bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quantitative Cell-Free DNA, KRAS, and BRAF Mutations in Plasma from Patients with Metastatic Colorectal Cancer during Treatment with Cetuximab and Irinotecan
Authors: Spindler Karen-Lise Garm , Pallisgaard Niels , Vogelius Ivan , Jakobsen Anders 
Published: January 2012

Abstract
Purpose: The present study investigated the levels of circulating cell-free DNA (cfDNA) in plasma from patients with metastatic colorectal cancer (mCRC) in relation to third-line treatment with cetuximab and irinotecan and the quantitative relationship of cfDNA with tumor-specific mutations in plasma.
Experimental Design: Inclusion criteria were histopathologically verified chemotherapy-resistant mCRC, adequate Eastern Cooperative Oncology Group performance status, and organ function. Treatment consisted of irinotecan being administered at 350 mg/m2 for 3 weeks and weekly administration of 250 mg/m2 cetuximab until progression or unacceptable toxicity. A quantitative PCR method was developed to assess the number of cfDNA alleles and KRAS and BRAF mutation alleles in plasma at baseline.
Results: The study included 108 patients. Only three patients were positive for BRAF mutations. The majority of KRAS mutations detected in tumors were also found in the plasma [32 of 41 (78%)]. Plasma cfDNA and plasma mutant KRAS levels (pmKRAS) were strongly correlated (r = 0.85, P &lt; 10−4). The disease control rate was 77% in patients with low cfDNA (&lt;25% quartile) and 30% in patients with high cfDNA [&gt;75% quartile (P = 0.009)]. Patients with pmKRAS levels higher than 75% had a disease control rate of 0% compared with 42% in patients with lower pmKRAS (P = 0.048). Cox analysis confirmed the prognostic importance of both cfDNA and pmKRAS. High levels were clear indicators of a poor outcome.
Conclusions: KRAS analysis in plasma is a viable alternative to tissue analysis. Quantitative levels of cfDNA and pmKRAS are strongly correlated and hold promise of clinical application. Clin Cancer Res; 18(4); 1177–85. ©2012 AACR.
Clarifying the Spectrum of Driver Oncogene Mutations in Biomarker-Verified Squamous Carcinoma of Lung: Lack of EGFR/KRAS and Presence of PIK3CA/AKT1 Mutations
Authors: Rekhtman Natasha , Paik Paul K. , Arcila Maria E. , Tafe Laura J. , Oxnard Geoffrey R. , Moreira Andre L. , Travis William D. , Zakowski Maureen F. , Kris Mark G. , Ladanyi Marc 
Published: January 2012

Abstract
Purpose: There is persistent controversy as to whether EGFR and KRAS mutations occur in pulmonary squamous cell carcinoma (SQCC). We hypothesized that the reported variability may reflect difficulties in the pathologic distinction of true SQCC from adenosquamous carcinoma (AD-SQC) and poorly differentiated adenocarcinoma due to incomplete sampling or morphologic overlap. The recent development of a robust immunohistochemical approach for distinguishing squamous versus glandular differentiation provides an opportunity to reassess EGFR/KRAS and other targetable kinase mutation frequencies in a pathologically homogeneous series of SQCC.
Experimental Design: Ninety-five resected SQCCs, verified by immunohistochemistry as ΔNp63+/TTF-1−, were tested for activating mutations in EGFR, KRAS, BRAF, PIK3CA, NRAS, AKT1, ERBB2/HER2, and MAP2K1/MEK1. In addition, all tissue samples from rare patients with the diagnosis of EGFR/KRAS-mutant “SQCC” encountered during 5 years of routine clinical genotyping were reassessed pathologically.
Results: The screen of 95 biomarker-verified SQCCs revealed no EGFR/KRAS [0%; 95% confidence interval (CI), 0%–3.8%], four PIK3CA (4%; 95% CI, 1%–10%), and one AKT1 (1%; 95% CI, 0%–5.7%) mutations. Detailed morphologic and immunohistochemical reevaluation of EGFR/KRAS-mutant “SQCC” identified during clinical genotyping (n = 16) resulted in reclassification of 10 (63%) cases as AD-SQC and five (31%) cases as poorly differentiated adenocarcinoma morphologically mimicking SQCC (i.e., adenocarcinoma with “squamoid” morphology). One (6%) case had no follow-up.
Conclusions: Our findings suggest that EGFR/KRAS mutations do not occur in pure pulmonary SQCC, and occasional detection of these mutations in samples diagnosed as “SQCC” is due to challenges with the diagnosis of AD-SQC and adenocarcinoma, which can be largely resolved by comprehensive pathologic assessment incorporating immunohistochemical biomarkers. Clin Cancer Res; 18(4); 1167–76. ©2012 AACR.
Epidermal Growth Factor Receptor Protein Detection in Head and Neck Cancer Patients: A Many-Faceted Picture
Authors: Thariat Juliette , Etienne-Grimaldi Marie-Christine , Grall Dominique , Bensadoun René-Jean , Cayre Anne , Penault-Llorca Frédérique , Veracini Laurence , Francoual Mireille , Formento Jean-Louis , Dassonville Olivier , De Raucourt Dominique , Geoffrois Lionel , Giraud Philippe , Racadot Séverine , Morinière Sylvain , Milano Gérard , Van Obberghen-Schilling Ellen 
Published: January 2012

