bluuebunny/crossref_metadata_2025_split huggingface dataset:
The IL-18 Antagonist IL-18–Binding Protein Is Produced in the Human Ovarian Cancer Microenvironment
Authors: Carbotti Grazia , Barisione Gaia , Orengo Anna Maria , Brizzolara Antonella , Airoldi Irma , Bagnoli Marina , Pinciroli Patrizia , Mezzanzanica Delia , Centurioni Maria Grazia , Fabbi Marina , Ferrini Silvano 
Published: July 2013

Abstract
Purpose: Interleukin (IL)-18 is an immune-enhancing cytokine, which induces IFN-γ production, T-helper 1 responses, and antitumor effects. In turn, IFN-γ stimulates IL-18–binding protein production, which blocks IL-18 activity. In view of the potential use of IL-18 in epithelial ovarian cancer (EOC) immunotherapy, here, we studied IL-18BP expression and its regulation by cytokines in EOC cells in vitro and in vivo.
Experimental Design: Expression and production of IL-18BP in EOC cell lines, primary ovarian carcinomas, and the corresponding normal tissues, patients' serum, and ascites were investigated by immunochemistry, ELISA, screening of gene expression profiles, and reverse-transcription PCR.
Results: Analysis of gene expression profiles revealed that IL18BP mRNA is increased in EOC tumors compared with normal ovary cells. Release of IL-18BP was detectable in EOC sera and to a greater extent in the ascites, indicating production at the tumor site. Indeed, immunochemical analyses on cells isolated from the ascites and on tumor sections indicated that IL-18BP is expressed in both tumor cells and tumor-associated leukocytes, which displayed a CD3−CD20−NKp46−CD13+CD14low phenotype. EOC cell lines do not constitutively express IL-18BP. However, its release is inducible both by IFN-γ stimulation in vitro and by xenotransplantation of EOC cells in immune-deficient mice, suggesting a role for the microenvironment. In vitro experiments and immunochemistry indicated that IL-27 is also involved in IL-18BP upregulation in EOC cell lines and primary cells through STAT1 activation. Together, these data indicate that IL-18BP, which is produced in EOC in response to microenvironmental factors, may inhibit endogenous or exogenous IL-18 activity. Clin Cancer Res; 19(17); 4611–20. ©2013 AACR.
Novel Role of MDA-9/Syntenin in Regulating Urothelial Cell Proliferation by Modulating EGFR Signaling
Authors: Dasgupta Santanu , Menezes Mitchell E. , Das Swadesh K. , Emdad Luni , Janjic Aleksandar , Bhatia Shilpa , Mukhopadhyay Nitai D. , Shao Chunbo , Sarkar Devanand , Fisher Paul B. 
Published: July 2013

