bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA13: Finding biomarkers of response to targeted cancer drugs through functional genetics
Authors: Bernards Rene 
Published: March 2013

Abstract
Unresponsiveness to therapy remains a significant problem in the treatment of cancer, also with the new classes of cancer drugs. In my laboratory, we use functional genetic approaches to identify biomarkers that can predict responsiveness to targeted cancer therapeutics; drugs that specifically inhibit molecules or pathways that are often activated in cancer. Nevertheless, it remains poorly explained why a significant number of tumors do not respond to these therapies. We aim to elucidate the molecular pathways that contribute to unresponsiveness to targeted cancer therapeutics using a functional genetic approach. This will yield biomarkers that may be useful to predict how individual patients will respond to these drugs. Furthermore, this work may allow the development of drugs that act in synergy with the established drug to prevent or overcome drug resistance.
To identify biomarkers that control tumor cell responsiveness to cancer therapeutics, we use multiple complementary approaches. First, we use genome wide loss-of-function genetic screens (with shRNA interference libraries) in cancer cells that are sensitive to the drug-of-interest to search for genes whose down-regulation confers resistance to the drug-of-interest (resistance screens). In addition, we use shRNA screens with a low dose of the drug to screen for genes whose inhibition enhances the toxicity of the cancer drug (sensitizer screens). As a third approach, we use gain of function genetic screens in which we search for genes whose over-expression modulates drug responsiveness. Once we have identified candidate drug response biomarkers in relevant cell line models, we ask if the expression of these genes is correlated with clinical response to the drug-of-interest. For this, we use tumor samples of cancer patients treated with the drug in question and whose response to therapy is documented.
In a fourth and distinct approach we perform high throughput sequencing of the “kinome” (some 600 genes) of tumor samples to identify connections between cancer genotype and drug responses.
Examples of these approaches to identify biomarkers of response to different cancer drugs will be presented.
Abstract IA15: VEGF-targeted therapies: Biomarkers, biology, and understanding resistance
Authors: Ellis Lee M. 
Published: March 2013

Abstract
Despite major advances in the clinical development of VEGF-targeted therapy, most patients' tumors are considered to be inherently resistant. When response is obtained, the benefit of VEGF inhibitors is transient, lasting weeks to months, in contrast to the original hypothesis that cancer would be converted to a chronic disease with this therapeutic approach. The mechanisms of action of this class of drugs vary among tumor types and therefore resistance mechanisms and biomarkers are likely to be tumor-type specific. Clinical studies have begun to uncover potential biomarkers that require validation in prospective studies. For example, data reported at the 2011 ESMO meeting suggested that circulating VEGF, as detected by a new ELISA, may be able to determine the population of patients likely to benefit from the use of bevacizumab, in some, but not all studies. In addition, several clinical studies reported this past year have shown that continued VEGF-inhibition through multiple lines of therapy may be of benefit to patients. These clinical studies suggest that resistance may be a relative term: although patients eventually progress, continued VEGF inhibition beyond initial progression may be of clinical benefit in selected patients. There is much work to be done in the field of biomarkers for VEGF-targeted therapies, but these recent clinical studies provide insights that will hopefully provide the foundation for significant improvements in patient outcomes.
Abstract IA3: PI3K inhibitors in ER+ breast cancer: Next steps
Authors: Ellis Matthew J. , Crowder Robert , Ma Cynthia X. 
Published: March 2013

Abstract
Gain and loss of function mutations in the PI3 kinase pathway are extremely common in breast cancer and can be seen in all five intrinsic subtypes (Luminal A, Luminal B, HER2+, Basal-like and Claudin Low). However there is a subtype-selective spectrum of activation events including gain of kinase mutations/amplifications (e.g. PIK3CA, HER2 and AKT1) and loss of negative regulators (e.g.PTEN, INPP4B and PIK3R 1). These lesions must be matched to a large number of agents in development that target PI3K, AKT and mTOR. These agents have variable specificities, toxicities, pharmacokinetics and administration routes which affect the development of combinations with standard therapies and also with each other. In keeping with very broad clinical opportunities, positive findings in preclinical models in both luminal and basal-like breast cancer will be presented. Ongoing clinical trial designs will also be discussed and biomarker approaches for patient selection and stratification will be considered.
Abstract IA6: Targeting PI3K in cancer, mechanistic insights from genetic mouse models
Authors: Zhao Jean J. 
Published: March 2013

