bluuebunny/crossref_metadata_2025_split huggingface dataset:
Changing Inequalities in Cervical Cancer: Modeling the Impact of Vaccine Uptake, Vaccine Herd Effects, and Cervical Cancer Screening in the Post-Vaccination Era
Authors: Malagón Talía , Drolet Mélanie , Boily Marie-Claude , Laprise Jean-François , Brisson Marc 
Published: November 2014

AbstractBackground: Inequalities in cervical cancer may be increased following mass vaccination against the human papillomavirus (HPV) if girls with low vaccine uptake also have low future participation in cervical cancer screening. We evaluated how vaccine uptake distribution affects inequalities in squamous cell carcinoma (SCC) incidence between groups with different screening participation.Methods: We used an individual-based transmission dynamic model of HPV infection and disease (HPV-ADVISE). Females were stratified by routine screening frequency. We modeled the impact of vaccination on SCC incidence rate differences (absolute inequality) and incidence rate ratios (relative inequality) between women who have routine screening intervals of &lt;5 years (frequently screened), ≥5 years (underscreened), and who are never screened. We compared simulations with uniform vaccine uptake with scenarios with unequal vaccine uptake, in which never and underscreened women have lower vaccine uptake than frequently screened women.Results: Absolute SCC inequalities between groups with different screening rates were predicted to decrease after vaccination, even when women with the lowest screening participation had the lowest vaccine uptake. Herd effects helped reduce absolute inequalities when vaccine uptake was unequal. Conversely, relative SCC inequalities remained unchanged or increased after vaccination. Results were robust to different overall vaccination coverages and sexual mixing scenarios.Conclusion: Though mass HPV vaccination is predicted to substantially decrease SCC incidence rates, never screened women will still have the highest disease burden after vaccination.Impact: To reduce both absolute and relative SCC inequalities, public health initiatives will need to address inequalities in both vaccine uptake and in cervical cancer screening participation. Cancer Epidemiol Biomarkers Prev; 24(1); 276–85. ©2014 AACR.
Deregulation of the PP2A Inhibitor SET Shows Promising Therapeutic Implications and Determines Poor Clinical Outcome in Patients with Metastatic Colorectal Cancer
Authors: Cristóbal Ion , Rincón Raúl , Manso Rebeca , Caramés Cristina , Zazo Sandra , Madoz-Gúrpide Juan , Rojo Federico , García-Foncillas Jesús 
Published: November 2014

Abstract
Purpose: SET is an endogenous PP2A inhibitor that might represent a novel molecular target for antitumor therapy. The aim of this study was to evaluate the molecular effects of SET deregulation and its potential clinical significance in metastatic colorectal cancer (mCRC).
Experimental Design: We studied the biologic effects of SET on cell growth, colonosphere formation, caspase activity, PP2A activation status, and sensitivity to oxaliplatin and FTY720 treatments. Moreover, we analyzed SET expression by immunostaining in 242 patients with mCRC.
Results: SET deregulation promotes cell growth and colonosphere formation and inhibits PP2A, thereby impairing its antitumor effects. Moreover, SET reduces sensitivity to oxaliplatin in colorectal cancer cell lines, which is restored after FTY720 treatment. SET overexpression was detected in 24.8% (60 of 242) of patients with mCRC and determined significantly shorter overall (8.6 vs. 27 months; P &lt; 0.001) and progression-free survival (7.1 vs. 13.7 months; P &lt; 0.001), and poor response to oxaliplatin-based chemotherapy (P = 0.004). Interestingly, its prognostic value was particularly evident in patients younger than 70 years and in those harboring KRAS mutations.
Conclusions: SET overexpression is a frequent event in mCRC that plays a potential oncogenic role associated with worse outcome and resistance to oxaliplatin. Moreover, this alteration defines a subgroup of patients who could benefit from therapies containing PP2A activators such as FTY720. Clin Cancer Res; 21(2); 347–56. ©2014 AACR.
Podoplanin-Positive Cancer-Associated Fibroblasts in the Tumor Microenvironment Induce Primary Resistance to EGFR-TKIs in Lung Adenocarcinoma with EGFR Mutation
Authors: Yoshida Tatsuya , Ishii Genichiro , Goto Koichi , Neri Shinya , Hashimoto Hiroko , Yoh Kiyotaka , Niho Seiji , Umemura Shigeki , Matsumoto Shingo , Ohmatsu Hironobu , Iida Shinsuke , Niimi Akio , Nagai Kanji , Ohe Yuichiro , Ochiai Atsushi 
Published: November 2014