Abstract
Purpose: Urothelial cell carcinoma (UCC) rapidly progresses from superficial to muscle-invasive tumors. The key molecules involved in metastatic progression and its early detection require clarification. The present study defines a seminal role of the metastasis-associated gene MDA-9/Syntenin in UCC progression.
Experimental Design: Expression pattern of MDA-9/Syntenin was examined in 44 primary UCC and the impact of its overexpression and knockdown was examined in multiple cells lines and key findings were validated in primary tumors.
Results: Significantly higher (P = 0.002–0.003) expression of MDA-9/Syntenin was observed in 64% (28 of 44) of primary tumors and an association was evident with stage (P = 0.01), grade (P = 0.03), and invasion status (P = 0.02). MDA-9/Syntenin overexpression in nontumorigenic HUC-1 cells increased proliferation (P = 0.0012), invasion (P = 0.0001), and EGF receptor (EGFR), AKT, phosphoinositide 3-kinase (PI3K), and c-Src expression. Alteration of β-catenin, E-cadherin, vimentin, claudin-1, ZO-1, and T-cell factor-4 (TCF4) expression was also observed. MDA-9/Syntenin knockdown in three UCC cell lines reversed phenotypic and molecular changes observed in the HUC-1 cells and reduced in vivo metastasis. Key molecular changes observed in the cell lines were confirmed in primary tumors. A physical interaction and colocalization of MDA-9/Syntenin and EGFR was evident in UCC cell lines and primary tumors. A logistic regression model analysis revealed a significant correlation between MDA-9/Syntenin:EGFR and MDA-9/Syntenin:AKT expressions with stage (P = 0.04, EGFR; P = 0.01, AKT). A correlation between MDA-9/Syntenin:β-catenin coexpression with stage (P = 0.03) and invasion (P = 0.04) was also evident.
Conclusions: Our findings indicate that MDA-9/Syntenin might provide an attractive target for developing detection, monitoring, and therapeutic strategies for managing UCC. Clin Cancer Res; 19(17); 4621–33. ©2013 AACR.
Preclinical Activity of the Type II CD20 Antibody GA101 (Obinutuzumab) Compared with Rituximab and Ofatumumab In Vitro and in Xenograft Models
Authors: Herter Sylvia , Herting Frank , Mundigl Olaf , Waldhauer Inja , Weinzierl Tina , Fauti Tanja , Muth Gunter , Ziegler-Landesberger Doris , Van Puijenbroek Erwin , Lang Sabine , Duong Minh Ngoc , Reslan Lina , Gerdes Christian A. , Friess Thomas , Baer Ute , Burtscher Helmut , Weidner Michael , Dumontet Charles , Umana Pablo , Niederfellner Gerhard , Bacac Marina , Klein Christian 
Published: July 2013

Abstract
We report the first preclinical in vitro and in vivo comparison of GA101 (obinutuzumab), a novel glycoengineered type II CD20 monoclonal antibody, with rituximab and ofatumumab, the two currently approved type I CD20 antibodies. The three antibodies were compared in assays measuring direct cell death (AnnexinV/PI staining and time-lapse microscopy), complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), and internalization. The models used for the comparison of their activity in vivo were SU-DHL4 and RL xenografts. GA101 was found to be superior to rituximab and ofatumumab in the induction of direct cell death (independent of mechanical manipulation required for cell aggregate disruption formed by antibody treatment), whereas it was 10 to 1,000 times less potent in mediating CDC. GA101 showed superior activity to rituximab and ofatumumab in ADCC and whole-blood B-cell depletion assays, and was comparable with these two in ADCP. GA101 also showed slower internalization rate upon binding to CD20 than rituximab and ofatumumab. In vivo, GA101 induced a strong antitumor effect, including complete tumor remission in the SU-DHL4 model and overall superior efficacy compared with both rituximab and ofatumumab. When rituximab-pretreated animals were used, second-line treatment with GA101 was still able to control tumor progression, whereas tumors escaped rituximab treatment. Taken together, the preclinical data show that the glyoengineered type II CD20 antibody GA101 is differentiated from the two approved type I CD20 antibodies rituximab and ofatumumab by its overall preclinical activity, further supporting its clinical investigation. Mol Cancer Ther; 12(10); 2031–42. ©2013 AACR.
Combination Drug Scheduling Defines a “Window of Opportunity” for Chemopotentiation of Gemcitabine by an Orally Bioavailable, Selective ChK1 Inhibitor, GNE-900
Authors: Blackwood Elizabeth , Epler Jennifer , Yen Ivana , Flagella Michael , O'Brien Tom , Evangelista Marie , Schmidt Stephen , Xiao Yang , Choi Jonathan , Kowanetz Kaska , Ramiscal Judi , Wong Kenton , Jakubiak Diana , Yee Sharon , Cain Gary , Gazzard Lewis , Williams Karen , Halladay Jason , Jackson Peter K. , Malek Shiva 
Published: July 2013

