bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prospective Assessment of Discontinuation and Reinitiation of Erlotinib or Gefitinib in Patients with Acquired Resistance to Erlotinib or Gefitinib Followed by the Addition of Everolimus
Authors: Riely Gregory J. , Kris Mark G. , Zhao Binsheng , Akhurst Tim , Milton Daniel T. , Moore Erin , Tyson Leslie , Pao William , Rizvi Naiyer A. , Schwartz Lawrence H. , Miller Vincent A. 
Published: September 2007

Abstract
Purpose: Ten percent of U.S. patients with non–small cell lung cancer experience partial radiographic responses to erlotinib or gefitinib. Despite initial regressions, these patients develop acquired resistance to erlotinib or gefitinib. In these patients, we sought to assess changes in tumor metabolism and size after stopping and restarting erlotinib or gefitinib and to determine the effect of adding everolimus.
Experimental Design: Patients with non–small cell lung cancer and acquired resistance to erlotinib or gefitinib were eligible. Patients had 18-fluoro-2-deoxy-d-glucose-positron emission tomography/computed tomography and computed tomography scans at baseline, 3 weeks after stopping erlotinib or gefitinib, and 3 weeks after restarting erlotinib or gefitinib. Three weeks after restarting erlotinib or gefitinib, everolimus was added to treatment.
Results: Ten patients completed all four planned studies. Three weeks after stopping erlotinib or gefitinib, there was a median 18% increase in SUVmax and 9% increase in tumor diameter. Three weeks after restarting erlotinib or gefitinib, there was a median 4% decrease in SUVmax and 1% decrease in tumor diameter. No partial responses (0 of 10; 95% confidence interval, 0-31%) were seen with the addition of everolimus to erlotinib or gefitinib.
Conclusions: In patients who develop acquired resistance, stopping erlotinib or gefitinib results in symptomatic progression, increase in SUVmax, and increase in tumor size. Symptoms improve and SUVmax decreases after restarting erlotinib or gefitinib, suggesting that some tumor cells remain sensitive to epidermal growth factor receptor blockade. No responses were observed with combined everolimus and erlotinib or gefitinib. We recommend a randomized trial to assess the value of continuing erlotinib or gefitinib after development of acquired resistance.
Monocyte Chemotactic Protein-1 Secreted by Primary Breast Tumors Stimulates Migration of Mesenchymal Stem Cells
Authors: Dwyer R.M. , Potter-Beirne S.M. , Harrington K.A. , Lowery A.J. , Hennessy E. , Murphy J.M. , Barry F.P. , O'Brien T. , Kerin M.J. 
Published: September 2007

Abstract
Purpose: Major barriers to effective adenovirus-based gene therapy include induction of an immune response and tumor-specific targeting of vectors. The use of mesenchymal stem cells (MSC) as systemic delivery vehicles for therapeutic genes has been proposed as a result of their combined ability to home in on the tumor site and evade the host immune response. This study is aimed at investigating factors mediating homing of human MSCs to breast cancer primary cultures and cell lines in vitro and in vivo.
Experimental Design: Fluorescently labeled MSCs were given to mice bearing breast cancer xenografts, and tumor tissue was harvested to detect MSC engraftment. MSC migration in response to primary breast tumors in vitro was quantified, and chemokines secreted by tumor cells were identified. The role of monocyte chemotactic protein-1 (MCP-1) in cell migration was investigated using antibodies and standards of the chemokine. Serum MCP-1 was measured in 125 breast cancer patients and 86 healthy controls.
Results: Engrafted MSCs were detected in metastatic breast tumors in mice after systemic administration. There was a significant increase in MSC migration in response to primary breast tumor cells in vitro (6-fold to 11-fold increase). Tumor explants secreted a variety of chemokines including GROα, MCP-1, and stromal cell–derived factor-1α. An MCP-1 antibody caused a significant decrease (37-42%) in MSC migration to tumors. Serum MCP-1 levels were significantly higher in postmenopausal breast cancer patients than age-matched controls (P &lt; 0.05).
Conclusions: These results highlight a role for tumor-secreted MCP-1 in stimulating MSC migration and support the potential of these cells as tumor-targeted delivery vehicles for therapeutic agents.
Radiation-Enhanced Vascular Targeting of Human Lung Cancers in Mice with a Monoclonal Antibody That Binds Anionic Phospholipids
Authors: He Jin , Luster Troy A. , Thorpe Philip E. 
Published: September 2007