Abstract
Purpose: The biologic characteristics of microenvironmental constituents, especially cancer-associated fibroblasts (CAF), can be key regulators of the cellular sensitivity to molecular-targeted therapy. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) have marked therapeutic effects against non–small cell lung cancer (NSCLC) with EGFR mutations, but some patients have exhibited primary resistance to EGFR-TKIs. We recently reported that podoplanin-positive fibroblasts are associated with a tumor-promoting phenotype of CAFs in lung adenocarcinoma. The aim of this study was to evaluate whether the susceptibility of NSCLC to EGFR-TKIs could be affected by podoplanin-expressing CAFs.
Experimental Design: We evaluated the EGFR-TKI sensitivity of EGFR-mutant lung adenocarcinoma cell lines cocultured with podoplanin-expressing CAFs. We also examined the association between the expression of podoplanin in CAFs in surgical specimens and EGFR-TKI response of postoperative recurrent patients with EGFR mutations (N = 106).
Results: Lung adenocarcinoma cell lines became more resistant to EGFR-TKI when cocultured with podoplanin-expressing CAFs, compared with control CAFs in vitro. The knockdown of podoplanin expression on CAFs cancelled the resistance to EGFR-TKIs in cancer cells. Compared with control CAFs, the cancer cells that were cocultured with podoplanin-positive CAFs continued to exhibit significantly higher p-ERK levels after treatment with gefitinib. Furthermore, postoperative recurrent patients with podoplanin-positive CAFs had a significantly lower overall response rate to EGFR-TKIs compared with those with podoplanin-negative CAFs (53% vs. 83%; P &lt; 0.01).
Conclusions: Podoplanin-positive CAFs play an important role in primary resistance to EGFR-TKIs and may be an ideal therapeutic target for use in combination therapy with EGFR-TKIs. Clin Cancer Res; 21(3); 642–51. ©2014 AACR.
A Phase I Monotherapy Study of RG7212, a First-in-Class Monoclonal Antibody Targeting TWEAK Signaling in Patients with Advanced Cancers
Authors: Lassen Ulrik N. , Meulendijks Didier , Siu Lilian L. , Karanikas Vaios , Mau-Sorensen Morten , Schellens Jan H.M. , Jonker Derek J. , Hansen Aaron R. , Simcox Mary E. , Schostack Kathleen J. , Bottino Dean , Zhong Hua , Roessler Markus , Vega-Harring Suzana M. , Jarutat Tiantom , Geho David , Wang Ka , DeMario Mark , Goss Glenwood D. 
Published: November 2014

Abstract
Purpose: Tumor necrosis factor (TNF)–like weak inducer of apoptosis (TWEAK) and fibroblast growth factor-inducible molecule 14 (Fn14) are a ligand–receptor pair frequently overexpressed in solid tumors. TWEAK:Fn14 signaling regulates multiple oncogenic processes through MAPK, AKT, and NFκB pathway activation. A phase I study of RG7212, a humanized anti-TWEAK IgG1κ monoclonal antibody, was conducted in patients with advanced solid tumors expressing Fn14.
Experimental Design: Dose escalations, over a 200- to 7,200-mg range, were performed with patients enrolled in weekly (QW), bi-weekly (Q2W), or every-three-week (Q3W) schedules. Primary objectives included determination of dose and safety profile. Secondary endpoints included assessments related to inhibition of TWEAK:Fn14 signaling, tumor proliferation, tumor immune cell infiltration, and pharmacokinetics.
Results: In 192 treatment cycles administered to 54 patients, RG7212 was well-tolerated with no dose-limiting toxicities observed. More than 95% of related adverse events were limited to grade 1/2. Pharmacokinetics were dose proportional for all cohorts, with a t1/2 of 11 to 12 days. Pharmacodynamic changes included clearance of free and total TWEAK ligand and reductions in tumor Ki-67 and TRAF1. A patient with BRAF wild-type melanoma who received 36 weeks of RG7212 therapy had tumor regression and pharmacodynamic changes consistent with antitumor effects. Fifteen patients (28%) received 16 or more weeks of RG7212 treatment.
Conclusion: RG7212 demonstrated excellent tolerability and favorable pharmacokinetics. Pharmacodynamic endpoints were consistent with reduced TWEAK:Fn14 signaling. Tumor regression was observed and prolonged stable disease was demonstrated in multiple heavily pretreated patients with solid tumors. These encouraging results support further study of RG7212. Clin Cancer Res; 21(2); 258–66. ©2014 AACR.
Significant Association of Oncogene YAP1 with Poor Prognosis and Cetuximab Resistance in Colorectal Cancer Patients
Authors: Lee Keun-Wook , Lee Sung Sook , Kim Sang-Bae , Sohn Bo Hwa , Lee Hyun-Sung , Jang Hee-Jin , Park Yun-Yong , Kopetz Scott , Kim Sung Soo , Oh Sang Cheul , Lee Ju-Seog 
Published: November 2014

