bluuebunny/crossref_metadata_2025_split huggingface dataset:
BMP-2 signaling in ovarian cancer and its association with poor prognosis
Authors: Le Page Cécile , Puiffe Marie-Line , Meunier Liliane , Zietarska Magdalena , de Ladurantaye Manon , Tonin Patricia N , Provencher Diane , Mes-Masson Anne-Marie 
Published: April 2009

Abstract

Background
We previously observed the over-expression of BMP-2 in primary cultures of epithelial ovarian cancer (EOC) cells as compared to normal epithelial cells based on Affymetrix microarray profiling [1]. Here we investigate the effect of BMP-2 on several parameters of ovarian cancer tumorigenesis using the TOV-2223, TOV-1946 and TOV-112D EOC cell lines.

Methods
We treated each EOC cell line with recombinant BMP-2 and assayed various parameters associated with tumorigenesis. More specifically, cell signaling events induced by BMP-2 treatment were investigated by western-blot using anti-phosphospecific antibodies. Induction of Id1, Snail and Smad6 mRNA expression was investigated by real time RT-PCR. The ability of cells to migrate was tested using the scratch assay. Cell-cell adhesion was analyzed by the ability of cells to form spheroids. We also investigated BMP-2 expression in tissue samples from a series of EOC patients.

Results
Treatment of these cell lines with recombinant BMP-2 induced a rapid phosphorylation of Smad1/5/8 and Erk MAPKs. Increased expression of Id1, Smad6 and Snail mRNAs was also observed. Only in the TOV-2223 cell line were these signaling events accompanied by an alteration in cell proliferation. We also observed that BMP-2 efficiently increased the motility of all three cell lines. In contrast, BMP-2 treatment decreased the ability of TOV-1946 and TOV-112D cell lines to form spheroids indicating an inhibition of cell-cell adhesion. The expression of BMP-2 in tumor tissues from patients was inversely correlated with survival.

Conclusion
These results suggest that EOC cell secretion of BMP-2 in the tumor environment contributes to a modification of tumor cell behavior through a change in motility and adherence. We also show that BMP-2 expression in tumor tissues is associated with a poorer prognosis for ovarian cancer patients.
Treating patients with fibromyalgia in primary care settings under routine medical practice: a claim database cost and burden of illness study
Authors: Sicras-Mainar Antoni , Rejas Javier , Navarro Ruth , Blanca Milagrosa , Morcillo Ángela , Larios Raquel , Velasco Soledad , Villarroya Carme 
Published: April 2009

Abstract
Introduction
The objective of this study was to analyze health care and non-health care resource utilization under routine medical practice in a primary care setting claims database and to estimate the incremental average cost per patient per year of fibromyalgia syndrome (FMS) compared with a reference population.

Methods
A 12-month cross-sectional and retrospective study was completed using computerized medical records from a health provider database. Analyses were conducted from the perspective of the provider and from the viewpoint of society. Health care and non-health care resource utilization included drugs, complementary tests, all types of medical visits, referrals, hospitalizations, sick leave, and early retirement because of disability due to FMS. Patients with a diagnosis of FMS in accordance with ICD-10 (International Statistical Classification of Diseases and Related Health Problems, 10th revision) criteria were included in the analysis if they had at least one claim for FMS during the 12 months prior to the end of May 2007. A non-FMS comparison group was also created with the remaining subjects.

Results
Of the 63,526 patients recruited for the study, 1,081 (1.7%) (96.7% of whom were women, 54.2 [10.1] years old) met the criteria for FMS. After an adjustment for age and gender, FMS subjects used significantly more health care resources than the reference population and had more sick leave and the percentage of subjects with premature retirement was also significantly higher (P < 0.001 in all cases). As a result, FMS subjects showed an incremental adjusted per-patient per-year total cost of €5,010 (95% confidence interval [CI] 3,494 to 6,076, +153%, P < 0.001) on average compared with non-FMS subjects. Significantly higher differences were observed in both health care and non-health care adjusted costs: €614 (404 to 823, +66%) and €4,394 (3,373 to 5,420, +189%), respectively (P < 0.001 in both cases). Annual drug expenditure per patient on average was considerably higher in FMS patients, €230 (124 to 335, +64%, P < 0.001), than the reference group.