AbstractPurpose: Epidermal growth factor receptor (EGFR) overexpression is associated with poor prognosis in head and neck squamous cell carcinoma (HNSCC). Despite intensive biomarker studies, a consensual method for assessing EGFR protein expression is still lacking. Here we set out to compare three EGFR detection methods in tumor specimens from HNSCC patients.Experimental Design: Tumors were prospectively excised from a series of 79 high-risk HNSCC patients enrolled in a GORTEC-sponsored clinical trial. EGFR expression was determined using a ligand-binding assay on membranes, Western blotting (WB) on membranes and total homogenates, and immunohistochemistry (IHC) on tissue microarrays. In addition, phosphorylated EGFR (pEGFR) was measured by WB on membranes.Results: Distributions and ranges of tumor EGFR expression were method dependent. Moderate positive correlations (Spearman coefficient r ≈ 0.50) were observed between EGFR expression measured by the binding assay and WB or IHC. pEGFR levels positively and significantly correlated with total EGFR expression measured by WB or ligand binding, but not by IHC. The highest correlation (r = 0.85) was observed between EGFR and pEGFR levels, both measured by WB on membranes. Interestingly, the fraction of phosphorylated receptor (pEGFR/EGFR both measured by WB on membranes) significantly declined with increasing tumor EGFR expression, by all assessment methods used.Conclusion: This study shows significant correlations between EGFR detection methods. The observed relationships between EGFR and pEGFR indicate that high-throughput pEGFR/EGFR analyses merit further investigations and consideration for routine use in patient samples. Clin Cancer Res; 18(5); 1313–22. ©2012 AACR.
Evaluation of Deuterated 18F- and 11C-Labeled Choline Analogs for Cancer Detection by Positron Emission Tomography
Authors: Witney Timothy H. , Alam Israt S. , Turton David R. , Smith Graham , Carroll Laurence , Brickute Diana , Twyman Frazer J. , Nguyen Quang-Dé , Tomasi Giampaolo , Awais Ramla O. , Aboagye Eric O. 
Published: January 2012

Abstract
Purpose: 11C-Choline–positron emission tomography (PET) has been exploited to detect the aberrant choline metabolism in tumors. Radiolabeled choline uptake within the imaging time is primarily a function of transport, phosphorylation, and oxidation. Rapid choline oxidation, however, complicates interpretation of PET data. In this study, we investigated the biologic basis of the oxidation of deuterated choline analogs and assessed their specificity in human tumor xenografts.
Experimental Design: 11C-Choline, 11C-methyl-[1,2-2H4]-choline (11C-D4-choline), and 18F-D4-choline were synthesized to permit comparison. Biodistribution, metabolism, small-animal PET studies, and kinetic analysis of tracer uptake were carried out in human colon HCT116 xenograft–bearing mice.
Results: Oxidation of choline analogs to betaine was highest with 11C-choline, with reduced oxidation observed with 11C-D4-choline and substantially reduced with 18F-D4-choline, suggesting that both fluorination and deuteration were important for tracer metabolism. Although all tracers were converted intracellularly to labeled phosphocholine (specific signal), the higher rate constants for intracellular retention (Ki and k3) of 11C-choline and 11C-D4-choline, compared with 18F-D4-choline, were explained by the rapid conversion of the nonfluorinated tracers to betaine within HCT116 tumors. Imaging studies showed that the uptake of 18F-D4-choline in three tumors with similar radiotracer delivery (K1) and choline kinase α expression—HCT116, A375, and PC3-M—were the same, suggesting that 18F-D4-choline has utility for cancer detection irrespective of histologic type.
Conclusion: We have shown here that both deuteration and fluorination combine to provide protection against choline oxidation in vivo. 18F-D4-choline showed the highest selectivity for phosphorylation and warrants clinical evaluation. Clin Cancer Res; 18(4); 1063–72. ©2012 AACR.
Pathway-Specific Analysis of Gene Expression Data Identifies the PI3K/Akt Pathway as a Novel Therapeutic Target in Cervical Cancer
Authors: Schwarz Julie K. , Payton Jacqueline E. , Rashmi Ramachandran , Xiang Tao , Jia Yunhe , Huettner Phyllis , Rogers Buck E. , Yang Qin , Watson Mark , Rader Janet S. , Grigsby Perry W. 
Published: January 2012