Abstract
The class 1a phosphatidylinositol 3-kinase (PI3K) signaling pathway is frequently activated in human cancer by a number of mechanisms, including amplification and/or activation of RTKs (receptor tyrosine kinases), loss of PTEN (phosphatase and tensin homologue) function and somatic mutation in the PIK3CA gene that encodes the p110α catalytic subunit of PI3K. Thus PI3K represents an attractive target for cancer therapy and tremendous efforts are being devoted to developing effective PI3K inhibitors for cancer treatment. Despite the great promise of targeted therapy, drug resistance is likely to develop, causing treatment failure. To elucidate resistance mechanisms to PI3K-targeted therapy, we constructed mouse models of breast cancer and brain tumors conditionally expressing an oncogenic allele of PIK3CA. Interestingly, we found that oncogenic PIK3CA-driven tumors in both mammary gland and brain tissues frequently recur in PI3K pathway-dependent and -independent manners. Genomic and functional analyses of recurrent tumors revealed multiple lesions, providing mechanistic insights for tumor recurrence and resistance to PI3K-targeted therapy.
Abstract PR4: Incomplete inhibition of phosphorylation of 4EBP1 is a mechanism for KRAS driven resistance to the ATP-competitive mTOR inhibitor PP242 in colorectal cancer
Authors: Ducker Gregory S. , Atreya Chloe E. , Shokat Kevan M. , Warren Robert S. 
Published: March 2013

Abstract
The mammalian target of rapamycin (mTOR) regulates cell growth by integrating nutrient and growth factor signaling and has been strongly implicated in cancer. But mTOR is not an oncogene, and which tumors will be resistant and sensitive to new ATP-competitive mTOR inhibitors now in clinical trials remains unknown. We screened a panel of 357 human cancer cell lines to identify common markers of resistance and sensitivity to the mTOR inhibitor PP242. Analysis by tissue of origin and genetic mutation revealed colorectal origin as the most statistically significant marker for resistance to therapy, while KRAS and PI3K mutations were the most significant genetic markers for resistance and sensitivity respectively. Notably, KRAS mutations are overrepresented in colorectal cancer (CRC) cell lines. Within CRC cell lines, those with KRAS mutations were most resistant to PP242 while those with other mutations were more sensitive; cell lines with co-mutation of PI3K and KRAS had intermediate sensitivity. Immunoblot analysis of the signaling networks downstream of mTOR revealed that the degree of cellular growth inhibition induced by PP242 was directly correlated with inhibition of phosphorylation of the translational repressor eIF4E binding protein 1 (4EBP1), but not ribosomal protein S6. We were able to recapitulate these observations using a pair of KRAS mutant isogenic cell lines differing only by a PI3K mutation. PP242 treatment of the PI3K mutant cell line increased the observed inhibition of 4EBP1 phosphorylation and improved the drug response. In an efficacy trial of PP242 in primary CRC xenograft tumors, resistance to inhibition of 4EBP1 phosphorylation was again observed in KRAS mutant tumors and these tumors responded poorly compared to KRAS WT controls. We show that, in the absence of PI3K co-mutation, KRAS mutations are associated with resistance to PP242 and that this is specifically linked to changes in the 4EBP1 phosphorylation state in both CRC cell lines and primary patient xenografts.
This proffered talk is also presented as Poster A35.
Effects of Lycopene on Protein Expression in Human Primary Prostatic Epithelial Cells
Authors: Qiu Xi , Yuan Yang , Vaishnav Avani , Tessel Michael A. , Nonn Larisa , van Breemen Richard B. 
Published: March 2013