Conclusions
Under routine medical practice, patients with FMS were associated with considerably higher annual total costs in the primary care setting compared with the reference population.
The transferome of metabolic genes explored: analysis of the horizontal transfer of enzyme encoding genes in unicellular eukaryotes
Authors: Whitaker John W , McConkey Glenn A , Westhead David R 
Published: April 2009

Abstract
Background
Metabolic networks are responsible for many essential cellular processes, and exhibit a high level of evolutionary conservation from bacteria to eukaryotes. If genes encoding metabolic enzymes are horizontally transferred and are advantageous, they are likely to become fixed. Horizontal gene transfer (HGT) has played a key role in prokaryotic evolution and its importance in eukaryotes is increasingly evident. High levels of endosymbiotic gene transfer (EGT) accompanied the establishment of plastids and mitochondria, and more recent events have allowed further acquisition of bacterial genes. Here, we present the first comprehensive multi-species analysis of E/HGT of genes encoding metabolic enzymes from bacteria to unicellular eukaryotes.

Results
The phylogenetic trees of 2,257 metabolic enzymes were used to make E/HGT assertions in ten groups of unicellular eukaryotes, revealing the sources and metabolic processes of the transferred genes. Analyses revealed a preference for enzymes encoded by genes gained through horizontal and endosymbiotic transfers to be connected in the metabolic network. Enrichment in particular functional classes was particularly revealing: alongside plastid related processes and carbohydrate metabolism, this highlighted a number of pathways in eukaryotic parasites that are rich in enzymes encoded by transferred genes, and potentially key to pathogenicity. The plant parasites Phytophthora were discovered to have a potential pathway for lipopolysaccharide biosynthesis of E/HGT origin not seen before in eukaryotes outside the Plantae.

Conclusions
The number of enzymes encoded by genes gained through E/HGT has been established, providing insight into functional gain during the evolution of unicellular eukaryotes. In eukaryotic parasites, genes encoding enzymes that have been gained through horizontal transfer may be attractive drug targets if they are part of processes not present in the host, or are significantly diverged from equivalent host enzymes.
Genomic Grade Index Is Associated With Response to Chemotherapy in Patients With Breast Cancer
Authors: Liedtke Cornelia , Hatzis Christos , Symmans William Fraser , Desmedt Christine , Haibe-Kains Benjamin , Valero Vicente , Kuerer Henry , Hortobagyi Gabriel N. , Piccart-Gebhart Martine , Sotiriou Christos , Pusztai Lajos 
Published: April 2009

Purpose The genomic grade index (GGI) is a 97-gene measure of histological tumor grade. High GGI is associated with decreased relapse-free survival in patients receiving either endocrine or no systemic adjuvant therapy. Herein we examined whether GGI predicts pathologic response to neoadjuvant chemotherapy in patients with HER-2–normal breast cancer. Methods Gene expression data (gene chips) was generated from fine-needle aspiration biopsies (n = 229) prospectively collected before neoadjuvant paclitaxel, fluorouracil, doxorubicin, and cyclophosphamide chemotherapy. Pathologic response was quantified using the residual cancer burden (RCB) method. The association between the GGI and pathologic response was assessed in univariate and multivariate analyses. The performance of a response predictor combining clinical variables and GGI was evaluated under cross-validation. Results Eighty-five percent of grade 1 tumors had low GGI, 89% of grade 3 tumors had high GGI, and 63% of grade 2 tumors had low GGI. Among both estrogen receptor (ER)-positive and -negative cancers, high GGI score was associated with pathologic complete response (RCB-0) or minimal residual disease (RCB-1). A multivariate model combining GGI and clinical parameters had an overall accuracy of 71%, compared with 58% for the GGI alone, for prediction of pathologic response. However, high GGI score was also associated with significantly worse distant relapse-free survival in patients with ER-positive cancer (P = .005), and was not associated with survival in patients with ER-negative cancer. Conclusion High GGI is associated with increased sensitivity to neoadjuvant paclitaxel plus fluorouracil, adriamycin, and cyclophosphamide chemotherapy in both ER-negative and ER-positive patients, but it remains a predictor of worse survival in ER-positive patients.
Predictive Role of the UGT1A1, UGT1A7, and UGT1A9 Genetic Variants and Their Haplotypes on the Outcome of Metastatic Colorectal Cancer Patients Treated With Fluorouracil, Leucovorin, and Irinotecan
Authors: Cecchin Erika , Innocenti Federico , D'Andrea Mario , Corona Giuseppe , De Mattia Elena , Biason Paola , Buonadonna Angela , Toffoli Giuseppe 
Published: April 2009