AbstractPurpose: New treatment strategies aimed at damaging tumor vasculature could potentially improve tumor response to radiation therapy. We recently showed that anionic phospholipids, principally phosphatidylserine, are specifically exposed on the luminal surface of tumor blood vessels. Here we tested the hypothesis that radiation therapy can increase phosphatidylserine exposure on lung tumor vasculature, thereby enhancing the antitumor properties of the anti-phosphatidylserine antibody 2aG4.Experimental Design: The therapeutic efficacy of radiation therapy plus 2aG4 was tested in nude mice bearing radiation-resistant A549 human lung tumors. Radiation-induced phosphatidylserine exposure on endothelial cells and A549 tumor cells was analyzed by immunofluoresence staining. The mechanism of the enhanced antitumor effect was examined by histology and antibody-dependent cell-mediated cytotoxicity experiments.Results: Focal irradiation of A549 human lung cancer xenografts increased the percentage of tumor vessels with exposed phosphatidylserine from 4% to 26%. Treatment of mice bearing A549 tumors with 2aG4 plus focal radiation therapy inhibited tumor growth by 80% and was superior to radiation therapy or 2aG4 alone (P &lt; 0.01). Combination therapy reduced blood vessel density and enhanced monocyte infiltration into the tumor mass beyond that observed with individual treatments. In vitro, 2aG4 enhanced the ability of macrophages to kill endothelial cells with exposed phosphatidylserine in an Fc′-dependent manner.Conclusion: These results suggest that 2aG4 enhances the antitumor effects of radiation therapy by increasing antibody-dependent cell-mediated cytotoxicity toward tumor vessels with externalized phosphatidylserine. Bavituximab, a chimeric version of 2aG4 in clinical trials, has the potential to enhance the therapeutic efficacy of radiation therapy in lung cancer patients.
CXCL12 G801A Polymorphism Is a Risk Factor for Sporadic Prostate Cancer Susceptibility
Authors: Hirata Hiroshi , Hinoda Yuji , Kikuno Nobuyuki , Kawamoto Ken , Dahiya Angela V. , Suehiro Yutaka , Tanaka Yuichiro , Dahiya Rajvir 
Published: September 2007

Abstract
Purpose: The chemokine CXCL12 and its receptor CXCR4 have been found to be associated with cancer metastasis. A single nucleotide polymorphism of CXCL12 G801A has been described and is regarded as a target for cis-acting factor that has the ability to up-regulate CXCL12 expression. Currently, there are no reports investigating the role of CXCL12 G801A polymorphism in prostate cancer (PC).
Experimental Design: We genotyped CXCL12 G801A and p53Arg72Pro in 167 PC patients and 167 age-matched healthy subjects. Genotyping was done with PCR-RFLP and confirmed by direct DNA sequencing. To investigate the effect of the CXCL12 G801A polymorphism on CXCL12 and CXCR4 expression, immunohistochemistry was done in genotyped PC tissues.
Results: A significant increase in the GA + AA genotype of the CXCL12 G801A polymorphism was observed in PC patients compared with healthy controls. The frequency of CXCL12 AA genotype was significantly higher in a group of patients with lymph node metastasis (23%) compared with those without metastasis (7%). The frequency of CXCL12 expression in AA + GA genotype carriers was significantly higher than that in GG genotype carriers. Among the carriers with CXCL12 GA + AA genotypes, CXCR4 expression was also significantly higher compared with those with the GG genotype. Moreover, among the groups with both CXCL12- and CXCR4-positive staining, the frequency of the CXCL12 GA + AA genotype was high. Although we did not find a significant relationship between the frequency of the Arg/Pro + Pro/Pro genotype of p53 Arg72Pro and susceptibility in PC, there was a combined effect of CXCL12 GA + AA genotype and the p53 72Arg/Pro + Pro/Pro genotype on the frequency of PC. These results indicate that the p53 codon 72 polymorphism may interact with CXCL12 G801A.
Conclusions: This is the first report showing that CXCL12 G801A polymorphism may be a risk factor for PC. Moreover, this study suggests that this polymorphism can be an important marker for detecting microinvasion and PC metastasis.
Inactivation of HOXA Genes by Hypermethylation in Myeloid and Lymphoid Malignancy is Frequent and Associated with Poor Prognosis
Authors: Strathdee Gordon , Holyoake Tessa L. , Sim Alyson , Parker Anton , Oscier David G. , Melo Junia V. , Meyer Stefan , Eden Tim , Dickinson Anne M. , Mountford Joanne C. , Jorgensen Heather G. , Soutar Richard , Brown Robert 
Published: September 2007