Abstract
Checkpoint kinase 1 (ChK1) is a serine/threonine kinase that functions as a central mediator of the intra-S and G2–M cell-cycle checkpoints. Following DNA damage or replication stress, ChK1-mediated phosphorylation of downstream effectors delays cell-cycle progression so that the damaged genome can be repaired. As a therapeutic strategy, inhibition of ChK1 should potentiate the antitumor effect of chemotherapeutic agents by inactivating the postreplication checkpoint, causing premature entry into mitosis with damaged DNA resulting in mitotic catastrophe. Here, we describe the characterization of GNE-900, an ATP-competitive, selective, and orally bioavailable ChK1 inhibitor. In combination with chemotherapeutic agents, GNE-900 sustains ATR/ATM signaling, enhances DNA damage, and induces apoptotic cell death. The kinetics of checkpoint abrogation seems to be more rapid in p53-mutant cells, resulting in premature mitotic entry and/or accelerated cell death. Importantly, we show that GNE-900 has little single-agent activity in the absence of chemotherapy and does not grossly potentiate the cytotoxicity of gemcitabine in normal bone marrow cells. In vivo scheduling studies show that optimal administration of the ChK1 inhibitor requires a defined lag between gemcitabine and GNE-900 administration. On the refined combination treatment schedule, gemcitabine's antitumor activity against chemotolerant xenografts is significantly enhanced and dose-dependent exacerbation of DNA damage correlates with extent of tumor growth inhibition. In summary, we show that in vivo potentiation of gemcitabine activity is mechanism based, with optimal efficacy observed when S-phase arrest and release is followed by checkpoint abrogation with a ChK1 inhibitor. Mol Cancer Ther; 12(10); 1968–80. ©2013 AACR.
Targeting Aberrant DNA Double-Strand Break Repair in Triple-Negative Breast Cancer with Alpha-Particle Emitter Radiolabeled Anti-EGFR Antibody
Authors: Song Hong , Hedayati Mohammad , Hobbs Robert F. , Shao Chunbo , Bruchertseifer Frank , Morgenstern Alfred , DeWeese Theodore L. , Sgouros George 
Published: July 2013

Abstract
The higher potential efficacy of alpha-particle radiopharmaceutical therapy lies in the 3- to 8-fold greater relative biological effectiveness (RBE) of alpha particles relative to photon or beta-particle radiation. This greater RBE, however, also applies to normal tissue, thereby reducing the potential advantage of high RBE. As alpha particles typically cause DNA double-strand breaks (DSB), targeting tumors that are defective in DSB repair effectively increases the RBE, yielding a secondary, RBE-based differentiation between tumor and normal tissue that is complementary to conventional, receptor-mediated tumor targeting. In some triple-negative breast cancers (TNBC; ER−/PR−/HER-2−), germline mutation in BRCA-1, a key gene in homologous recombination DSB repair, predisposes patients to early onset of breast cancer. These patients have few treatment options once the cancer has metastasized. In this study, we investigated the efficacy of alpha-particle emitter, 213Bi-labeled anti-EGF receptor antibody, cetuximab, in BRCA-1–defective TNBC. 213Bi-cetuximab was found to be significantly more effective in the BRCA-1–mutated TNBC cell line HCC1937 than BRCA-1–competent TNBC cell MDA-MB-231. siRNA knockdown of BRCA-1 or DNA-dependent protein kinase, catalytic subunit (DNA-PKcs), a key gene in non–homologous end-joining DSB repair pathway, also sensitized TNBC cells to 213Bi-cetuximab. Furthermore, the small-molecule inhibitor of DNA-PKcs, NU7441, sensitized BRCA-1–competent TNBC cells to alpha-particle radiation. Immunofluorescent staining of γ-H2AX foci and comet assay confirmed that enhanced RBE is caused by impaired DSB repair. These data offer a novel strategy for enhancing conventional receptor-mediated targeting with an additional, potentially synergistic radiobiological targeting that could be applied to TNBC. Mol Cancer Ther; 12(10); 2043–54. ©2013 AACR.
Uracil–DNA Glycosylase Expression Determines Human Lung Cancer Cell Sensitivity to Pemetrexed
Authors: Weeks Lachelle D. , Fu Pingfu , Gerson Stanton L. 
Published: July 2013

