bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular Characteristics Predict Clinical Outcomes: Prospective Trial Correlating Response to the EGFR Tyrosine Kinase Inhibitor Gefitinib with the Presence of Sensitizing Mutations in the Tyrosine Binding Domain of the EGFR Gene
Authors: Rizvi Naiyer A. , Rusch Valerie , Pao William , Chaft Jamie E. , Ladanyi Marc , Miller Vincent A. , Krug Lee M. , Azzoli Christopher G. , Bains Manjit , Downey Robert , Flores Raja , Park Bernard , Singh Bhuvanesh , Zakowski Maureen , Heelan Robert T. , Shen Ronglai , Kris Mark G. 
Published: May 2011

Abstract
Purpose: To determine if tumor regression following treatment with gefitinib correlates with the presence of sensitizing mutations in epidermal growth factor receptor (EGFR).
Patients and Methods: Patients with resectable stage I and II non–small cell lung cancer (NSCLC) enriched for the likelihood of EGFR mutation (≤15 pack-year cigarette smoking history and/or a component of bronchioloalveolar carcinoma) received preoperative gefitinib for 21 days. Tumor specimens were analyzed for EGFR and KRAS mutations and EGFR protein expression and amplification. Patients with 25% or more reduction in tumor size measured bidimensionally at 3 weeks and/or patients with an EGFR mutation received adjuvant gefitinib for 2 years postoperatively.
Results: Fifty patients with stage I/II NSCLC were treated. After 21 days of preoperative gefitinib a response of 25% or more was observed in 21 of 50 (42%) patients. Seventeen of 21 patients with a response had an EGFR mutation and 4 of 21 patients with a response did not (P = 0.0001). Twenty-five of 50 patients were eligible to receive adjuvant gefitinib. With a median follow-up of 44.1 months, 2-year disease free survival for EGFR mutant patients and for those who received adjuvant gefitinib was not statistically different than those who were EGFR wild-type and those who did not receive adjuvant gefitinib. The median disease free and overall survivals have not been reached.
Conclusions: The presence of sensitizing EGFR mutations correlates with radiographic response. A short course of preoperative treatment serves a platform for evaluating activity of new agents and assures sufficient tumor availability for correlative analyses. Clin Cancer Res; 17(10); 3500–6. ©2011 AACR.
The Selective Class I PI3K Inhibitor CH5132799 Targets Human Cancers Harboring Oncogenic PIK3CA Mutations
Authors: Tanaka Hiroshi , Yoshida Miyuki , Tanimura Hiromi , Fujii Toshihiko , Sakata Kiyoaki , Tachibana Yukako , Ohwada Jun , Ebiike Hirosato , Kuramoto Shino , Morita Keiichi , Yoshimura Yasushi , Yamazaki Toshikazu , Ishii Nobuya , Kondoh Osamu , Aoki Yuko 
Published: May 2011

Abstract
Purpose: The phosphatidylinositol 3-kinase (PI3K) pathway plays a central role in cell proliferation and survival in human cancer. PIK3CA mutations, which are found in many cancer patients, activate the PI3K pathway, resulting in cancer development and progression. We previously identified CH5132799 as a novel PI3K inhibitor. Thus, this study aimed to clarify the biochemical and antitumor activity of CH5132799 and elucidate the correlation between CH5132799 response and genetic alterations in the PI3K pathway.
Experimental Design: Kinase inhibitory activity was profiled in cell-free assays. A large panel of human breast, ovarian, prostate, and endometrial cancer cell lines, as well as xenograft models, were used to evaluate the antitumor activity of CH5132799, followed by analysis for genetic alterations. Effects on Akt phosphorylation induced by mTORC1 inhibition were tested with CH5132799 and compared with mTORC1 and PI3K/mTOR inhibitors.
Results: CH5132799 selectively inhibited class I PI3Ks and PI3Kα mutants in in vitro kinase assays. Tumors harboring PIK3CA mutations were significantly sensitive to CH5132799 in vitro and were remarkably regressed by CH5132799 in in vivo mouse xenograft models. In combination with trastuzumab, tumors disappeared in the trastuzumab-insensitive breast cancer model with the PIK3CA mutation. Moreover, CH5132799 did not reverse a negative feedback loop of PI3K/Akt/mTOR signaling and induced regression against tumors regrown after long-term mTORC1 inhibitor treatment.
Conclusions: CH5132799 is a selective class I PI3K inhibitor with potent antitumor activity against tumors harboring the PIK3CA mutations. Prediction of CH5132799 response on the basis of PIK3CA mutations could enable patient stratification in clinical settings. Clin Cancer Res; 17(10); 3272–81. ©2011 AACR.
Analysis of Promoter CpG Island Hypermethylation in Cancer: Location, Location, Location!
Authors: van Vlodrop Iris J.H. , Niessen Hanneke E.C. , Derks Sarah , Baldewijns Marcella M.L.L. , van Criekinge Wim , Herman James G. , van Engeland Manon 
Published: May 2011

