 2010

Abstract

Background
Activation of the extrinsic apoptosis pathway by tumour necrosis factor related apoptosis inducing ligand (TRAIL) is a novel therapeutic strategy for treating cancer that is currently under clinical evaluation. Identification of molecular biomarkers of resistance is likely to play an important role in predicting clinical anti tumour activity. The involvement of the mitochondrial type 1 voltage dependent anion channel (VDAC1) in regulating apoptosis has been highly debated. To date, a functional role in regulating the extrinsic apoptosis pathway has not been formally excluded.

Methods
We carried out stable and transient RNAi knockdowns of VDAC1 in non-small cell lung cancer cells, and stimulated the extrinsic apoptotic pathway principally by incubating cells with the death ligand TRAIL. We used in-vitro apoptotic and cell viability assays, as well as western blot for markers of apoptosis, to demonstrate that TRAIL-induced toxicity is VDAC1 dependant. Confocal microscopy and mitochondrial fractionation were used to determine the importance of mitochondria for caspase-8 activation.

Results
Here we show that either stable or transient knockdown of VDAC1 is sufficient to antagonize TRAIL mediated apoptosis in non-small cell lung cancer (NSCLC) cells. Specifically, VDAC1 is required for processing of procaspase-8 to its fully active p18 form at the mitochondria. Loss of VDAC1 does not alter mitochondrial sensitivity to exogenous caspase-8-cleaved BID induced mitochondrial depolarization, even though VDAC1 expression is essential for TRAIL dependent activation of the intrinsic apoptosis pathway. Furthermore, expression of exogenous VDAC1 restores the apoptotic response to TRAIL in cells in which endogenous VDAC1 has been selectively silenced.

Conclusions
Expression of VDAC1 is required for full processing and activation of caspase-8 and supports a role for mitochondria in regulating apoptosis signaling via the death receptor pathway.
Non-uniform recovery of left ventricular transmural mechanics in ST-segment elevation myocardial infarction
Authors: Caracciolo Giuseppe , Eleid Mackram F , Abe Haruhiko , Bhatia Nisha , Fortuin F David , Wilansky Susan , Carerj Scipione , Sengupta Partho P 
Published: August 2010

Abstract

Background
After a transient ischemic episode, the subendocardial region is more severely injured than outer subepicardial layers and may regain a proportionately greater degree of mechanical function in the longitudinal direction. We sought to explore left ventricular (LV) transmural mechanics in patients with ST-segment elevation myocardial infarction (STEMI) for determining the mechanism underlying recovery of global LV function after primary percutaneous coronary intervention (PCI).

Methods
A total of 42 patients (62 ± 11 years old, 71% male) with a first STEMI underwent serial assessments of LV longitudinal, circumferential and radial strains (LS, CS and RS) by selective tracking of subendocardial and subepicardial regions within 48 hours and a median of 5 months after PCI. LV mechanical parameters were compared with sixteen age and gender matched normal controls.

Results
In comparison with controls, endocardial and epicardial LS were markedly attenuated at 48 hours following PCI (P < 0.001). An improvement in LV ejection fraction (EF > 5%) following PCI was seen in 24 (57%) patients and was associated with improvement in endocardial and epicardial LS (P < 0.001 and P = 0.003, respectively) and endocardial CS (P = 0.01). Radial strain and wall motion score index, however, remained persistently abnormal. The change in endocardial LS (OR 1.2, 95% CI 1.03 to 1.42, P = 0.01) and the change in epicardial LS (OR 1.2, 95% 1.03 to 1.46, P = 0.02) were significantly associated with the improvement in LVEF, independent of the location of STEMI and the presence of underlying multivessel disease.