AbstractClinical trials and animal studies have suggested that lycopene, the red carotenoid found in tomatoes, might be useful for the prevention of prostate cancer in the diet or as a dietary supplement through a variety of chemoprevention mechanisms. As most mechanism of action studies have used prostate cancer cells or males with existing prostate cancer, we investigated the effects of lycopene on protein expression in human primary prostatic epithelial cells. After treatment with lycopene at a physiologically relevant concentration (2 μmol/L) or placebo for 48 hours, the primary prostatic epithelial cells were lysed and fractionated using centrifugation into cytosolic/membrane and nuclear fractions. Proteins from lycopene-treated and placebo-treated cells were trypsinized and derivatized for quantitative proteomics using isobaric tags for relative and absolute quantitation (iTRAQ) reagent. Peptides were analyzed using two-dimensional microcapillary high-performance liquid chromatography-tandem mass spectrometry to identify proteins that were significantly upregulated or downregulated following lycopene exposure. Proteins that were most affected by lycopene were those involved in antioxidant responses, cytoprotection, apoptosis, growth inhibition, androgen receptor signaling, and the Akt/mTOR cascade. These data are consistent with previous studies suggesting that lycopene can prevent cancer in human prostatic epithelial cells at the stages of cancer initiation, promotion, and/or progression. Cancer Prev Res; 6(5); 419–27. ©2013 AACR.
Is Lycopene an Effective Agent for Preventing Prostate Cancer?
Authors: Sporn Michael B. , Liby Karen T. 
Published: March 2013

Abstract
The role of lycopene, an open-chain carotenoid found in tomatoes and devoid of retinoid activity, as an anticarcinogenic, chemopreventive agent, especially for use in prostate cancer, is still under active investigation. In this issue, Qui and colleagues show that lycopene induces responses in human prostate epithelial cells that are antiproliferative, antioxidative, and anti-inflammatory, as well as downregulating targets in the androgen receptor signaling pathway. In this perspective, we review aspects of the molecular and cellular biology of lycopene that support its use for prevention of prostate cancer. Whether lycopene itself or its metabolites induce most of its benefits is still uncertain. At present, meta-analysis of clinical studies of lycopene for prevention of prostate cancer in men does not yet support the definitive clinical use of this carotenoid in a preventive setting. Cancer Prev Res; 6(5); 384–6. ©2013 AACR.
Centers for Cardiovascular Outcomes Research
Authors: Cook Nakela L. , Bonds Denise E. , Kiefe Catarina I. , Curtis Jeptha P. , Krumholz Harlan M. , Kressin Nancy R. , Peterson Eric D. 
Published: March 2013

Background—
Recognizing the value of outcomes research to understand and bridge translational gaps, to establish evidence in clinical practice and delivery of medicine, and to generate new hypotheses on ongoing questions of treatment and care, the National Heart, Lung, and Blood Institute of the National Institutes of Health established the Centers for Cardiovascular Outcomes Research program in 2010.

Methods and Results—
The National Heart, Lung, and Blood Institute funded 3 centers and a research coordinating unit. Each center has an independent project focus, including (1) characterizing care transition and predicting clinical events and quality of life for patients discharged after an acute coronary syndrome; (2) identifying center and regional factors associated with better patient outcomes across several cardiovascular conditions and procedures; and (3) examining the impact of healthcare reform in Massachusetts on overall and disparate care and outcomes for several cardiovascular conditions and venous thromboembolism. Cross-program collaborations seek to advance the field methodologically and to develop early-stage investigators committed to careers in outcomes research.

Conclusions—
The Centers for Cardiovascular Outcomes Research program represents a significant investment in cardiovascular outcomes research by the National Heart, Lung, and Blood Institute. The vision of this program is to leverage scientific rigor and cross-program collaboration to advance the science of healthcare delivery and outcomes beyond what any individual unit could achieve alone.
Quantifying the Effect of Cardiopulmonary Resuscitation Quality on Cardiac Arrest Outcome
Authors: Wallace Sarah K. , Abella Benjamin S. , Becker Lance B. 
Published: March 2013

Background—
Evidence has accrued that cardiopulmonary resuscitation quality affects cardiac arrest outcome. However, the relative contributions of chest compression components (such as rate and depth) to successful resuscitation remain unclear.