Abstract
Purpose: Activation of YAP1, a novel oncogene in the Hippo pathway, has been observed in many cancers, including colorectal cancer. We investigated whether activation of YAP1 is significantly associated with prognosis or treatment outcomes in colorectal cancer.
Experimental Design: A gene expression signature reflecting YAP1 activation was identified in colorectal cancer cells, and patients with colorectal cancer were stratified into two groups according to this signature: activated YAP1 colorectal cancer (AYCC) or inactivated YAP1 colorectal cancer (IYCC). Stratified patients in five test cohorts were evaluated to determine the effect of the signature on colorectal cancer prognosis and response to cetuximab treatment.
Results: The activated YAP1 signature was associated with poor prognosis for colorectal cancer in four independent patient cohorts with stage I–III disease (total n = 1,028). In a multivariate analysis, the impact of the YAP1 signature on disease-free survival was independent of other clinical variables [hazard ratio (HR), 1.63; 95% confidence interval (CI), 1.25–2.13; P &lt; 0.001]. In patients with stage IV colorectal cancer and wild-type KRAS, IYCC patients had a better disease control rate and progression-free survival (PFS) after cetuximab monotherapy than did AYCC patients; however, in patients with KRAS mutations, PFS duration after cetuximab monotherapy was not different between IYCC and AYCC patients. In multivariate analysis, the effect of YAP1 activation on PFS was independent of KRAS mutation status and other clinical variables (HR, 1.82; 95% CI, 1.05–3.16; P = 0.03).
Conclusions: Activation of YAP1 is highly associated with poor prognosis for colorectal cancer and may be useful in identifying patients with metastatic colorectal cancer resistant to cetuximab. Clin Cancer Res; 21(2); 357–64. ©2014 AACR.
The NEDD8-Activating Enzyme Inhibitor MLN4924 Disrupts Nucleotide Metabolism and Augments the Efficacy of Cytarabine
Authors: Nawrocki Steffan T. , Kelly Kevin R. , Smith Peter G. , Keaton Mignon , Carraway Hetty , Sekeres Mikkael A. , Maciejewski Jaroslaw P. , Carew Jennifer S. 
Published: November 2014

Abstract
Purpose: New therapies are urgently needed for patients with acute myelogenous leukemia (AML). The novel NEDDylation inhibitor MLN4924 (pevonedistat) has demonstrated significant preclinical antileukemic activity and preliminary efficacy in patients with AML in a phase I trial. On the basis of its antimyeloid and DNA-damaging properties, we investigated the ability of MLN4924 to augment conventional cytarabine (ara-C) therapy.
Experimental Design: The effects of MLN4924/ara-C on viability, clonogenic survival, apoptosis, DNA damage, and relevant pharmacodynamic targets were determined. The efficacy and pharmacodynamics of MLN4924/ara-C were assessed in an AML xenograft model.
Results: Cotreatment of AML cell lines and primary patient specimens with MLN4924 and ara-C led to diminished clonogenic survival, increased apoptosis, and synergistic levels of DNA damage. RNAi demonstrated that stabilization of CDT-1, an event previously shown to mediate the DNA-damaging effects of MLN4924, was not a key regulator of sensitivity to the MLN4924/ara-C combination. Global metabolic profiling revealed that MLN4924 disrupts nucleotide metabolism and depletes intracellular nucleotide pools in AML cells. Subsequent experiments showed that MLN4924 promoted increased incorporation of ara-C into the DNA of AML cells. This effect as well as the therapeutic benefit of the MLN4924/ara-C combination was antagonized by supplementation with the nucleotide building block ribose. Coadministration of MLN4924 and ara-C to mice bearing FLT3-ITD+ AML xenografts stably inhibited disease progression and increased DNA damage in vivo.
Conclusions: Our findings provide strong rationale for clinical investigation of the MLN4924/ara-C combination and establish a new link between therapeutic inhibition of NEDDylation and alterations in nucleotide metabolism. Clin Cancer Res; 21(2); 439–47. ©2014 AACR.
Darinaparsin Inhibits Prostate Tumor–Initiating Cells and Du145 Xenografts and Is an Inhibitor of Hedgehog Signaling
Authors: Bansal Nitu , Farley Nadine Johnson , Wu Lisa , Lewis Jonathan , Youssoufian Hagop , Bertino Joseph R. 
Published: November 2014