Abstract
Uracil misincorporation into DNA is a consequence of pemetrexed inhibition of thymidylate synthase. The base excision repair (BER) enzyme uracil–DNA glycosylase (UNG) is the major glycosylase responsible for removal of misincorporated uracil. We previously illustrated hypersensitivity to pemetrexed in UNG−/− human colon cancer cells. Here, we examined the relationship between UNG expression and pemetrexed sensitivity in human lung cancer. We observed a spectrum of UNG expression in human lung cancer cells. Higher levels of UNG are associated with pemetrexed resistance and are present in cell lines derived from pemetrexed-resistant histologic subtypes (small cell and squamous cell carcinoma). Acute pemetrexed exposure induces UNG protein and mRNA, consistent with upregulation of uracil–DNA repair machinery. Chronic exposure of H1299 adenocarcinoma cells to increasing pemetrexed concentrations established drug-resistant sublines. Significant induction of UNG protein confirmed upregulation of BER as a feature of acquired pemetrexed resistance. Cotreatment with the BER inhibitor methoxyamine overrides pemetrexed resistance in chronically exposed cells, underscoring the use of BER-directed therapeutics to offset acquired drug resistance. Expression of UNG-directed siRNA and shRNA enhanced sensitivity in A549 and H1975 cells, and in drug-resistant sublines, confirming that UNG upregulation is protective. In human lung cancer, UNG deficiency is associated with pemetrexed-induced retention of uracil in DNA that destabilizes DNA replication forks resulting in DNA double-strand breaks and cell death. Thus, in experimental models, UNG is a critical mediator of pemetrexed sensitivity that warrants evaluation to determine clinical value. Mol Cancer Ther; 12(10); 2248–60. ©2013 AACR.
The Dual Pathway Inhibitor Rigosertib Is Effective in Direct Patient Tumor Xenografts of Head and Neck Squamous Cell Carcinomas
Authors: Anderson Ryan T. , Keysar Stephen B. , Bowles Daniel W. , Glogowska Magdalena J. , Astling David P. , Morton J. Jason , Le Phuong , Umpierrez Adrian , Eagles-Soukup Justin , Gan Gregory N. , Vogler Brian W. , Sehrt Daniel , Takimoto Sarah M. , Aisner Dara L. , Wilhelm Francois , Frederick Barbara A. , Varella-Garcia Marileila , Tan Aik-Choon , Jimeno Antonio 
Published: July 2013

Abstract
The dual pathway inhibitor rigosertib inhibits phosphoinositide 3-kinase (PI3K) pathway activation as well as polo-like kinase 1 (PLK1) activity across a broad spectrum of cancer cell lines. The importance of PIK3CA alterations in squamous cell carcinoma of the head and neck (HNSCC) has raised interest in exploring agents targeting PI3K, the product of PIK3CA. The genetic and molecular basis of rigosertib treatment response was investigated in a panel of 16 HNSCC cell lines, and direct patient tumor xenografts from eight patients with HNSCC [four HPV-serotype16 (HPV16)–positive]. HNSCC cell lines and xenografts were characterized by pathway enrichment gene expression analysis, exon sequencing, gene copy number, Western blotting, and immunohistochemistry (IHC). Rigosertib had potent antiproliferative effects on 11 of 16 HPV− HNSCC cell lines. Treatment sensitivity was confirmed in two cell lines using an orthotopic in vivo xenograft model. Growth reduction after rigosertib treatment was observed in three of eight HNSCC direct patient tumor lines. The responsive tumor lines carried a combination of a PI3KCA-activating event (amplification or mutation) and a p53-inactivating event (either HPV16- or mutation-mediated TP53 inactivation). In this study, we evaluated the in vitro and in vivo efficacy of rigosertib in both HPV+ and HPV− HNSCCs, focusing on inhibition of the PI3K pathway. Although consistent inhibition of the PI3K pathway was not evident in HNSCC, we identified a combination of PI3K/TP53 events necessary, but not sufficient, for rigosertib sensitivity. Mol Cancer Ther; 12(10); 1994–2005. ©2013 AACR.
Plasma Adiponectin and Soluble Leptin Receptor and Risk of Colorectal Cancer: A Prospective Study
Authors: Song Mingyang , Zhang Xuehong , Wu Kana , Ogino Shuji , Fuchs Charles S. , Giovannucci Edward L. , Chan Andrew T. 
Published: July 2013