AbstractThe genetic and epigenetic alterations that underlie cancer pathogenesis are rapidly being identified. This provides novel insights in tumor biology as well as in potential cancer biomarkers. The somatic mutations in cancer genes that have been implemented in clinical practice are well defined and very specific. For epigenetic alterations, and more specifically aberrant methylation of promoter CpG islands, evidence is emerging that these markers could be used for the early detection of cancer as well as prediction of prognosis and response to therapy. However, the exact location of biologically and clinically relevant hypermethylation has not been identified for the majority of methylation markers. The most widely used approaches to analyze DNA methylation are based on primer- and probe-based assays that provide information for a limited number of CpG dinucleotides and thus for only part of the information available in a given CpG island. Validation of the current data and implementation of hypermethylation markers in clinical practice require a more comprehensive and critical evaluation of DNA methylation and limitations of the techniques currently used in methylation marker research. Here, we discuss the emerging evidence on the importance of the location of CpG dinucleotide hypermethylation in relation to gene expression and associations with clinicopathologic characteristics in cancer. Clin Cancer Res; 17(13); 4225–31. ©2011 AACR.
HSP90 Inhibition Is Effective in Breast Cancer: A Phase II Trial of Tanespimycin (17-AAG) Plus Trastuzumab in Patients with HER2-Positive Metastatic Breast Cancer Progressing on Trastuzumab
Authors: Modi Shanu , Stopeck Alison , Linden Hannah , Solit David , Chandarlapaty Sarat , Rosen Neal , D'Andrea Gabriella , Dickler Maura , Moynahan Mary E. , Sugarman Steven , Ma Weining , Patil Sujata , Norton Larry , Hannah Alison L. , Hudis Clifford 
Published: May 2011

Abstract
Purpose: HSP90 is a chaperone protein required for the stability of a variety of client proteins. 17-Demethoxygeldanamycin (17-AAG) is a natural product that binds to HSP90 and inhibits its activity, thereby inducing the degradation of these clients. In preclinical studies, HER2 is one of the most sensitive known client proteins of 17-AAG. On the basis of these data and activity in a phase I study, we conducted a phase II study of 17-AAG (tanespimycin) with trastuzumab in advanced trastuzumab-refractory HER2-positive breast cancer.
Experimental Design: We enrolled patients with metastatic HER2+ breast cancer whose disease had previously progressed on trastuzumab. All patients received weekly treatment with tanespimycin at 450 mg/m2 intravenously and trastuzumab at a conventional dose. Therapy was continued until disease progression. The primary endpoint was response rate by Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
Results: Thirty-one patients were enrolled with a median age of 53 years and a median Karnofsky performance status (KPS) of 90%. The most common toxicities, largely grade 1, were diarrhea, fatigue, nausea, and headache. The overall response rate was 22%, the clinical benefit rate [complete response + partial response + stable disease] was 59%, the median progression-free survival was 6 months (95% CI: 4–9), and the median overall survival was 17 months (95% CI: 16–28).
Conclusions: This is the first phase II study to definitively show RECIST-defined responses for 17-AAG in solid tumors. Tanespimycin plus trastuzumab has significant anticancer activity in patients with HER2-positive, metastatic breast cancer previously progressing on trastuzumab. Further research exploring this therapeutic interaction and the activity of HSP90 inhibitors is clearly warranted. Clin Cancer Res; 17(15); 5132–9. ©2011 AACR.
Effects of Human Oral Mucosal Tissue, Saliva, and Oral Microflora on Intraoral Metabolism and Bioactivation of Black Raspberry Anthocyanins
Authors: Mallery Susan R. , Budendorf Deric E. , Larsen Matthew P. , Pei Ping , Tong Meng , Holpuch Andrew S. , Larsen Peter E. , Stoner Gary D. , Fields Henry W. , Chan Kenneth K. , Ling Yonghua , Liu Zhongfa 
Published: May 2011