Abstract
Prostate cancer is the leading cause of cancer-related death in men in the United States. A major cause of drug resistance in prostate and other epithelial tumors may be due to the presence of a fraction of tumor cells that retain the ability to initiate tumors and hence are termed tumor-initiating cells (TIC) or cancer stem cells. Here, we report that darinaparsin, an organic derivative of arsenic trioxide, is cytotoxic to prostate cancer cell lines as well as fresh prostate cancer cells from patients at low micromolar concentrations, and importantly inhibits the TIC subpopulations. It also inhibits growth of the castrate-resistant Du145 prostate tumor propagated as xenograft in mice and inhibits the tumor-initiating potential of prostate cancer cells. Although the mechanism by which darinaparsin acts is not completely known, we show that it kills prostate cancer cells by blocking cells in the G2–M phase of the cell cycle and inhibits Hedgehog signaling by downregulating Gli-2 transcriptional activity. These data provide a rationale for evaluating darinaparsin in patients with castrate-resistant prostate cancer. Mol Cancer Ther; 14(1); 23–30. ©2014 AACR.
A Multiplexable, Microfluidic Platform for the Rapid Quantitation of a Biomarker Panel for Early Ovarian Cancer Detection at the Point-of-Care
Authors: Shadfan Basil H. , Simmons Archana R. , Simmons Glennon W. , Ho Andy , Wong Jorge , Lu Karen H. , Bast Robert C. , McDevitt John T. 
Published: November 2014

Abstract
Point-of-care (POC) diagnostic platforms have the potential to enable low-cost, large-scale screening. As no single biomarker is shed by all ovarian cancers, multiplexed biomarker panels promise improved sensitivity and specificity to address the unmet need for early detection of ovarian cancer. We have configured the programmable bio-nano-chip (p-BNC)—a multiplexable, microfluidic, modular platform—to quantify a novel multi-marker panel comprising CA125, HE4, MMP-7, and CA72-4. The p-BNC is a bead-based immunoanalyzer system with a credit-card–sized footprint that integrates automated sample metering, bubble and debris removal, reagent storage and waste disposal, permitting POC analysis. Multiplexed p-BNC immunoassays demonstrated high specificity, low cross-reactivity, low limits of detection suitable for early detection, and a short analysis time of 43 minutes. Day-to-day variability, a critical factor for longitudinally monitoring biomarkers, ranged between 5.4% and 10.5%, well below the biologic variation for all four markers. Biomarker concentrations for 31 late-stage sera correlated well (R2 = 0.71 to 0.93 for various biomarkers) with values obtained on the Luminex platform. In a 31 patient cohort encompassing early- and late-stage ovarian cancers along with benign and healthy controls, the multiplexed p-BNC panel was able to distinguish cases from controls with 68.7% sensitivity at 80% specificity. Utility for longitudinal biomarker monitoring was demonstrated with prediagnostic plasma from 2 cases and 4 controls. Taken together, the p-BNC shows strong promise as a diagnostic tool for large-scale screening that takes advantage of faster results and lower costs while leveraging possible improvement in sensitivity and specificity from biomarker panels. Cancer Prev Res; 8(1); 37–48. ©2014 AACR.
Afucosylated Antibodies Increase Activation of FcγRIIIa-Dependent Signaling Components to Intensify Processes Promoting ADCC
Authors: Liu Scot D. , Chalouni Cecile , Young Judy C. , Junttila Teemu T. , Sliwkowski Mark X. , Lowe John B. 
Published: November 2014