Purpose UGT1A1★28 is considered the main pharmacogenetic predictor of the toxicity outcome of irinotecan-treated patients. We evaluated the effect of other UGT1A variants and haplotypes involved in 7-ethyl-10-hydroxycamptothecin (SN-38) glucuronidation on severe toxicity and efficacy of fluorouracil, leucovorin, and irinotecan (FOLFIRI). Patients and Methods In addition to UGT1A1★28, UGT1A1★60, UGT1A1★93, UGT1A7★3, and UGT1A9★22 were genotyped in 250 metastatic colorectal cancer patients, and associations with severe hematologic and nonhematologic toxicity, objective response, time to progression (TTP), and overall survival were evaluated. In a subset of 71 patients, pharmacokinetic data were also available. Results UGT1A7★3 was the only marker of severe hematologic toxicity after the first cycle (odds ratio [OR], 3.94; 95% CI, 1.05 to 14.82; P = .04) in a multivariate analysis. It was also associated with glucuronidation ratio (SN-38G area under the curve [AUC]/SN-38 AUC) and biliary index (irinotecan AUC) × (SN-38 AUC/SN-38G AUC). Haplotype I (all the reference sequence alleles but UGT1A9★22) was a predictor of severe hematologic toxicity during the entire course of therapy (OR, 0.39; 95% CI, 0.19 to 0.82; P = .01), together with sex (OR, 2.08; 95% CI, 1.01 to 4.28; P = .05). In addition to UGT1A1★28, haplotype II (all the variant alleles but UGT1A9★22) was associated with a response rate (OR, 8.61; 95% CI, 1.75 to 42.38; P = .01). UGT1A1★28 was the only marker associated with TTP. Conclusion We propose that UGT1A variants additional to UGT1A1★28 might improve the prediction of the outcome of colorectal cancer patients treated with FOLFIRI. A UGT1A haplotype-based approach might be an efficacious strategy to achieve treatment individualization of FOLFIRI.
Disease-Free Survival According to Degree of HER2 Amplification for Patients Treated With Adjuvant Chemotherapy With or Without 1 Year of Trastuzumab: The HERA Trial
Authors: Dowsett Mitch , Procter Marion , McCaskill-Stevens Worta , de Azambuja Evandro , Dafni Urania , Rueschoff Josef , Jordan Bruce , Dolci Stella , Abramovitz Mark , Stoss Oliver , Viale Giuseppe , Gelber Richard D. , Piccart-Gebhart Martine , Leyland-Jones Brian 
Published: April 2009

Purpose To determine whether (1) immunohistochemical (IHC) HER2 status (ie, 2+ or 3+), (2) degree of fluorescence in situ hybridization (FISH) amplification according to (2a) HER2/CEP17 ratio or (2b) HER2 gene copy number, or (3) polysomy significantly influenced clinical outcome for patients with human epidermal growth factor receptor 2 (HER2) –positive breast cancer enrolled in the Herceptin Adjuvant trial of trastuzumab versus no trastuzumab administered after completion of chemotherapy. Patients and Methods IHC and/or FISH analyses were performed locally and required central confirmation as indicating HER2 positivity for trial entry. FISH data from the central HER2 analysis on patients in the 1-year trastuzumab and no trastuzumab arms were assessed in relation to disease-free survival (DFS) after a median 2 years of follow-up. Results Central FISH results were available for 2,071 (61%) of the 3,401 patients randomized to the 2 arms. Among patients with FISH-positive disease, (1) the hazard ratios for trastuzumab versus no trastuzumab were 0.56 (95% CI, 0.32 to 0.99) for locally IHC2+ cases (n = 340) and 0.80 (95% CI, 0.40 to 1.61) for centrally IHC2+ cases (n = 299). There was no significant prognostic relationship between (2a) HER2 FISH ratio, (2b) HER2 copy number, or (3) polysomy and DFS in the control arm or predictive relationship defining differential benefit from trastuzumab. Conclusion There was no evidence for reduced benefit of trastuzumab in HER2 IHC2+FISH+ cases. The degree of HER2 amplification does not influence prognosis or benefit from adjuvant trastuzumab in patients treated with prior adjuvant chemotherapy.
Intensive Dose-Dense Compared With Conventionally Scheduled Preoperative Chemotherapy for High-Risk Primary Breast Cancer
Authors: Untch Michael , Möbus Volker , Kuhn Walther , Muck Bernd Rudolph , Thomssen Christoph , Bauerfeind Ingo , Harbeck Nadia , Werner Christoph , Lebeau Annette , Schneeweiss Andreas , Kahlert Stephen , von Koch Franz , Petry Karl Ulrich , Wallwiener Diethelm , Kreienberg Rolf , Albert Ute-Susann , Lück Hans-Joachim , Hinke Axel , Jänicke Fritz , Konecny Gottfried E. 
Published: April 2009

