bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of biomarkers for apoptosis in cancer cell lines using metabolomics: tools for individualized medicine
Authors: Halama A. , Riesen N. , Möller G. , Hrabě de Angelis M. , Adamski J. 
Published: October 2013

AbstractBackgroundMetabolomics is a versatile unbiased method to search for biomarkers of human disease. In particular, one approach in cancer therapy is to promote apoptosis in tumour cells; this could be improved with specific biomarkers of apoptosis for monitoring treatment. We recently observed specific metabolic patterns in apoptotic cell lines; however, in that study, apoptosis was only induced with one pro‐apoptotic agent, staurosporine.ObjectiveThe aim of this study was to find novel biomarkers of apoptosis by verifying our previous findings using two further pro‐apoptotic agents, 5‐fluorouracil and etoposide, that are commonly used in anticancer treatment.MethodsMetabolic parameters were assessed in HepG2 and HEK293 cells using the newborn screening assay adapted for cell culture approaches, quantifying the levels of amino acids and acylcarnitines with mass spectrometry.ResultsWe were able to identify apoptosis‐specific changes in the metabolite profile. Moreover, the amino acids alanine and glutamate were both significantly up‐regulated in apoptotic HepG2 and HEK293 cells irrespective of the apoptosis inducer.ConclusionOur observations clearly indicate the potential of metabolomics in detecting metabolic biomarkers applicable in theranostics and for monitoring drug efficacy.
Analysis of growth and stable isotopes in teeth of male Australian fur seals reveals interannual variability in prey resources
Authors: Knox Travis C. , Stuart‐Williams Hilary , Warneke Robert M. , Hoskins Andrew J. , Arnould John P. Y. 
Published: October 2013

AbstractTo detect and monitor long‐term ecosystem responses to environmental variability, managers must utilize reliable and quantitative techniques to predict future ecosystem responses. Canine teeth from 67 male Australian fur seals (aged 2–19 yr), collected at Seal Rocks, between 1967 and 1976, were measured for relative growth within the dentine growth layer groups (GLGs), as an index of body growth. Fluctuations in relative growth were apparent during 1956–1971, suggesting interannual variation in prey resources within Bass Strait. These were positively correlated with the Southern Oscillation Index and negatively with the Indian Ocean Subtropical Dipole, both on a 2 yr lag. The observed delay may reflect the time required for the nutrient cascade to filter through to the predominantly benthic prey of Australian fur seals. Stable isotope analysis (δ15N/δ13C) was also used to investigate whether fluctuations in growth were associated with differences in diet. Relative growth was found to be negatively correlated with δ15N, suggesting years of greater resource availability may be associated with individuals consuming proportionally more prey biomass of lower isotopic value. This study demonstrates that fluctuations in the dentine GLGs of male Australian fur seals are related to environmental parameters, suggesting variation in body growth is mediated by changes in prey resources.
Agrobacterium T‐DNA‐encoded protein Atu6002 interferes with the host auxin response
Authors: Lacroix Benoît , Gizatullina Diana I. , Babst Benjamin A. , Gifford Andrew N. , Citovsky Vitaly 
Published: October 2013

SummarySeveral genes in the Agrobacterium tumefaciens transferred (T)‐DNA encode proteins that are involved in developmental alterations, leading to the formation of tumours in infected plants. We investigated the role of the protein encoded by the Atu6002 gene, the function of which is completely unknown. Atu6002 expression occurs in Agrobacterium‐induced tumours, and is also activated on activation of plant cell division by growth hormones. Within the expressing plant cells, the Atu6002 protein is targeted to the plasma membrane. Interestingly, constitutive ectopic expression of Atu6002 in transgenic tobacco plants leads to a severe developmental phenotype characterized by stunted growth, shorter internodes, lanceolate leaves, increased branching and modified flower morphology. These Atu6002‐expressing plants also display impaired response to auxin. However, auxin cellular uptake and polar transport are not significantly inhibited in these plants, suggesting that Atu6002 interferes with auxin perception or signalling pathways.
Characteristics of flattening filter free beams at low monitor unit settings
Authors: Akino Yuichi , Ota Seiichi , Inoue Shinichi , Mizuno Hirokazu , Sumida Iori , Yoshioka Yasuo , Isohashi Fumiaki , Ogawa Kazuhiko 
Published: October 2013