Abstract
Purpose: Cervical tumor response on posttherapy 2[18F]fluoro-2-deoxy-d-glucose-positron emission tomography (FDG-PET) is predictive of survival outcome. The purpose of this study was to use gene expression profiling to identify pathways associated with tumor metabolic response.
Experimental Design: This was a prospective tissue collection study for gene expression profiling of 62 pretreatment biopsies from patients with advanced cervical cancer. Patients were treated with definitive radiation. Fifty-three patients received concurrent chemotherapy. All patients underwent a pretreatment and a 3-month posttherapy FDG-PET/computed tomography (CT). Tumor RNA was harvested from fresh frozen tissue and hybridized to Affymetrix U133Plus2 GeneChips. Gene set enrichment analysis (GSEA) was used to identify signaling pathways associated with tumor metabolic response. Immunohistochemistry and in vitro FDG uptake assays were used to confirm our results.
Results: There were 40 biopsies from patients with a complete metabolic response (PET-negative group) and 22 biopsies from patients with incomplete metabolic response (PET-positive group). The 3-year cause-specific survival estimates were 98% for the PET-negative group and 39% for the PET-positive group (P &lt; 0.0001). GSEA identified alterations in expression of genes associated with the PI3K/Akt signaling pathway in patients with a positive follow-up PET. Immunohistochemistry using a tissue microarray of 174 pretreatment biopsies confirmed p-Akt as a biomarker for poor prognosis in cervical cancer. The phosphoinositide 3-kinase (PI3K) inhibitor LY294002 inhibited FDG uptake in vitro in cervical cancer cell lines.
Conclusions: Activation of the PI3K/Akt pathway is associated with incomplete metabolic response in cervical cancer. Targeted inhibition of PI3K/Akt may improve response to chemoradiation. Clin Cancer Res; 18(5); 1464–71. ©2012 AACR.
TheEGFRT790M Mutation in Acquired Resistance to an Irreversible Second-Generation EGFR Inhibitor
Authors: Kim Youngwook , Ko Jeonghun , Cui ZhengYun , Abolhoda Amir , Ahn Jin Seok , Ou Sai-Hong , Ahn Myung-Ju , Park Keunchil 
Published: January 2012

AbstractMolecular target therapies using first-generation, reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), such as gefitinib or erlotinib, have been shown to be effective for patients with non-small cell lung cancer (NSCLC) who harbor activating mutations in EGFR. However, these patients eventually develop resistance to the reversible TKIs, and this has led to the development of second-generation, irreversible EGFR inhibitors. Currently, the mechanism of acquired resistance to irreversible EGFR inhibitors is not clear. Using an in vitro cell culture system, we modeled the acquired resistance to first-line treatment with second-generation EGFR-TKIs using an EGFR-mutant NSCLC cell line. Here, we report a mechanism of resistance involving T790M secondary mutation as well as a corresponding clinical case. The results of these findings suggest that inhibition of EGFR by currently available second-generation EGFR-TKIs may not be sufficient to physiologically prevent the emergence of cells that are still dependent on EGFR signaling. This finding bears important implications on the limitations of currently available second-generation EGFR-TKIs. Mol Cancer Ther; 11(3); 784–91. ©2012 AACR.
The CXCR4 antagonist POL5551 is equally effective as sirolimus in reducing neointima formation without impairing re-endothelialisation
Authors: Hamesch Karim , Subramanian Pallavi , Li Xiaofeng , Dembowsky Klaus , Chevalier Eric , Weber Christian , Schober Andreas 
Published: January 2012