Abstract
Purpose: The HOX genes comprise a large family of homeodomain-containing transcription factors, present in four separate clusters, which are key regulators of embryonic development, hematopoietic differentiation, and leukemogenesis. We aimed to study the role of DNA methylation as an inducer of HOX gene silencing in leukemia.
Experimental Design: Three hundred and seventy-eight samples of myeloid and lymphoid leukemia were quantitatively analyzed (by COBRA analysis and pyrosequencing of bisulfite-modified DNA) for methylation of eight HOXA and HOXB cluster genes. The biological significance of the methylation identified was studied by expression analysis and through re-expression of HOXA5 in a chronic myeloid leukemia (CML) blast crisis cell line model.
Results: Here, we identify frequent hypermethylation and gene inactivation of HOXA and HOXB cluster genes in leukemia. In particular, hypermethylation of HOXA4 and HOXA5 was frequently observed (26-79%) in all types of leukemias studied. HOXA6 hypermethylation was predominantly restricted to lymphoid malignancies, whereas hypermethylation of other HOXA and HOXB genes was only observed in childhood leukemia. HOX gene methylation exhibited clear correlations with important clinical variables, most notably in CML, in which hypermethylation of both HOXA5 (P = 0.00002) and HOXA4 (P = 0.006) was strongly correlated with progression to blast crisis. Furthermore, re-expression of HOXA5 in CML blast crisis cells resulted in the induction of markers of granulocytic differentiation.
Conclusion: We propose that in addition to the oncogenic role of some HOX family members, other HOX genes are frequent targets for gene inactivation and normally play suppressor roles in leukemia development.
Is There a Human Homologue to the Murine Proteolysis-Inducing Factor?
Authors: Wieland Barbara M. , Stewart Grant D. , Skipworth Richard J.E. , Sangster Kathryn , Fearon Kenneth C.H. , Ross James A. , Reiman Tony J. , Easaw Jay , Mourtzakis Marina , Kumar Vishesh , Pak Brian J. , Calder Kathryn , Filippatos Gerasimos , Kremastinos Dimitris T. , Palcic Monica , Baracos Vickie E. 
Published: September 2007

Abstract
Purpose: A tumor-derived proteolysis-inducing factor (PIF) is suggested to be a potent catabolic factor in skeletal muscle of mice and humans. We aimed to establish the clinical significance of PIF in cancer patients and to elucidate its structural features.
Experimental Design: PIF was detected in human urine using a monoclonal antibody (mAb) and related to clinical outcomes. PIF immunoaffinity-purified using the mAb was purified/separated using reverse-phase high-performance liquid chromatography and two-dimensional electrophoresis. Ten human cancer cell lines were tested for expression of mRNA encoding PIF core peptide.
Results: PIF immunoreactivity was present in 160 of 262 patients with advanced cancers of the lung, esophagus/stomach, and other organs. In a Kaplan-Meier survival analysis of 181 lung cancer patients, PIF was unrelated to survival; PIF status was also unrelated to skeletal muscle loss confirmed by computed tomography imaging. PIF was seen in 16 of 24 patients with chronic heart failure and thus is not exclusive to malignant disease. In-gel digestion and mass spectrometric analysis of immunoaffinity purified PIF from cancer patients consistently identified human albumin and immunoglobulins. We showed nonspecific binding of purified albumin and immunoglobulins to the anti-PIF mAb, which is thus not a useful tool for PIF detection or purification in humans. Finally, the human PIF core peptide was detected in human cancer cell lines using reverse transcription-PCR and nucleotide sequencing; however, none of the amplified products had a site for the glycosylation critical to the proteolysis-inducing activity of murine PIF.
Conclusions: A putative human homologue of murine PIF and its role in human cancer cachexia cannot be verified.
Dissecting the Akt/Mammalian Target of Rapamycin Signaling Network: Emerging Results from the Head and Neck Cancer Tissue Array Initiative
Authors: Molinolo Alfredo A. , Hewitt Stephen M. , Amornphimoltham Panomwat , Keelawat Somboon , Rangdaeng Samraeung , Meneses García Abelardo , Raimondi Ana R. , Jufe Rafael , Itoiz María , Gao Yan , Saranath Dhananjaya , Kaleebi George S. , Yoo George H. , Leak Lee , Myers Ernest M. , Shintani Satoru , Wong David , Massey H. Davis , Yeudall W. Andrew , Lonardo Fulvio , Ensley John , Gutkind J. Silvio 
Published: September 2007