Purpose To compare preoperative intense dose-dense (IDD) chemotherapy with conventionally scheduled preoperative chemotherapy in high-risk primary breast cancer (BC). Patients and Methods In this randomized phase III trial a total of 668 eligible primary BC patients stratified for tumors ≥ 3 cm (n = 567) or inflammatory BC (n = 101) were randomly assigned to receive concurrent preoperative epirubicin/paclitaxel every 3 weeks or dose-dense and dose-escalated sequential epirubicin followed by paclitaxel every 2 weeks. All patients received three cycles of cyclophosphamide, methotrexate, and fluorouracil chemotherapy after surgery. Results IDD treatment significantly improved pathologic complete response rate (18% v 10%; odds ratio [OR] 1.89; P = .008), disease-free survival (DFS; hazard ratio [HR], 0.71; P = .011), and overall survival (OS; HR, 0.83; P = .041) compared to epirubicin/paclitaxel. Patients with inflammatory BC had a particularly poor prognosis and did not appear to benefit from IDD therapy in this trial (DFS HR, 1.10; P = .739; OS HR, 1.25; P = .544). In contrast, patients with noninflammatory BC significantly benefited from IDD treatment (DFS HR, 0.65, P = .005; OS HR, 0.77, P = .013). Treatment effects in multivariate analysis were significant for noninflammatory BC (DFS HR, 0.65, P = .015; OS HR, 0.79, P = .034), but not for all patients (DFS HR, 0.76; P = .088; OS HR, 0.82; P = .059). IDD therapy was associated with significantly more nonhematologic toxicities, anemia, and thrombocytopenia, but with similar neutropenia and infection rates. Conclusion Our results support the efficacy and short-term safety of IDD as preoperative chemotherapy. IDD was less well tolerated compared to standard treatment, but improved clinical outcomes in patients with noninflammatory high-risk primary BC.
Phase II Study of Tirapazamine, Cisplatin, and Etoposide and Concurrent Thoracic Radiotherapy for Limited-Stage Small-Cell Lung Cancer: SWOG 0222
Authors: Le Quynh-Thu X. , Moon James , Redman Mary , Williamson Stephen K. , Lara Primo N. , Goldberg Zelanna , Gaspar Laurie E. , Crowley John J. , Moore Dennis F. , Gandara David R. 
Published: April 2009

Purpose A SWOG pilot study (S0004) showed that tirapazamine (TPZ) when combined with concurrent chemoradiotherapy yielded a promising median survival of 22 months in limited-stage small-cell lung cancer (LSCLC). We report results of the phase II study designed to confirm this result. Patients and Methods The concurrent phase consisted of two cycles of cisplatin, etoposide, and once-daily radiation to 61 Gy. TPZ was given at 260 mg/m2 on days 1, 29, and at 160 mg/m2 on days 8, 10, 12, 36, 38, and 40. Consolidation consisted of two cycles of cisplatin and etoposide. Complete responders received prophylactic cranial irradiation. Results were considered promising if the median survival time was at least 21 months and of no further interest if ≤ 14 months. Results S0222 was closed early due to a report of excess toxicity for TPZ in a head and neck cancer trial elsewhere. Of planned 85 patients, 69 were accrued. In 68 assessable patients, 17 (25%) had grade 3 to 4 esophagitis and eight (12%) had grade 3 febrile neutropenia during the concurrent phase. There were three possible treatment-related deaths, two in concurrent phase (one progressive disease not otherwise specified within 30 days, one pericardial effusion) and one in consolidation phase (esophageal hemorrhage). At a median follow-up of 35 months, median progression-free survival was 11 months (95% CI, 10 to 13 months) and median overall survival was 21 months (95% CI, 17 to 33 months). Conclusion S0222 showed acceptable levels of toxicity and similar promising median survival as S0004. Further study of hypoxia-targeted therapy is warranted in LSCLC.
Plasma Carboxy-Terminal Provasopressin (Copeptin): A Novel Marker of Insulin Resistance and Metabolic Syndrome
Authors: Saleem Umer , Khaleghi Mahyar , Morgenthaler Nils G. , Bergmann Andreas , Struck Joachim , Mosley Thomas H. , Kullo Iftikhar J. 
Published: April 2009