SummaryImpaired endothelial recovery after the implantation of drug-eluting stents is a major concern because of the increased risk for late stent thrombosis. The disruption of the chemokine axis CXCL12/CXCR4 inhibits neointima formation by blocking the recruitment of smooth muscle progenitor cells. To directly compare a CXCR4-targeting treatment strategy with drugs that are currently used for stent coating, we studied the effects of the CXCR4 antagonist POL5551 and the drug sirolimus on neointima formation. Apolipoprotein E-deficient mice were treated with POL5551 or sirolimus continuously for 28 days after a carotid wire injury. POL5551 inhibited neointima formation by 63% (for a dosage of 2 mg/kg/day) and by 70% (for a dosage of 20 mg/kg/day). In comparison, sirolimus reduced the neointimal area by 69%. In contrast to treatment with POL5551 during the first three days after injury, injection of POL5551 (20 mg/kg) once per day for 28 days diminished neointimal hyperplasia by 53%. An analysis of the cellular composition of the neointima showed a reduction in the relative smooth muscle cell (SMC) and macrophage content in mice that had been treated with a high dose of POL5551. In contrast, the diminished SMC content after sirolimus treatment was associated with a neointimal enrichment of macrophages. Furthermore, endothelial recovery was impaired by sirolimus, but not by POL5551. Therefore, the inhibition of CXCR4 by POL5551 is equally effective in preventing neointima formation as sirolimus, but POL5551 might be more beneficial because treatment with it results in a more stable lesion phenotype and because it does not impair re-endothelialisation.
Complement activation in patients with isolated antiphospholipid antibodies or primary antiphospholipid syndrome
Authors: Seed Paul , Parmar Kiran , Moore Gary W. , Stuart-Smith Sara E. , Hunt Beverley J. , Breen Karen A. 
Published: January 2012

SummaryThe antiphospholipid syndrome (APS) is the association of thrombosis and recurrent pregnancy loss and/or pregnancy morbidity with persistent antiphospholipid antibodies (aPL). Increased complement activation has been implicated in the pathogenesis of APS in animal models. It was our objective to evaluate complement activation in patients with aPL or primary antiphospholipid syndrome (PAPS). We measured complement activation products, fragments Bb and C3a–desArg by ELISA in 186 aPL/PAPS patients and 30 healthy controls. All patients with aPL had significantly increased levels of complement activation products. Fragment Bb levels (mean, 95% CI); (thrombotic APS 0.54 units/ml, 0.31–0.83, obstetric APS 0.60 units/ml,0.39–1.02, isolated aPL 0.48 units/ml, 0.29–0.85, overall 0.39 units/ml, 0.33–0.47) and C3a–desArg levels (mean, 95% CI): (thrombotic APS 261 ng/ml, 219–311, obstetric APS 308 ng/ml, 243–391, isolated aPL 258 ng/ml, 193–337, overall 225 ng/ml, 202–251) were significantly higher compared to controls (fragment Bb 0.06 units/ml, 0.03–0.11, C3a–desArg 69 ng/ml, 50–92). There were correlations between Fragment Bb and C3a–desArg levels in all patients with aPL. Receiver operator characteristic (ROC) analysis showed increased fragment Bb and C3a–desArg levels had strong associations with the presence of persistent lupus anticoagulant (area under ROC: Bb 0.89, and C3a–desArg 0.90), dual and triple aPL positivity (Bb 0.71–0.82, C3a–desArg 0.71–0.80) but not with high titre anti-cardiolipin antibodies (Bb 0.62, C3a–desArg 0.65), or anti β2-glycoprotein 1 antibodies (Bb 0.66, C3a–desArg 0.67). Complement activation is present in all patient groups within this large cohort of patients aPL. This suggests it may have a major role in the pathogenesis of APS and merits further study.
THEOLOGY, RATIONALITY AND TRUTH-CLAIMS: METATHEORETICAL REFLECTIONS ON SELF-DECEPTION
Authors: BOTHA PIETER J. J. 
Published: January 2012

Abstract<title> Abstract </title>Reflecting on self-deception makes us aware that this phenomenon is far more complex than a 'problem' or 'illness' in need of solution or therapy. It confronts us with the question of who we are and what kind of person we want to be. Truth and honesty are intertwined, and reality must also be conceived ethically: one cannot overestimate the precautions that must be taken to guard against obtaining proof from research that fits with what we expect to obtain, because our wishes and our preferences have led us to affect our awareness and cognitive faculties to respond in accordance with our expectations.
WISDOM LOST AND REGAINED? THE POSSIBILITY OF REINTEGRATING A FRACTURED TECHNOSCIENTIFIC CULTURE
Authors: DU TOIT CORNEL W. 
Published: January 2012