Conclusions
In patients with STEMI treated by PCI, the recovery of LV subendocardial shortening strain seen in the longitudinal direction underlies the improvement in LV global function despite persistent abnormalities in radial mechanics and wall motion score index.
Mutations at positions 186 and 194 in the HA gene of the 2009 H1N1 pandemic influenza virus improve replication in cell culture and eggs
Authors: Suphaphiphat Pirada , Franti Michael , Hekele Armin , Lilja Anders , Spencer Terika , Settembre Ethan , Palmer Gene , Crotta Stefania , Tuccino Annunziata B , Keiner Bjoern , Trusheim Heidi , Balabanis Kara , Sackal Melissa , Rothfeder Mithra , Mandl Christian W , Dormitzer Philip R , Mason Peter W 
Published: August 2010

Abstract
Obtaining suitable seed viruses for influenza vaccines poses a challenge for public health authorities and manufacturers. We used reverse genetics to generate vaccine seed-compatible viruses from the 2009 pandemic swine-origin influenza virus. Comparison of viruses recovered with variations in residues 186 and 194 (based on the H3 numbering system) of the viral hemagglutinin showed that these viruses differed with respect to their ability to grow in eggs and cultured cells. Thus, we have demonstrated that molecular cloning of members of a quasispecies can help in selection of seed viruses for vaccine manufacture.
3'-coterminal subgenomic RNAs and putative cis-acting elements of Grapevine leafroll-associated virus 3 reveals 'unique' features of gene expression strategy in the genus Ampelovirus
Authors: Jarugula Sridhar , Gowda Siddarame , Dawson William O , Naidu Rayapati A 
Published: August 2010

AbstractBackgroundThe familyClosteroviridaecomprises genera with monopartite genomes,ClosterovirusandAmpelovirus, and with bipartite and tripartite genomes,Crinivirus. By contrast to closteroviruses in the generaClosterovirusandCrinivirus, much less is known about the molecular biology of viruses in the genusAmpelovirus, although they cause serious diseases in agriculturally important perennial crops like grapevines, pineapple, cherries and plums.ResultsThe gene expression andcis-acting elements ofGrapevine leafroll-associated virus 3(GLRaV-3; genusAmpelovirus) was examined and compared to that of other members of the familyClosteroviridae. Six putative 3'-coterminal subgenomic (sg) RNAs were abundantly present in grapevine (Vitis vinifera) infected with GLRaV-3. The sgRNAs for coat protein (CP), p21, p20A and p20B were confirmed using gene-specific riboprobes in Northern blot analysis. The 5'-termini of sgRNAs specific to CP, p21, p20A and p20B were mapped in the 18,498 nucleotide (nt) virus genome and their leader sequences determined to be 48, 23, 95 and 125 nt, respectively. No conserved motifs were found around the transcription start site or in the leader sequence of these sgRNAs. The predicted secondary structure analysis of sequences around the start site failed to reveal any conserved motifs among the four sgRNAs. The GLRaV-3 isolate from Washington had a 737 nt long 5' nontranslated region (NTR) with a tandem repeat of 65 nt sequence and differed in sequence and predicted secondary structure with a South Africa isolate. Comparison of the dissimilar sequences of the 5'NTRs did not reveal any common predicted structures. The 3'NTR was shorter and more conserved. The lack of similarity among thecis-acting elements of the diverse viruses in the familyClosteroviridaeis another measure of the complexity of their evolution.ConclusionsThe results indicate that transcription regulation of GLRaV-3 sgRNAs appears to be different from members of the genusClosterovirus. An analysis of the genome sequence confirmed that GLRaV-3 has an unusually long 5'NTR of 737 nt compared to other monopartite members of the familyClosteroviridae, with distinct differences in the sequence and predicted secondary structure when compared to the corresponding region of the GLRaV-3 isolate from South Africa.
Persistent sciatica induced by quadratus femoris muscle tear and treated by surgical decompression: a case report
Authors: Bano Artan , Karantanas Apostolos , Pasku Dritan , Datseris George , Tzanakakis George , Katonis Pavlos 
Published: August 2010

Abstract

Introduction
Quadratus femoris tear is an uncommon injury, which is only rarely reported in the literature. In the majority of cases the correct diagnosis is delayed due to non-specific symptoms and signs. A magnetic resonance imaging scan is crucial in the differential diagnosis since injuries to contiguous soft tissues may present with similar symptoms. Presentation with sciatica is not reported in the few cases existing in the English literature and the reported treatment has always been conservative.

Case presentation
We report here on a case of quadratus femoris tear in a 22-year-old Greek woman who presented with persistent sciatica. She was unresponsive to conservative measures and so was treated with surgical decompression.

Conclusion
The correct diagnosis of quadratus muscle tear is a challenge for physicians. The treatment is usually conservative, but in cases of persistent sciatica surgical decompression is an alternative option.