Abstract
Purpose: As an approach to evaluate the expression pattern and status of activation of signaling pathways in clinical specimens from head and neck squamous cell carcinoma (HNSCC) patients, we established the Head and Neck Cancer Tissue Array Initiative, an international consortium aimed at developing a high-density HNSCC tissue microarray, with a high representation of oral squamous cell carcinoma.
Experimental Design: These tissue arrays were constructed by acquiring cylindrical biopsies from multiple individual tumor tissues and transferring them into tissue microarray blocks. From a total of 1,300 cases, 547 cores, including controls, were selected and used to build the array.
Results: Emerging information by the use of phosphospecific antibodies detecting the activated state of signaling molecules indicates that the Akt-mammalian target of rapamycin (mTOR) pathway is frequently activated in HNSCC, but independently from the activation of epidermal growth factor receptor or the detection of mutant p53. Indeed, we identified a large group of tissue samples displaying active Akt and mTOR in the absence of epidermal growth factor receptor activation. Furthermore, we have also identified a small subgroup of patients in which the mTOR pathway is activated but not Akt, suggesting the existence of an Akt-independent signaling route stimulating mTOR.
Conclusions: These findings provide important information about the nature of the dysregulated signaling networks in HNSCC and may also provide the rationale for the future development of novel mechanism-based therapies for HNSCC patients.
STS Requires Changes in Teaching
Authors: Yager Robert E. 
Published: September 2007

The major advantage of STS is the kind of teaching it allows and demands. Twelve middle school teachers who were enthused with STS teaching selected two sections for a research study. One section was the experimental STS section; the other followed the course syllabus and textbook closely. The major findings indicate the advantages for STS as a teaching approach. Students at the STS approach learned as many science concepts as students who were taught such concepts directly. But the students in the STS sections were superior in all other aspects, including understanding and use of 14 process skills, use of creative thinking skills, development of more positive attitudes, better ability to apply and connect ideas and skills to other situations, and developing a better understanding of the nature and history of science.
The PreCardio-study protocol – a randomized clinical trial of a multidisciplinary electronic cardiovascular prevention programme
Authors: Claes Neree , Jacobs Nele 
Published: September 2007

AbstractBackgroundCardiovascular diseases (CVD) are the leading cause of death and the third cause of disability in Europe. Prevention programmes should include interventions aimed at a reduction of medical risk factors (hypertension, hypercholesterol, hyperglycemia, overweight and obesity) as well as behavioural risk factors (sedentary lifestyle, high fat intake and low fruit and vegetable intake, smoking). The aim of this study is to investigate the effects of a multifaceted, multidisciplinary electronic prevention programme on cardiovascular risk factors.Methods/DesignIn a randomized controlled trial, one group will receive a maximal intervention (= intervention group). The intervention group will be compared to the control group receiving a minimal intervention. An inclusion of 350 patients in total, with a follow-up of 3 years is foreseen. The inclusion criteria are age between 25–65 and insured by the Onderlinge Ziekenkas, insuring for guaranteed income in case of illness for self-employed. The maximal intervention group receives several prevention consultations by their general practitioner (GP) using a new type of cardiovascular risk calculator with personalised feedback on behavioural risk factors. These patients receive a follow-up with intensive support of health behaviour change via different methods, i.e. a tailored website and personal advice of a multidisciplinary team (psychologist, physiotherapist and dietician). The aim of this strategy is to reduce cardiovascular risk factors according to the guidelines. The primary outcome measures will be cardiovascular risk factors. The secondary outcome measures are cardiovascular events, quality of life, costs and incremental cost effectiveness ratios. The control group receives prevention consultations using a new type of cardiovascular risk calculator and general feedback.DiscussionThis trial incorporates interventions by GPs and other health professionals aiming at a reduction of medical and behavioural cardiovascular risk factors. An assessment of clinical, psychological and economical outcome measures will be performed.Trial registrationISRCTN23940498
Effect of oral lactulose on clinical and immunohistochemical parameters in patients with inflammatory bowel disease: a pilot study
Authors: Hafer Anne , Krämer Sigrid , Duncker Swantje , Krüger Martin , Manns Michael P , Bischoff Stephan C 
Published: September 2007