Abstract
Adipokines are adipocyte-secreted hormones that may mediate the etiologic link between obesity and colorectal cancer; however, the evidence from large prospective studies is limited. We prospectively evaluated the association of plasma adiponectin and soluble leptin receptor (sOB-R) with colorectal cancer risk within the Nurses' Health Study (1990–2008) and the Health Professionals Follow-up Study (1994–2008) among 616 incident colorectal cancer cases and 1,205 controls selected using risk-set sampling and matched on age and date of blood draw. In unconditional logistic regression with adjustment for matching factors and multiple risk factors, plasma adiponectin was significantly associated with reduced risk of colorectal cancer among men, but not among women. Compared with men in the lowest quartile of adiponectin, men in the highest quartile had a relative risk (RR) for colorectal cancer of 0.55 [95% confidence interval (CI), 0.35–0.86; Ptrend = 0.02]. The corresponding RR in women was 0.96 (95% CI, 0.67–1.39; Ptrend = 0.74). Plasma sOB-R was not associated with overall colorectal cancer risk in either men or women. A significant heterogeneity was noted in the association between sOB-R and colorectal cancer by subsite in women (Pheterogeneity = 0.004); sOB-R was significantly associated with increased risk of rectal cancer but not colon cancer. These findings support a role for adiponectin in colorectal carcinogenesis in men. Further studies are warranted to confirm these associations and elucidate potential underlying mechanisms. Cancer Prev Res; 6(9); 875–85. ©2013 AACR.
Myocardial Infarction and Atrial Fibrillation
Authors: Alasady Muayad , Shipp Nicholas J. , Brooks Anthony G. , Lim Han S. , Lau Dennis H. , Barlow David , Kuklik Pawel , Worthley Matthew I. , Roberts-Thomson Kurt C. , Saint David A. , Abhayaratna Walter , Sanders Prashanthan 
Published: July 2013

Background—
Myocardial infarction (MI) is associated with the development of atrial fibrillation (AF). We aimed to characterize the atrial abnormalities because of MI and determine the role of ischemia to the AF substrate.

Methods and Results—

Forty-four sheep were studied. MI was induced by occlusion of the left circumflex artery (LCX) or left anterior descending artery (LAD). Excluding 11 with fatal arrhythmias, equal groups of animals (LCX; LAD; and sham-operated) underwent sequential electrophysiology study for 45 minutes to determine atrial effective refractory periods, conduction velocity, conduction heterogeneity index, and AF inducibility. Postmortem evaluation was performed with 2,3,5 triphenyl tetrazolium chloride staining. MI resulted in greater left ventricular dysfunction (
P
<0.05), LA pressure (
P
<0.0003), and reduction in atrial effective refractory periods (
P
<0.0001) compared with control. 2,3,5 triphenyl tetrazolium chloride staining demonstrated that the left circumflex artery, and not the LAD, group had atrial infarction. The left circumflex artery group demonstrated the following compared with the LAD or control groups: greater slowing in atrial conduction velocity (
P
<0.0001 and
P
<0.001); increased absolute range of conduction phase delay (
P
<0.001 and
P
<0.001); increased conduction heterogeneity index (
P
<0.0001 and
P
<0.001); greater AF vulnerability (
P
<0.05 for both); and longer AF duration (
P
<0.05 for both). LAD group had modest but significant slowing in conduction velocity (
P
<0.01) but no change in conduction heterogeneity index or AF duration compared with control.