Methods and Results—

We sought to measure the effect of cardiopulmonary resuscitation quality on cardiac arrest outcome through systematic review and meta-analysis. We searched for any clinical study assessing cardiopulmonary resuscitation performance on adult cardiac arrest patients in which survival was a reported outcome, either return of spontaneous circulation or survival to admission or discharge. Of 603 identified abstracts, 10 studies met inclusion criteria. Effect sizes were reported as mean differences. Missing data were resolved by author contact. Estimates were segregated by cardiopulmonary resuscitation metric (chest compression rate, depth, no-flow fraction, and ventilation rate), and a random-effects model was applied to estimate an overall pooled effect. Arrest survivors were significantly more likely to have received deeper chest compressions than nonsurvivors (mean difference, 2.44 mm; 95% confidence interval, 1.19–3.69 [
P
<0.001]; n=6 studies;
I
2
=0.0%;
P
for heterogeneity=0.9). Likewise, survivors were significantly more likely to have received chest compression rates closer to 85 to 100 compressions per minute (cpm) than nonsurvivors (absolute mean difference from 85 cpm, −4.81 cpm; 95% confidence interval, −8.19 to −1.43 [
P
=0.005]; from 100 cpm, −5.04 cpm; 95% confidence interval, −8.44 to −1.65 [
P
=0.004]; n=6 studies;
I
2
<49%;
P
for heterogeneity >0.2). No significant difference in no-flow fraction (n=7 studies) or ventilation rate (n=4 studies) was detected between survivors and nonsurvivors.

Conclusions—
Deeper chest compressions and rates closer to 85 to 100 cpm are significantly associated with improved survival from cardiac arrest.
Priorities for Comparative Effectiveness Reviews in Cardiovascular Disease
Authors: Eapen Zubin J. , McBroom Amanda J. , Gray Rebecca , Musty Michael D. , Hadley Corey , Hernandez Adrian F. , Sanders Gillian D. 
Published: March 2013

Background—
Comparative effectiveness reviews offer a systematic method to critically appraise existing research and to identify unaddressed clinical areas in cardiovascular disease where significant morbidity, mortality, and variation in the use of resources persist. To delineate and help select areas where comparative effectiveness reviews are needed, the Effective Health Care Program of the Agency for Healthcare Research and Quality involved stakeholders in prioritization of the research agenda.

Methods and Results—
We involved a diverse panel of stakeholders representing a broad range of clinical, policy, and patient perspectives. To assist in prioritization of topics for evidence synthesis, we created a framework evaluating 12 cardiovascular disease subcategories that reflect American College of Cardiology/American Heart Association disease-based guidelines. We performed an environmental scan for each disease subcategory to populate this framework with existing knowledge, levels of evidence, and degrees of public interest. Through a formalized process, 4 disease subcategories were prioritized: chronic coronary artery disease, ventricular arrhythmias, heart failure, and cerebrovascular disease. Within these subcategories, 11 topics that address the comparative safety and effectiveness of existing treatments and evaluate emerging treatments were nominated by the stakeholder panel to proceed for feasibility assessment before developing comparative effectiveness reviews.

Conclusions—
Using a systematic process deriving consensus from multiple stakeholders across cardiovascular disease states, we generated a prioritized list of evidence synthesis topics to inform decision makers. The topics vetted through this process seek to determine the comparative safety and effectiveness of a range of treatments, both established and emerging, and are immediately relevant for prevalent disease states.
The UK National Health Service
Authors: Hawkins Nathaniel M. , Scholes Shaun , Bajekal Madhavi , Love Hande , O’Flaherty Martin , Raine Rosalind , Capewell Simon 
Published: March 2013

Background—
Social gradients in cardiovascular mortality across the United Kingdom may reflect differences in incidence, disease severity, or treatment. It is unknown whether a universal healthcare system delivers equitable lifesaving medical therapy for coronary heart disease. We therefore examined secular trends in the use of key medical therapies stratified by socioeconomic circumstances across a broad spectrum of coronary disease presentations, including acute coronary syndromes, secondary prevention, and clinical angina.

Methods and Results—
This was a cross-sectional observational analysis of nationally representative primary and secondary care data from the United Kingdom. Data on treatments for all myocardial infarction patients in 2003 and 2007 were derived from the Myocardial Ischemia National Audit Project (n=51 755). Data on treatments for patients with chronic angina (n=33 211) or requiring secondary prevention (n=32 976) in 1999 and 2007 were extracted from the General Practice Research Database. Socioeconomic circumstances were defined using a weighted composite of 7 area-level deprivation domains. Treatment estimates were age-standardized. Use of all therapies increased in all patient groups, both men and women. Improvements were most marked in primary care, where use of β-blockers, statins, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for secondary prevention and treatment of angina doubled, from ≈30% to >60%. Small age gradients persisted for some therapies. No consistent socioeconomic gradients or sex differences were observed for myocardial infarction and postrevascularization (hard diagnoses). However, some sex inequality was apparent in the treatment of younger women with angina.