Purpose:Newer linear accelerators (linacs) have been equipped to deliver flattening filter free (FFF) beams. When FFF beams are used for step‐and‐shoot intensity‐modulated radiotherapy (IMRT), the stability of delivery of small numbers of monitor units (MU) is important. The authors developed automatic measurement techniques to evaluate the stability of the dose profile, dose linearity, and consistency. Here, the authors report the performance of the Artiste™ accelerator (Siemens, Erlangen, Germany) in delivering low‐MU FFF beams.Methods:A 6 MV flattened beam (6X) with 300 MU/min dose rate and FFF beams of 7 (7XU) and 11 MV (11XU), each with a 500 MU/min dose rate, were measured at 1, 2, 3, 5, 8, 10, and 20 MU settings. For the 2000 MU/min dose rate, the 7 (7XUH) and 11 MV (11XUH) beams were set at 10, 15, 20, 25, and 30 MU because of the limits of the minimum MU settings. Beams with 20 × 20 and 10 × 10 cm2 field sizes were alternately measured ten times in intensity modulated (IM) mode, with which Siemens linacs regulate beam delivery for step‐and‐shoot IMRT. The in‐ and crossplane beam profiles were measured using a Profiler™ Model 1170 (Sun Nuclear Corporation, Melbourne, FL) in multiframe mode. The frames of 20 × 20 cm2 beams were identified at the off‐axis profile. The 6X beam profile was normalized at the central axis. The 7 and 11 MV FFF beam profiles were rescaled to set the dose at the central axis at 145% and 170%, respectively. Point doses were also measured using a Farmer‐type ionization chamber and water‐equivalent solid phantom to evaluate the linearity and consistency of low‐MU beam delivery. The values displayed on the electrometer were recognized with a USB‐type camera and read with open‐source optical character recognition software.Results:The symmetry measurements of the 6X, 7XU, and 11XU beam profiles were better than 2% for beams ≥2 MU and improved with increasing MU. The variations in flatness of FFF beams ≥2 MU were ±5%. The standard deviation of the symmetry and flatness also decreased with increasing MU. The linearity of the 6X beam was ±1% and ±2% for the beams of ≥5 and ≥3 MU, respectively. The 7XU and 11XU beams of ≥2 MU showed linearity with ±2% except the 7XU beam of 8 MU (+2.9%). The profiles of the FFF beams with 2000 and 500 MU/min dose rate were similar.Conclusions:The characteristics of low‐MU beams delivered in IM mode were evaluated using an automatic measurement system developed in this study. The authors demonstrated that the profiles of FFF beams of the Artiste™ linac were highly stable, even at low MU. The linearity of dose output was also stable for beams ≥2 MU.
Sym004, a Novel Anti-EGFR Antibody Mixture, Augments Radiation Response in Human Lung and Head and Neck Cancers
Authors: Huang Shyhmin , Peet Chimera R. , Saker Jarob , Li Chunrong , Armstrong Eric A. , Kragh Michael , Pedersen Mikkel W. , Harari Paul M. 
Published: October 2013

Abstract
Sym004 represents a novel EGF receptor (EGFR)-targeting approach comprising a mixture of two anti-EGFR antibodies directed against distinct epitopes of EGFR. In contrast with single anti-EGFR antibodies, Sym004 induces rapid and highly efficient degradation of EGFR. In the current study, we examine the capacity of Sym004 to augment radiation response in lung cancer and head and neck cancer model systems. We first examined the antiproliferative effect of Sym004 and confirmed 40% to 60% growth inhibition by Sym004. Using clonogenic survival analysis, we identified that Sym004 potently increased cell kill by up to 10-fold following radiation exposure. A significant increase of γH2AX foci resulting from DNA double-strand breaks was observed in Sym004-treated cells following exposure to radiation. Mechanistic studies further showed that Sym004 enhanced radiation response via induction of cell-cycle arrest followed by induction of apoptosis and cell death, reflecting inhibitory effects on DNA damage repair. The expression of several critical molecules involved in radiation-induced DNA damage repair was significantly inhibited by Sym004, including DNAPK, NBS1, RAD50, and BRCA1. Using single and fractionated radiation in human tumor xenograft models, we confirmed that the combination of Sym004 and radiation resulted in significant tumor regrowth delay and superior antitumor effects compared with treatment with Sym004 or radiation alone. Taken together, these data reveal the strong capacity of Sym004 to augment radiation response in lung and head and neck cancers. The unique action mechanism of Sym004 warrants further investigation as a promising EGFR targeting agent combined with radiotherapy in cancer therapy. Mol Cancer Ther; 12(12); 2772–81. ©2013 AACR.
Screening Entire Health System ECG Databases to Identify Patients at Increased Risk of Death
Authors: Strauss David G. , Mewton Nathan , Verrier Richard L. , Nearing Bruce D. , Marchlinski Francis E. , Killian Tony , Moxley John , Tereshchenko Larisa G. , Wu Katherine C. , Winslow Raimond , Cox Christopher , Spooner Peter M. , Lima João A.C. 
Published: October 2013