Context: Stress-mediated hypothalamic-pituitary-adrenal axis activation, regulated by arginine vasopressin (AVP), may have a role in the pathophysiology of metabolic syndrome (MetSyn).
Objective: The objective of the study was to investigate whether plasma C-terminal provasopressin fragment (copeptin), a surrogate for circulating AVP, was associated with measures of insulin resistance and presence of MetSyn.
Design, Setting, and Participants: This was a multicenter, community-based study, investigating novel biomarkers for vascular disease. Participants included 1293 African-Americans (AA) (64 ± 9 yr) and 1197 non-Hispanic whites (NHW) (59 ± 10 yr) belonging to hypertensive sibships.
Main Outcome Measures: Plasma copeptin levels were measured by an immunoluminometric assay. MetSyn was defined per Adult Treatment Panel III criteria. Generalized estimating equations were used to assess whether plasma copeptin was associated with measures of insulin resistance and MetSyn.
Results: The prevalence of MetSyn was 50% in AA and 49% in NHW. In each group, after adjustment for age and sex, plasma copeptin levels significantly correlated with body mass index, fasting plasma glucose and insulin, homeostasis model assessment of insulin resistance, triglycerides, and (inversely) high-density lipoprotein cholesterol (P &lt; 0.05 for each variable). In multivariable logistic regression models that adjusted for age, sex, smoking, statin use, serum creatinine, education, physical activity, and diuretic use, plasma copeptin levels in the highest quartile were associated with an increased odds ratio of having MetSyn compared with bottom quartile: odds ratio (95% confidence interval) in AA, 2.07 (1.45–2.95); in NHW, 1.74 (1.21–2.5).
Conclusions: Our findings indicate a novel cross-sectional association between plasma copeptin and measures of insulin resistance and MetSyn.
Commentary—Assumptions, Explanation, and Prediction in Marketing Science: “It's the Findings, Stupid, Not the Assumptions”
Authors: Tsang Eric W. K. 
Published: April 2009

In his July–August 2007 editorial of Marketing Science, Steven Shugan argues that the realism of assumptions does not matter as long as a theory or model produces satisfactory predictions and claims further that unrealistic assumptions breed good theories. This commentary discusses the problems of his argument and presents a very different view about the realism of assumptions. Assumptions need not be realistic if the only goal of science is prediction. However, a major function of theory is also to explain and not just to predict. The role of explanation is more important in the social sciences because it is far more difficult to produce accurate predictions in the social than the natural sciences. Assumptions, especially core assumptions, often constitute the foundation of the mechanismic explanations provided by a theory. Unrealistic assumptions may lead to faulty explanations and false predictions. Contrary to Shugan's view, the realism of an assumption cannot be assessed just based on the output of a theory. It has to be tested independently of or in conjunction with the hypotheses of the theory. Also, contrary to Shugan's claim, more realistic assumptions result in better theories. As theory development advances, efforts should be directed toward making assumptions more realistic.
Rejoinder—Think Theory Testing, Not Realism
Authors: Shugan Steven M. 
Published: April 2009

Eric Tsang's response makes the legitimate point that prediction and explanation can be different goals. However, his arguments also suffer from several errors in logic, most often the converse error. I do not claim that unrealistic assumptions breed good theories. I only claim that breakthrough theories usually have assumptions deemed unrealistic. Hence, unrealistic assumptions breed both good and bad theories. That is why science tests theories, not assumptions. Moreover, one can easily prove that realistic assumptions are not required. Consider situations when one of two competing theories must be correct. For example, in criminal cases, the prosecution's theory is that the accused committed the crime. The defense's theory is that the accused is innocent. One theory is correct despite the fact that both could make obviously unrealistic assumptions. For example, the prosecution might unrealistically assume that unreliable eyewitness testimony is sufficient to convict. The defense might unrealistically assume that a dubious alibi is sufficient to acquit. Juries decide on all the evidence and not each assumption. I now answer some of Eric Tsang's questions.