Abstract<title> Abstract </title>Technology has taken on a life of its own and it now seems impossible to work out who manages it. Humans have created a technoscientific environment that has surpassed the guidelines of their wisdom. The question: what is it to be human? can no longer be isolated from the question: what is it to possess technology? The renewed search for wisdom is regarded as a metaphor for expressing different sentiments, such as the attempt to link values to technology; the search for unity between the different sciences, and between science and the life world; the restoration of values, especially in the realm of the natural sciences; the best way to cope in a technoscientific culture; and, finally, decisions about research policies. in this article some of the main factors responsible for the exclusivity of the natural sciences and for the division of the sciences, and the detachment of science from the life world are discussed. the detachment of natural science from values, ethics and the human sciences are traced back to the scientific revolution and the establishment by Galileo and Kepler of mathematics as the language of the natural sciences. The subject of scientific research has shifted from the scientific community to the political and economic realm. the realm of power and the prerequisites for academic accomplishment compromise the integrity of science and the wellbeing of society. The democratisation of technoscience requires some progress in the concilience of the sciences.
VIOLENCE AND SOCIAL IMAGINATION: RETHINKING THEOLOGY AND POLITICS IN AFRICA
Authors: KATONGOLE EMMANUEL M. 
Published: January 2012

Abstract<title> Abstract </title>In this article the author argues that the greatest challenge facing Christians In Africa has to do with the cultivation of new social imaginations that can both resist and provide alternatives to the ever-increasing phenomenon of violence. For this to happen, Christian social ethics in Africa must rethink the relation between theology and politics, and thus assume new methodologies and directions. This argument is only spelt out more explicitly In the fourth and last section of the essay. The reason for this is that the reality of violence in Africa does not occur in isolation nor does it arise spontaneously out of some incomprehensible contradictions within 'African culture.' Violence, at least the sort of violence experienced in Africa, is the result of political formation, which is connected to stories that sustain nation-state politics in Africa. That is why it is important to attend to the story of Africa's politics, and the underlying stories and imaginations that sustain it. Once attention has been drawn to the story of nation-state politics in Africa, and the imagination and patterns of violence it forms, it becomes evident that Christian social ethics cannot proceed as usual - by offering recommendations to help nation-state politics. Rather, it will have to reposition itself as a form of politics that is based on distinct stories, and that is capable of forming alternative imaginations and patterns of social existence
CONTEXTUALISING PAUL IN ATHENS: THE PROCLAMATION OF THE GOSPEL BEFORE PAGAN AUDIENCES IN THE GRAECO-ROMAN WORLD
Authors: SCHNABEL ECKHARD J. 
Published: January 2012

Abstract<title> Abstract </title>This article contextualises Paul's speech on the Areopagus as reported in Acts 17 in the light of the contemporary religious situation obtaining in Athens in the middle of the first century C.E. Against the background of the pluralistic and polytheistic religious context of life in Athens, Paul's speech is interpreted and situated primarily in the light of the role of the Council of the Areopagus as guardians of traditional Athenian ways. The speech before the Council is characterised by agreements with Graeco-Roman philosophy (Stoicism and Epicureanism), as well as by contradictions with these. It is clear that the thrust of the speech derives from Old Testament prophetic traditions and contemporary Jewish apologetics. Rather than drawing on Graeco-Roman philosophical traditions as a kind of preparation for the gospel, then, Paul is transcending these with revealed theology.
Plasma Glucose Levels in Exclusively Breastfed Newborns in the First 48 Hours of Life in Ile-Ife, Nigeria
Authors: Adejuyigbe E.A. , Fasubaa O.B. , Ajose O.A. , Onayade A.A. 
Published: January 2012

This study aims to determine the effectiveness of exclusive breastfeeding of newborns in maintaining a normal blood glucose level in the first 48 hours of life. One hundred and twelve consecutive newborns were initially recruited and 91 completed the study. All neonates of mothers with complicated pregnancy such as diabetes, hypertension and infections were excluded from the study. Maternal and cord glucose estimation were carried out within 30 minutes of delivery. All mothers were assisted in positioning and attaching their babies to the breast. All newborn were weighed and glucose levels were measured at 24 and 48 hours of life before breastfeeding. All mothers were euglycaemic while seven neonates had plasma glucose level less than 1.7 mmol/l at birth. Only one neonate had persistent hypoglycemia from birth to 12 hours of age and required treatment. All other neonates had blood glucose level above 1.7 mmol/l at 24 and 48 hours of life. The weight loss was 0.176 ± 0.134 kg and 0.211 ± 0.157 kg at 24 and 48 hours respectively. We therefore conclude that the exclusively breastfed newborns have adequate glucose supply and are not at risk of having hypoglycemia in the first 48 hours of life.