Conclusions—
Cardiovascular treatment is generally equitable and independent of socioeconomic circumstances. Future strategies should aim to further increase overall treatment levels and to eradicate remaining age and sex inequalities.
Impact of Aortic Stenosis on Postoperative Outcomes After Noncardiac Surgeries
Authors: Agarwal Shikhar , Rajamanickam Anitha , Bajaj Navkaranbir S. , Griffin Brian P. , Catacutan Thadeo , Svensson Lars G. , Anabtawi Abdel G. , Tuzcu E. Murat , Kapadia Samir R. 
Published: March 2013

Background—
Preoperative management of patients with aortic stenosis (AS) who need noncardiac surgery (NCS) remains controversial. We sought to determine the impact of AS on the postoperative outcomes after NCS.

Methods and Results—

Patients undergoing NCS with moderate AS (valve area: 1.0–1.5 cm
2
) or severe AS (valve area: <1.0 cm
2
) were identified using the surgical and the echocardiographic databases. Using propensity score analysis, we obtained 4 matched control patients without AS for each patient with AS undergoing NCS. The propensity score matching used the 6 revised cardiac risk index criteria, in addition to age and sex. Primary outcome was a composite of 30-day mortality and postoperative myocardial infarction. We matched 634 patients with AS undergoing NCS to 2536 controls. There were 244 patients with severe AS and 390 patients with moderate AS. Thirty-day mortality was 2.1% for AS patients compared with 1.0% in non-AS controls (
P
=0.036). Postoperative myocardial infarction was more frequent in patients with AS compared with controls (3.0% versus 1.1%;
P
=0.001). Combined primary outcome was significantly worse for both moderate and severe AS patients compared with respective controls (4.4% versus 1.7%;
P
=0.002; and 5.7% versus 2.7%;
P
=0.02, respectively). High-risk surgery, symptomatic severe AS, coexisting mitral regurgitation, and preexisting coronary disease were significant predictors of primary outcome in patients with AS.

Conclusion—
Presence of AS adversely affects postoperative outcomes among patients undergoing NCS, evidenced by a higher 30-day mortality and postoperative myocardial infarction after NCS.
Smoking, Surgery, and Venous Thromboembolism Risk in Women
Authors: Sweetland Siân , Parkin Lianne , Balkwill Angela , Green Jane , Reeves Gillian , Beral Valerie 
Published: March 2013

Background—
Evidence about the effect of smoking on venous thromboembolism risk, generally and in the postoperative period, is limited and inconsistent. We examined the incidence of venous thromboembolism in relation to smoking habits, both in the absence of surgery and in the first 12 postoperative weeks, in a large prospective study of women in the United Kingdom.

Methods and Results—
During 6 years’ follow-up of 1 162 718 women (mean age 56 years), 4630 were admitted to hospital for or died of venous thromboembolism. In the absence of surgery, current smokers had a significantly increased incidence of venous thromboembolism compared with never-smokers (adjusted relative risk 1.38, 95% confidence interval 1.28–1.48), with significantly greater risks in heavier than lighter smokers (relative risks 1.47 [95% confidence interval 1.34–1.62] and 1.29 [95% confidence interval 1.17–1.42] for ≥15 versus <15 cigarettes per day). Current smokers were also more likely to have surgery than never-smokers (relative risk 1.12, 95% confidence interval 1.12–1.13). Among women who had surgery, the incidence of venous thromboembolism in the first 12 postoperative weeks was significantly greater in current than never-smokers (relative risk 1.16, 95% confidence interval 1.02–1.30).

Conclusions—
Venous thromboembolism incidence was increased in current smokers, both in the absence of surgery and in the 12 weeks after surgery. Smoking is another factor to consider in the assessment of venous thromboembolism risk in patients undergoing surgery.