Background—
Current methods to identify patients at higher risk for sudden cardiac death, primarily left ventricular ejection fraction ≤35%, miss ≈80% of patients who die suddenly. We tested the hypothesis that patients with elevated QRS-scores (index of myocardial scar) and wide QRS-T angles (index abnormal depolarization–repolarization relationship) have high 1-year all-cause mortality and could be further risk stratified with clinical characteristics.

Methods and Results—

We screened all 12-lead ECGs over 6 months at 2 large hospital systems and analyzed clinical characteristics and 1-year mortality. Patients with ECGs obtained in hospital areas with known high mortality rates were excluded. At the first hospital, QRS-score ≥5 and QRS-T angle ≥105° identified 8.0% of patients and was associated with an odds ratio of 2.79 (95% confidence interval, 2.10–3.69) for 1-year mortality compared with patients below both ECG thresholds (13.9% versus 5.5% death rate). Left ventricular ejection fraction was >35% in 82% of the former group of patients, and addition of ECG measures to left ventricular ejection fraction increased the discrimination of death risk (
P
<0.0001). At the second hospital, the odds ratio was 2.42 (1.95–3.01) for 1-year mortality (8.8% versus 3.8%). Adjustment for patient characteristics eliminated interhospital differences. Multivariable adjusted odds ratio combining data from both hospitals was 1.53 (1.28–1.83). Increasing heart rate and chronic renal impairment further predicted mortality.

Conclusions—
Screening hospital ECG databases with QRS-scoring and QRS-T angle analysis identifies patients with high 1-year all-cause mortality and predominantly preserved left ventricular ejection fraction. This approach may represent a widely available method to identify patients at increased risk of death.
Shaping up the Form of the Tabernacle
Authors: Hrobon Bohdan 
Published: October 2013

AbstractSketches of the Tabernacle based on Ex 26 depend on the understanding of the obscure Hebrew termqršymand the even more obscure v. 24 that describes twoqršymof special use. Being a determinative element of a relatively complex construction, the exposition ofqršyminevitably involves some discussion of the other components. Therefore, close attention is paid to the arrangements of the tent curtains as prescribed in vv. 9, 12, and 13, proposing an alternative reading of v. 9 and determining the length of the Tabernacle. Consequently, a novel interpretation of Ex 26:24 that contributes to the Tabernacle’s symmetry and plausibility is suggested.
Translating the Preposition ‘m in the Book of Ruth
Authors: Schipper Jeremy 
Published: October 2013

Abstract
This article argues that there are six cases in the Book of Ruth where the preposition ‘m may be translated as “under the authority of . . .” (1:7, 11, 22; 2:6, 19 [2x]). The preposition means more than just “with” in these verses.
Notes on the Temple ‘Restorations’ of Jehoash and Josiah
Authors: Na’aman Nadav 
Published: October 2013

Abstract
The article discusses the descriptions of Jehoash’s and Josiah’s restorations of the temple in the Book of Kings. Two Neo-Babylonian legal documents are examined in order to demonstrate how ideological the descriptions of the repair works undertaken by the two kings are. The comparison further shows the cooperation of the royal and temple administrations in Babylonia and Judah in supervising the internal affairs of temples. Epigraphic Judahite documents shed some light on the management of workers in the kingdom. However, in spite of the many cuneiform and epigraphic documents published so far, fundamental elements in the administration of building projects in the First Temple Judah remain practically unknown.
Translating חנם in Job 1:9 and 2:3: On the Relationship between Job’s Piety and His Interiority
Authors: Linafelt Tod , Linafelt Tod , Davis Andrew R. 
Published: October 2013

Abstract
The adverb חנם occurs twice (1:9 and 2:3) in the prose narrative of the book of Job. Despite their close proximity, there is a tendency among translators and commentators to interpret the two occurrences differently. Against the consensus that understands חנם in 1:9 as indicating ends (“for no reason”) and in 2:3 as indicating origins (“without cause”), we argue that one can and should interpret חנם in both cases to mean “without effect.” In our reading of 2:3, then, God is saying to the Adversary “You incited me against him, to destroy him with no effect,” that is, with no achieved purpose. The first round of testing has failed to solve the central question driving the opening narrative—namely, the motivation for Job’s piety—and so has been judged by God to have been חנם, thus making another round of testing necessary.
Present Affliction Affects the Representation of the Past: An Alternative Dating of the Levitical Prayer in Nehemiah 9
Authors: Kugler Gili 
Published: October 2013