Abstract
Our oral cancer chemoprevention trial data implied that patient-specific differences in local retention and metabolism of freeze-dried components of black raspberries (BRB) affected therapeutic responsiveness. Subsequent studies have confirmed that anthocyanins are key contributors to BRB's chemopreventive effects. Consequently, functional assays, immunoblotting, and immunohistochemical analyses to evaluate levels and distribution of BRB anthocyanin-relevant metabolic enzymes in human oral tissues were conducted. Liquid chromatography/tandem mass spectrometry (LC/MS-MS) analyses of time course saliva samples collected following BRB rinses were conducted to assess local pharmacokinetics and compare the capacities of three different BRB rinse formulations to provide sustained intraoral levels of anthocyanins. Protein profiles showed the presence of key metabolic enzymes in all 15 oral mucosal tissues evaluated, whereas immunohistochemistry confirmed these enzymes were distributed within surface oral epithelia and terminal salivary ducts. β-Glucosidase assays confirmed that whole and microflora-reduced saliva can deglycosylate BRB anthocyanins, enabling generation of the bioactive aglycone, cyanidin. LC/MS-MS analyses showed retention of parent anthocyanins and their functional, stable metabolite, protocatechuic acid, in saliva for up to 4 hours after rinsing. Furthermore, postrinse saliva samples contained glucuronidated anthocyanin conjugates, consistent with intracellular uptake and phase II conversion of BRB anthocyanins into forms amenable to local recycling. Our data show that comparable to the small intestine, the requisite hydrolytic, phase II and efflux transporting enzymes necessary for local enteric recycling are present and functional in human oral mucosa. Notably, interpatient differences in anthocyanin bioactivation and capacities for enteric recycling would impact treatment as retention of bioactivated chemopreventives at the target site would sustain therapeutic effectiveness. Cancer Prev Res; 4(8); 1209–21. ©2011 AACR.
Intramyocardial BNP Gene Delivery Improves Cardiac Function Through Distinct Context-Dependent Mechanisms
Authors: Moilanen Anne-Mari , Rysä Jaana , Mustonen Erja , Serpi Raisa , Aro Jani , Tokola Heikki , Leskinen Hanna , Manninen Aki , Levijoki Jouko , Vuolteenaho Olli , Ruskoaho Heikki 
Published: May 2011

Background—
B-type natriuretic peptide (BNP) is an endogenous peptide produced under physiological and pathological conditions mainly by ventricular myocytes. It has natriuretic, diuretic, blood pressure–lowering, and antifibrotic actions that could mediate cardiorenal protection in cardiovascular diseases. In the present study, we used BNP gene transfer to examine functional and structural effects of BNP on left ventricular (LV) remodeling.

Methods and Results—

Human BNP was overexpressed by using adenovirus-mediated gene delivery in normal rat hearts and in hearts during the remodeling process after infarction and in an experimental model of angiotensin II–mediated hypertension. In healthy hearts, BNP gene delivery into the anterior wall of the LV decreased myocardial fibrosis (
P
<0.01, n=7 to 8) and increased capillary density (
P
<0.05, n=7 to 8) associated with a 7.3-fold increase in LV BNP peptide levels. Overexpression of BNP improved LV fractional shortening by 22% (
P
<0.05, n=6 to 7) and ejection fraction by 19% (
P
<0.05, n=6 to 7) after infarction. The favorable effect of BNP gene delivery on cardiac function after infarction was associated with normalization of cardiac sarcoplasmic reticulum Ca
2+
-ATPase expression and phospholamban Thr17-phosphorylation. BNP gene delivery also improved fractional shortening and ejection fraction in angiotensin II–mediated hypertension as well as decreased myocardial fibrosis and LV collagen III mRNA levels but had no effect on angiogenesis or Ca
2+
-ATPase expression and phospholamban phosphorylation.