AbstractAntibody-dependent cellular cytotoxicity (ADCC) is a key mechanism by which therapeutic antibodies mediate their antitumor effects. The absence of fucose on the heavy chain of the antibody increases the affinity between the antibody and FcγRIIIa, which results in increased in vitro and in vivo ADCC compared with the fucosylated form. However, the cellular and molecular mechanisms responsible for increased ADCC are unknown. Through a series of biochemical and cellular studies, we find that human natural killer (NK) cells stimulated with afucosylated antibody exhibit enhanced activation of proximal FcγRIIIa signaling and downstream pathways, as well as enhanced cytoskeletal rearrangement and degranulation, relative to stimulation with fucosylated antibody. Furthermore, analysis of the interaction between human NK cells and targets using a high-throughput microscope-based antibody-dependent cytotoxicity assay shows that afucosylated antibodies increase the number of NK cells capable of killing multiple targets and the rate with which targets are killed. We conclude that the increase in affinity between afucosylated antibodies and FcγRIIIa enhances activation of signaling molecules, promoting cytoskeletal rearrangement and degranulation, which, in turn, potentiates the cytotoxic characteristics of NK cells to increase efficiency of ADCC. Cancer Immunol Res; 3(2); 173–83. ©2014 AACR.
Access Site Complications After Peripheral Vascular Interventions
Authors: Ortiz Daniel , Jahangir Arshad , Singh Maharaj , Allaqaband Suhail , Bajwa Tanvir K. , Mewissen Mark W. 
Published: November 2014

Background—
Access site hematomas and pseudoaneurysms are the most frequent complications of peripheral vascular intervention (PVI); however, their incidence and risk factors remain unclear.

Methods and Results—

We retrospectively analyzed data from the multicenter Vascular Quality Initiative on 22 226 patients who underwent 27 048 PVI from August 2007 to May 2013. Primary end points included incidence and predictors of access site complications (ASCs), length of postprocedural hospitalization, discharge status, and 30-day and 1-year mortality. ASC complicated 936 procedures (3.5%). Of these, 74.4% were minor complications, 9.7% were moderate requiring transfusion, 5.4% were moderate requiring thrombin injection, and 10.5% were severe requiring surgery. Predictors of ASC were age >75 years, female sex, white race, no prior PVI, nonfemoral arterial access site, >6-Fr sheath size, thrombolytics, arterial dissection, fluoroscopy time >30 minutes, nonuse of vascular closure device, bedridden preoperative ambulatory status, and urgent indication. Mean hospitalization was longer after procedures complicated by ASC (1.2±1.6 versus 1.9±1.9 days; range, 0–7 days;
P
=0.002). Severity of ASC correlated with higher rates of discharge to rehabilitation/nursing facilities compared with home discharge. Patients with severe ASC had higher 30-day mortality (6.1% versus 1.4%;
P
<0.001), and those with moderate ASC requiring transfusion had elevated 1-year mortality (12.1% versus 5.7%;
P
<0.001).

Conclusions—
Several factors independently predict ASC after PVI. Appropriate use of antithrombotic therapies and vascular closure device in patients at increased risk of ASC may improve post-PVI outcomes.
Hospital-Level Variation in Angina and Mortality at 1 Year After Myocardial Infarction
Authors: Vigen Rebecca , Spertus John A. , Maddox Thomas M. , Ho P. Michael , Jones Philip G. , Arnold Suzanne V. , Masoudi Frederick A. , Bradley Steven M. 
Published: November 2014

Background—
Despite calls to expand measurement of acute myocardial infarction (AMI) outcomes to include symptom burden, little has been done to describe hospital-level variation in this patient-centered outcome, or its association with mortality. Understanding the relationship between symptoms and longer-term mortality could inform the importance of these outcomes for monitoring quality of care.

Methods and Results—

Among 4316 patients with AMI treated at 24 hospitals participating in the Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients' Health Status (TRIUMPH) study, we assessed risk-standardized 1-year symptom burden as measured by the Seattle Angina Questionnaire Angina Frequency Score and mortality attributed to the hospital that provided AMI care. Median odds ratios were used to assess outcome variation and reflect the relative odds of an outcome for 2 patients with identical covariates at different, randomly selected, hospitals. We then evaluated the correlation between hospital-level mortality and angina. Finally, we determined the extent to which variation in mortality and angina was explained by achievement of AMI performance measures. We observed hospital variation in risk-adjusted 1-year mortality (range, 4.9%–8.6%; median odds ratio, 1.30;
P
=0.01) and angina (range, 17.7%–29.4%; median odds ratio, 1.34;
P
<0.001). At the hospital level, mortality and angina at 1 year were weakly correlated (
r
=0.40; 95% confidence interval, 0.00–0.68;
P
=0.05). Accounting for the quality of AMI care did not attenuate variation in risk-adjusted 1-year mortality or angina.

Conclusions—
Symptom burden and mortality vary at the hospital level after AMI and are only weakly correlated. These findings suggest that symptom burden should be considered a separate quality domain that is not well captured by current quality metrics.