Abstract
This article examines a group of confessional prayers found in Second Temple literature uttered by known/identifiable figures that are characterized by an admission of guilt on the part of the speaker and a request for divine deliverance and redemption. In Nehemiah 9, these elements are very obscure, the passage also demonstrating linguistic and historical signs that suggest it does not belong to this group or the same date. On the basis of the disparity between the prayer and its introduction, an analysis of its content, linguistic elements, and the features stressed in the historical review, this paper proposes that the prayer belongs not to the Second Temple period but to the days prior to the Babylonian exile, when the people were under bondage to foreign kings in their own land.
Hemodialysis clearance of iosimenol, a novel iso-osmolar radiographic contrast medium
Authors: Hirao Yukihiro , Kashiyama Eiji , Umehara Ken , Kohno Makoto , Ikei Nobuhiro , Hogstrom Barry 
Published: October 2013

Background Iodinated contrast media (CM) have molecular and pharmacokinetic properties likely to make them highly dialyzable. Controlled clinical studies allowing for comparisons of hemodialysis clearance between different test substances and in multiple hemodialysis filters are, however, complex and not always practically feasible. A miniaturized in vitro method was therefore developed to evaluate the dialyzability of a new CM. Purpose To evaluate hemodialysis clearance of iosimenol, a novel iso-osmolar contrast medium (CM), in a select variety of hemodialysis filters and in comparison to commercially available CM. Material and Methods Three different high-flux and one low-flux membrane were used in miniaturized dialyzers to evaluate the in vitro blood clearance of iosimenol. Commercially available CM (iodixanol and iohexol) served as control substances. In vitro dialysis parameters were then used to predict clinical hemodialysis clearances. Residual ratios of endogenous substances (inorganic phosphate, urea nitrogen, creatinine, total bilirubin, and albumin) were used as proof of reliability of the in vitro dialysis system. Results Dialyzable small endogenous molecules were readily eliminated in all membranes. The removal ratios of iosimenol were generally similar to that of iodixanol in all membranes except the high-flux polysulfone but were consistently lower than that of iohexol. The blood clearance of iosimenol during clinical hemodialysis was predicted as, on average, approximately 85 mL/min with the high-flux membranes and 47 mL/min with the low-flux membrane. Conclusion The dialyzability of iosimenol was evaluated using a newly developed in vitro dialysis system, and iosimenol was readily cleared from blood with all four tested membranes. And it is suggested that the dialysis parameters can predict clinical hemodialysis clearance of CM.
Plasticity of primary microglia on micropatterned geometries and spontaneous long-distance migration in microfluidic channels
Authors: Amadio Susanna , De Ninno Adele , Montilli Cinzia , Businaro Luca , Gerardino Annamaria , Volonté Cinzia 
Published: October 2013

AbstractBackgroundMicroglia possess an elevated grade of plasticity, undergoing several structural changes based on their location and state of activation. The first step towards the comprehension of microglia’s biology and functional responses to an extremely mutable extracellular milieu, consists in discriminating the morphological features acquired by cells maintainedin vitrounder diverse environmental conditions. Previous work described neither primary microglia grown on artificially patterned environments which impose physical cues and constraints, nor long distance migration of microgliain vitro. To this aim, the present work exploits artificial bio-mimetic microstructured substrates with pillar-shaped or line-grating geometries fabricated on poly(dimethylsiloxane) by soft lithography, in addition to microfluidic devices, and highlights some morphological/functional characteristics of microglia which were underestimated or unknown so far.ResultsWe report that primary microglia selectively adapt to diverse microstructured substrates modifying accordingly their morphological features and behavior. On micropatterned pillar-shaped geometries, microglia appear multipolar, extend several protrusions in all directions and form distinct pseudopodia. On both micropatterned line-grating geometries and microfluidic channels, microglia extend the cytoplasm from a roundish to a stretched, flattened morphology and assume a filopodia-bearing bipolar structure. Finally, we show that in the absence of any applied chemical gradient, primary microglia spontaneously moves through microfluidic channels for a distance of up to 500 μm in approximately 12 hours, with an average speed of 0.66 μm/min.ConclusionsWe demonstrate an elevated grade of microglia plasticity in response to a mutable extracellular environment, thus making these cells an appealing population to be further exploited for lab on chip technologies. The development of microglia-based microstructured substrates opens the road to novel hybrid platforms for testing drugs for neuroinflammatory diseases.
Effectiveness of first-line antiretroviral therapy and correlates of longitudinal changes in CD4 and viral load among HIV-infected children in Ghana
Authors: Barry Oliver , Powell Jonathan , Renner Lorna , Bonney Evelyn Y , Prin Meghan , Ampofo William , Kusah Jonas , Goka Bamenla , Sagoe Kwamena WC , Shabanova Veronika , Paintsil Elijah 
Published: October 2013