Conclusions—
Local intramyocardial BNP gene delivery improves cardiac function and attenuates adverse postinfarction and angiotensin II–induced remodeling. These results also indicate that myocardial BNP has pleiotropic, context-dependent, favorable actions on cardiac function and suggest that BNP acts locally as a key mechanical load–activated regulator of angiogenesis and fibrosis.
TVP1022 Attenuates Cardiac Remodeling and Kidney Dysfunction in Experimental Volume Overload-Induced Congestive Heart Failure
Authors: Abassi Zaid A. , Barac Yaron D. , Kostin Sawa , Roguin Ariel , Ovcharenko Elena , Awad Hoda , Blank Ayelet , Bar-Am Orit , Amit Tamar , Schaper Jutta , Youdim Moussa , Binah Ofer 
Published: May 2011

Background—

Despite the availability of many pharmacological and mechanical therapies, the mortality rate among patients with congestive heart failure (CHF) remains high. We tested the hypothesis that TVP1022 (the
S
-isomer of rasagiline; Azilect), a neuroprotective and cytoprotective molecule, is also cardioprotective in the settings of experimental CHF in rats.

Methods and Results—

In rats with volume overload-induced CHF, we investigated the therapeutic efficacy of TVP1022 (7.5 mg/kg) on cardiac function, structure, biomarkers, and kidney function. Treatment with TVP1022 for 7 days before CHF induction prevented the increase in left ventricular end-diastolic area and end-systolic area, and the decrease in fractional shortening measured 14 days after CHF induction. Additionally, TVP1022 pretreatment attenuated CHF-induced cardiomyocyte hypertrophy, fibrosis, plasma and ventricular B-type natriuretic peptide levels, and reactive oxygen species expression. Further, in CHF rats, TVP1022 decreased cytochrome
c
and caspase 3 expression, thereby contributing to the cardioprotective efficacy of the drug. TVP1022 also enhanced the urinary Na
+
excretion and improved the glomerular filtration rate. Similar cardioprotective effects were obtained when TVP1022 was given to rats after CHF induction.

Conclusions—
TVP1022 attenuated the adverse functional, structural, and molecular alterations in CHF, rendering this drug a promising candidate for improving cardiac and renal function in this disease state.
What to do about depression? Self-help recommendations of the public
Authors: Holzinger Anita , Matschinger Herbert , Angermeyer Matthias 
Published: May 2011

Background: While help-seeking and treatment preferences for depression have been assessed in a number of population studies, little is known about the public’s self-help beliefs. Aims: To explore public beliefs about self-help actions to be taken in case of depression. Methods: In spring 2009, a population-based survey was conducted by telephone in the city of Vienna. A fully structured interview was carried out, which began with the presentation of a vignette describing a case of depression. Subsequently, respondents were asked to indicate to what extent they would recommend various self-help actions. Results: Among the self-help options proposed, confiding in a close friend or someone in the family were most frequently recommended. Apart from that, a variety of interpersonal actions (socializing with others, joining a self-help group), psychological methods (thinking positively), lifestyle changes (engaging in sport, listening to music, going on vacation, reading a good book) and dietary methods (eating healthy food) were endorsed by over half of respondents. While women were more ready to recommend self-help actions, the better educated were less enthusiastic about them. Conclusions: As only some of the self-help measures endorsed by the public are evidence based, more research is needed before promulgating their use.
Assessment of cardiac structure and function in patients without and with peripheral oedema during rosiglitazone treatment
Authors: Narang Nikhil , Armstead Sumiko I , Stream Amanda , Abdullah Shuaib M , See Raphael , Snell Peter G , McGavock Jonathan , Ayers Colby R , Gore M Odette , Khera Amit , de Lemos James A , McGuire Darren K 
Published: May 2011

Background: Thiazolidinediones cause peripheral oedema, the aetiology of which remains poorly understood. Methods: In a sub-study of a 6-month trial comparing rosiglitazone (Rsg) versus placebo, we compared those with versus without oedema among the 74 subjects treated with Rsg with respect to peak oxygen consumption indexed to fat-free mass (VO2peak-FFM ), cardiac MRI and markers of plasma volume expansion. Results: Almost half (49%) of the Rsg-treated patients developed oedema. Baseline VO 2peak-FFM was not different between those with versus without oedema (25.8 versus 28.2 ml/kg/min; p = 0.22) and declined 5% in the oedema group (Δ -1.3 ml/min/kg; p = 0.005) with no change in those without oedema. Stroke volume increased in both groups (Δ 8.7 and 8.8 ml; p < 0.001 for each); end-diastolic volume increased only in those with oedema (+13.1 ml; p = 0.001). No other cardiac function changes were observed. In both groups, weight increased (3.6 and 2.2 kg) and haematocrit decreased (-3.2% and -2.1%; p < 0.001 for each). In those with oedema, albumin decreased (-0.2 g/dl) and brain natriuretic peptide increased (11.9 pg/ml; p < 0.03 for each). Conclusions: Oedema was associated with a small decline in VO2peak FFM, no adverse effects on cardiac function, and changes in selected measures suggesting that volume expansion underpins Rsg oedema.
The predictive value of inflammatory activity and markers of the adipo-insular axis on restenosis in patients with type 2 diabetes
Authors: Hage Camilla , Grip Lars , Malmberg Klas , Rydén Lars , Wallander Märit , Saleh Nawsad 
Published: May 2011