Conclusions—
Left ventricular infarction, which is known to result in atrial stretch, hemodynamic change, and neurohumoral activation, contributes partially to the atrial abnormalities in MI. Atrial ischemia/infarction results in greater atrial electrophysiological changes and propensity for AF forming the dominant substrate for AF in MI.
Low Heart Rates Predict Incident Atrial Fibrillation in Healthy Middle-Aged Men
Authors: Grundvold Irene , Skretteberg Per Torger , Liestøl Knut , Erikssen Gunnar , Engeseth Kristian , Gjesdal Knut , Kjeldsen Sverre E. , Arnesen Harald , Erikssen Jan , Bodegard Johan 
Published: July 2013

Background—
Low resting heart rate (HR) has been associated with atrial fibrillation (AF) in athletes. We aimed to study whether low HR at rest or during exercise testing was a predictor of AF in initially healthy middle-aged men.

Methods and Results—
A total of 2014 healthy Norwegian men participated in a prospective cardiovascular survey, including a standardized bicycle exercise test in 1972 to 1975. During ≤35 years of follow-up (53 000 person-years of observation), 270 men developed incident AF, documented by scrutiny of health charts in all Norwegian hospitals. Risk estimation was analyzed with Cox proportional hazard models. Low exercise HR after 6 minutes exercise on the moderate workload of 100 W (HR100W) was a predictor of incident AF. Men with HR100W <100 beats per minute (n=260) were characterized by high physical fitness, low resting and low maximum HR, and they had 1.60-fold AF risk (95% confidence interval, 1.11–2.26) compared with men with HR100W ≥100 beats per minute when adjusted for age, systolic blood pressure, and physical fitness. Additional adjustment for relative heart volume slightly reduced the association. The subgroup of men (n=860) with hypertensive blood pressure measurements at baseline had the highest risk difference between low and high HR100W with hazard ratio 2.08 (1.19–3.45).

Conclusions—
Our data indicate that low exercise HR on a moderate workload is a long-term predictor of incident AF in healthy middle-aged men. Elevated baseline blood pressure substantially amplifies this risk. The present results suggest a relationship between increased vagal tone, high stroke volumes and incident AF, and particularly so in physically fit men.
Incremental His-To-Coronary Sinus Maneuver
Authors: Vallès Ermengol , Bazán Victor , Benito Begoña , Jáuregui Miguel Eduardo , Bruguera Jordi , Guijo Miguel Angel , Altaba Carmen , Martí-Almor Julio 
Published: July 2013

Background—
Achievement of complete cavotricuspid isthmus (CTI) conduction block reduces typical atrial flutter recurrences after ablation. The lack of increase in the His-to-Coronary sinus ostium atrial interval during incremental pacing (IP) from the low lateral right atrium may distinguish slow conduction from complete CTI conduction block.

Methods and Results—
Sixty-six consecutive patients (age, 65±13 years; 18% female) were prospectively included. A <10 ms increase in the His-to-Coronary sinus ostium atrial timing during low lateral right atrium IP at cycle length of 600 ms through 300 ms was compared with the previously reported IP maneuver for the confirmation of complete CTI block. On the basis of the IP maneuver, complete CTI block (phase 2) was achieved in 59 patients, in 13 of whom an intermediate phase of functional CTI block (phase 1) was observed. In the remaining 7 patients, the IP maneuver did not allow for assessment of complete CTI block because of the presence of inconclusive potentials in the CTI ablation line. As compared with the IP maneuver, the incremental His-to-Coronary sinus ostium maneuver was consistent with functional CTI block during phase 1 in all cases and conclusive of complete CTI block in 98% of cases during phase 2.

Conclusions—
The incremental His-to-Coronary sinus ostium maneuver is analogous to the IP maneuver in distinguishing complete CTI block from persistent CTI conduction. This maneuver may provide confirmation of CTI block in those patients in whom assessment of local electrogram–based criteria is not feasible because of inconclusive potentials in the CTI ablation line.