AbstractBackgroundAntiretroviral therapy (ART) scale-up in resource-limited countries, with limited capacity for CD4 and HIV viral load monitoring, presents a unique challenge. We determined the effectiveness of first-line ART in a real world pediatric HIV clinic and explored associations between readily obtainable patient data and the trajectories of change in CD4 count and HIV viral load.MethodsWe performed a longitudinal study of a cohort of HIV-infected children initiating ART at the Korle-Bu Teaching Hospital Pediatric HIV clinic in Accra, Ghana, aged 0-13 years from 2009-2012. CD4 and viral load testing were done every 4 to 6 months and genotypic resistance testing was performed for children failing therapy. A mixed linear modeling approach, combining fixed and random subject effects, was employed for data analysis.ResultsNinety HIV-infected children aged 0 to 13 years initiating ART were enrolled. The effectiveness of first-line regimen among study participants was 83.3%, based on WHO criteria for virologic failure. Fifteen of the 90 (16.7%) children met the criteria for virologic treatment failure after at least 24 weeks on ART. Sixty-seven percent virologic failures harbored viruses with ≥ 1 drug resistant mutations (DRMs); M184V/K103N was the predominant resistance pathway. Age at initiation of therapy, child’s gender, having a parent as a primary care giver, severity of illness, and type of regimen were associated with treatment outcomes.ConclusionsFirst-line ART regimens were effective and well tolerated. We identified predictors of the trajectories of change in CD4 and viral load to inform targeted laboratory monitoring of ART among HIV-infected children in resource-limited countries.
MT1-MMP in breast cancer: induction of VEGF-C correlates with metastasis and poor prognosis
Authors: Yao Guangyu , He Ping , Chen Lujia , Hu Xiaolei , Gu Fan , Ye Changsheng 
Published: October 2013

AbstractBackgroundRecent evidence suggests that vascular endothelial growth factor-C (VEGF-C)- dependent tumour production promotes lymphangiogenesis, while membrane-type matrix 1 metalloproteinase (MT1-MMP) is involved in the critical steps leading to carcinogenesis. However, the role of MT1-MMP in lymphangiogenesis and lymphatic metastasis remains poorly understood. In the present study, we investigated the relationship between MT1-MMP and VEGF-C in human breast cancer and correlated MT1-MMP and VEGF-C expression with lymphangiogenesis and prognosis.MethodsMT1-MMP and VEGF-C levels were compared in five breast carcinoma cell lines. We used a membrane invasion assay to assess the effect of MT1-MMP and VEGF-C expression, as well as anti-MT1-MMP and VEGF-C antibodies, on cancer cell invasion. We further assessed MT1-MMP and VEGF-C immunoreactivity and lymph vessels in a cohort of human breast cancer specimens (n = 106) and associated MT1-MMP and VEGF-C expression with clinicopathological parameters, such as lymphatic vessel density (LVD), and patient prognosis.ResultsMT1-MMP and VEGF-C expression differed among the five breast cancer cell lines and MT1-MMP and VEGF-C expression were correlated with tumour cell invasion. VEGF-C mRNA expression levels and invasive activity of MDA-MB-231 cells was inhibited by an anti-MT1-MMP antibody in a concentration-dependent manner. A significant correlation was found between the expression of MT1-MMP and VEGF-C in breast cancer patient samples and elevated MT1-MMP and VEGF-C expression was associated with higher LVD, lymph node metastasis, cancer stage, and a decline in overall survival rates.ConclusionsOur data demonstrate that MT1-MMP expression is closely correlated with VEGF-C expression, and that MT1-MMP promotes lymphangiogenesis by up-regulating VEGF-C expression in human breast cancer. Thus, elevated MT1-MMP may serve as a significant prognostic factor in breast cancer.