Aims: Patients with type 2 diabetes (T2DM) have a high restenosis rate after percutaneous coronary intervention (PCI). This study investigated whether markers of inflammation and the adipo-insular axis associated with T2DM and poor metabolic control were able to predict restenosis after PCI in T2DM patients. Methods and results: The predictive value of traditional and non-traditional risk markers, including IL-1β, IL-6, TNF-α, hsCRP, interferon gamma, leptin, IGF-I, insulin, proinsulin and NT-proBNP, was investigated in 82 patients with T2DM. A re-angiography 6 months after the index percutaneous coronary intervention (PCI) revealed that 43% of the patients had a restenosis. In a multiple regression analysis, the only independent predictors of restenosis were fasting glucose before the PCI and previous myocardial infarction (odds ratio [OR] 1.44, 95% confidence interval [CI] 1.07—1.92; p = 0.015 and OR 8.00, 95% CI 2.49—25.67; p ≤ 0.001, respectively). None of the other markers remained as significant predictors. Conclusion: Fasting glucose prior to the PCI was an independent predictor of restenosis in patients with T2DM while analyses of a variety of markers related to inflammation and the adipo-insular axis did not add any further information.
No association of maternal vitamin E intake with higher risk of cardiovascular malformations in children: a population-based case–control study
Authors: Szilasi Mária , Bártfai Liza , Bártfai Zoltán , Bánhidy Ferenc , Czeizel Andrew E. 
Published: May 2011

Objective: In Hungary, vitamin E is frequently used to prevent repeated or threatened abortion. A previous study showed a higher risk of cardiovascular malformations in the children of pregnant women who had a high vitamin E intake either in their diet or by taking supplements. The objective was to examine this association. Methods: The Hungarian Case–Control Surveillance System of Congenital Abnormalities, 1980–1996, is a large, population-based dataset including 22,843 cases with congenital abnormalities, 38,151 healthy controls matched to the cases, and 834 patient controls with Down syndrome. Vitamin E treatment was compared in the mothers of these children. Results: The mothers of 1418 cases with congenital abnormalities (6.2%), 2267 controls (6.0%) and 43 patient controls (5.2%) had vitamin E treatment during pregnancy. A preliminary comparison of cases and controls showed a higher risk for four congenital abnormality groups, including cardiovascular malformations. However, if only prospectively and medically recorded vitamin E treatments in the prenatal maternity logbook were evaluated during the critical period of different congenital abnormalities, the higher risk for these congenital abnormalities was not found. Conclusions: The results of this study were based on relatively high-dose vitamin E intake in pregnant women and were not able to confirm the previously reported teratogenic effect of vitamin E.
Inferring functional modules of protein families with probabilistic topic models
Authors: Konietzny Sebastian GA , Dietz Laura , McHardy Alice C 
Published: May 2011

Abstract

Background
Genome and metagenome studies have identified thousands of protein families whose functions are poorly understood and for which techniques for functional characterization provide only partial information. For such proteins, the genome context can give further information about their functional context.

Results
We describe a Bayesian method, based on a probabilistic topic model, which directly identifies functional modules of protein families. The method explores the co-occurrence patterns of protein families across a collection of sequence samples to infer a probabilistic model of arbitrarily-sized functional modules.

Conclusions
We show that our method identifies protein modules - some of which correspond to well-known biological processes - that are tightly interconnected with known functional interactions and are different from the interactions identified by pairwise co-occurrence. The modules are not specific to any given organism and may combine different realizations of a protein complex or pathway within different taxa.