Abstract

Background
The prebiotic potential of lactulose is well established and preclinical studies demonstrated a protective effect of lactulose in murine models of colitis. The aim of the present study was to investigate the clinical and histological efficacy of lactulose in patients with inflammatory bowel disease (IBD), for which probiotic therapy yielded promising results.

Methods
Patients were treated with standard medication alone or combined with 10 g lactulose daily as adjuvant therapy for 4 months. Clinical efficacy of treatment was assessed using clinical activity indices, a quality of life index (IBDQ), endoscopic scores, defecation frequency and monitoring corticosteroid medication. Orsomucoid, alpha1-antitrypsin and other laboratory parameters were determined. In addition, in some participants colonic biopsies were analyzed with haematoxylin-eosin staining or with antibodies against HLA-DR, CD68, IgA and CD3, and evaluated systematically. All measurements were performed both at enrolment and at the end of the trial.

Results
14 patients presenting ulcerative colitis (UC) and 17 patients presenting Crohn's disease (CD), most of them in a clinically active state, were enrolled in this pilot study. After 4 month no significant improvement of clinical activity index, endoscopic score or immunohistochemical parameters was observed in CD or UC patients receiving lactulose in comparison to the control group. However, significant improvement of quality of life was observed in UC patients receiving lactulose compared to the control group (p = 0.04).

Conclusion
The findings of the present pilot study indicate that oral lactulose has no beneficial effects in IBD patients in particular with regard to clinical activity, endoscopic score or immunohistochemical parameters. The importance of the beneficial effect of lactulose in UC patients regarding the quality of life needs further evaluation in larger controlled clinical trials.

Trial registration
Current Controlled Trials ISRCTN92101486
Association between the BRCA2N372H variant and male breast cancer risk: a population-based case-control study in Tuscany, Central Italy
Authors: Palli Domenico , Falchetti Mario , Masala Giovanna , Lupi Ramona , Sera Francesco , Saieva Calogero , D'Amico Cristina , Ceroti Marco , Rizzolo Piera , Caligo Maria Adelaide , Zanna Ines , Ottini Laura 
Published: September 2007

Abstract

Background
Male breast cancer (MBC) is a rare disease and little is known about its aetiology. Germ-line mutations of BRCA2 and, at lower frequency, of BRCA1 are implicated in a relatively small proportion of MBC cases. Common polymorphic variants in BRCA1 and BRCA2 genes may represent breast cancer (BC) susceptibility alleles and could be associated with a modestly increased risk of MBC at population level. Considering the relevant role of BRCA2 in MBC, we investigated whether the BRCA2 N372H variant, representing the only common non-synonymous polymorphism in BRCA2, might modulate the risk of BC in male populations.

Methods
A case-control study was performed comparing a population-based series of 99 MBC cases, characterized for BRCA1 and BRCA2 mutations, with 261 male population controls, all residing in Tuscany, Central Italy. All MBC cases and controls were genotyped for the BRCA2 N372H allele by TaqMan allelic discrimination assays. To evaluate the genotype specific risk of the BRCA2 N372H variant, MBC carriers of germ-line BRCA1/2 mutations were excluded from the analyses.

Results
No association emerged in univariate and age-adjusted analyses. Age-specific analyses suggested an increased risk for the HH homozygous genotype in subjects younger than 60 years. A statistically significant interaction emerged between this genotype and age (p = 0.032). When analyses were restricted to MBC cases enrolled in the first 4 years following diagnosis, a recessive model showed a significantly increased risk of MBC in HH subjects younger than 60 years (OR = 5.63; 95% CI = 1.70;18.61).

Conclusion
Overall, our findings, although based on a relatively small series, suggest that the BRCA2 HH homozygous genotype might be positively associated with an increased risk of MBC in men younger than 60 years.