bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcription-Induced DNA Double Strand Breaks: Both Oncogenic Force and Potential Therapeutic Target?
Authors: Haffner Michael C. , De Marzo Angelo M. , Meeker Alan K. , Nelson William G. , Yegnasubramanian Srinivasan 
Published: March 2011

Abstract
An emerging model of transcriptional activation suggests that induction of transcriptional programs, for instance by stimulating prostate or breast cells with androgens or estrogens, respectively, involves the formation of DNA damage, including DNA double strand breaks (DSB), recruitment of DSB repair proteins, and movement of newly activated genes to transcription hubs. The DSB can be mediated by the class II topoisomerase TOP2B, which is recruited with the androgen receptor and estrogen receptor to regulatory sites on target genes and is apparently required for efficient transcriptional activation of these genes. These DSBs are recognized by the DNA repair machinery triggering the recruitment of repair proteins such as poly(ADP-ribose) polymerase 1 (PARP1), ATM, and DNA-dependent protein kinase (DNA-PK). If illegitimately repaired, such DSBs can seed the formation of genomic rearrangements like the TMPRSS2-ERG fusion oncogene in prostate cancer. Here, we hypothesize that these transcription-induced, TOP2B-mediated DSBs can also be exploited therapeutically and propose that, in hormone-dependent tumors like breast and prostate cancers, a hormone-cycling therapy, in combination with topoisomerase II poisons or inhibitors of the DNA repair components PARP1 and DNA-PK, could overwhelm cancer cells with transcription-associated DSBs. Such strategies may find particular utility in cancers, like prostate cancer, which show low proliferation rates, in which other chemotherapeutic strategies that target rapidly proliferating cells have had limited success. Clin Cancer Res; 17(12); 3858–64. ©2011 AACR.
Involvement of the TGF-β and β-Catenin Pathways in Pelvic Lymph Node Metastasis in Early-Stage Cervical Cancer
Authors: Noordhuis Maartje G. , Fehrmann Rudolf S.N. , Wisman G. Bea A. , Nijhuis Esther R. , van Zanden Jelmer J. , Moerland Perry D. , Ver Loren van Themaat Emiel , Volders Haukeline H. , Kok Mirjam , ten Hoor Klaske A. , Hollema Harry , de Vries Elisabeth G.E. , de Bock Geertruida H. , van der Zee Ate G.J. , Schuuring Ed 
Published: March 2011

AbstractPurpose: Presence of pelvic lymph node metastases is the main prognostic factor in early-stage cervical cancer patients, primarily treated with surgery. Aim of this study was to identify cellular tumor pathways associated with pelvic lymph node metastasis in early-stage cervical cancer.Experimental Design: Gene expression profiles (Affymetrix U133 plus 2.0) of 20 patients with negative (N0) and 19 with positive lymph nodes (N+), were compared with gene sets that represent all 285 presently available pathway signatures. Validation immunostaining of tumors of 274 consecutive early-stage cervical cancer patients was performed for representatives of the identified pathways.Results: Analysis of 285 pathways resulted in identification of five pathways (TGF-β, NFAT, ALK, BAD, and PAR1) that were dysregulated in the N0, and two pathways (β-catenin and Glycosphingolipid Biosynthesis Neo Lactoseries) in the N+ group. Class comparison analysis revealed that five of 149 genes that were most significantly differentially expressed between N0 and N+ tumors (P &lt; 0.001) were involved in β-catenin signaling (TCF4, CTNNAL1, CTNND1/p120, DKK3, and WNT5a). Immunohistochemical validation of two well-known cellular tumor pathways (TGF-β and β-catenin) confirmed that the TGF-β pathway (positivity of Smad4) was related to N0 (OR: 0.20, 95% CI: 0.06–0.66) and the β-catenin pathway (p120 positivity) to N+ (OR: 1.79, 95%CI: 1.05–3.05).Conclusions: Our study provides new, validated insights in the molecular mechanism of lymph node metastasis in cervical cancer. Pathway analysis of the microarray expression profile suggested that the TGF-β and p120-associated noncanonical β-catenin pathways are important in pelvic lymph node metastasis in early-stage cervical cancer. Clin Cancer Res; 17(6); 1317–30. ©2011 AACR.
Targeting the BMK1 MAP Kinase Pathway in Cancer Therapy
Authors: Yang Qingkai , Lee Jiing-Dwan 
Published: March 2011

Abstract
The big mitogen activated protein kinase 1 (BMK1) pathway is the most recently discovered and least-studied mammalian mitogen-activated protein (MAP) kinase cascade, ubiquitously expressed in all types of cancer cells tested so far. Mitogens and oncogenic signals strongly activate this cellular MAP kinase pathway, thereby passing down proliferative, survival, chemoresistance, invasive, and angiogenic signals in tumor cells. Recently, several pharmacologic small molecule inhibitors of this pathway have been developed. Among them, the BMK1 inhibitor XMD8–92 blocks cellular BMK1 activation and significantly suppresses tumor growth in lung and cervical tumor models and is well tolerated in animals. On the other hand, MEK5 inhibitors, BIX02188, BIX02189, and compound 6, suppress cellular MEK5 activity, but no data exist to date on their effectiveness in animals. Clin Cancer Res; 17(11); 3527–32. ©2011 AACR.
Drozitumab, a Human Antibody to Death Receptor 5, Has Potent Antitumor Activity against Rhabdomyosarcoma with the Expression of Caspase-8 Predictive of Response
Authors: Kang Zhigang , Chen Jun-Jie , Yu Yunkai , Li Bo , Sun Shi-Yong , Zhang Baolin , Cao Liang 
Published: March 2011

Abstract
Purpose: Rhabdomyosarcoma (RMS) is a common pediatric soft-tissue tumor. In this study, we evaluated the efficacy and selectivity of drozitumab, a death receptor DR5-targeted therapeutic antibody, in RMS preclinical models.
Experimental Design: A panel of 11 RMS cell lines was used for in vitro studies. The molecular marker predictive of response to drozitumab was interrogated. Selected RMS cell lines were injected into the gastrocnemius muscle of mice for in vivo assessment of the potency and selectivity of drozitumab.
Results: We report that DR5, but not DR4, persisted at high levels and on the surface of all RMS cell lines. DR5 antibody drozitumab was effective in vitro against the majority of RMS cell lines. There was a strong correlation between caspase-8 expression and the sensitivity to drozitumab, which induced the rapid assembly of the death-induced signaling complex and the cleavage of caspase-8 only in sensitive cells. More importantly, caspase-8 catalytic activity was both necessary and sufficient for mediating the sensitivity to drozitumab. Furthermore, drozitumab had potent antitumor activity against established RMS xenografts with a specificity predicted from the in vitro analysis and with tumor-free status in half of the treated mice.
Conclusion: Our study provides the first preclinical evaluation of the potency and selectivity of a death receptor antibody in RMS. Drozitumab is effective, in vitro, against the majority of RMS cell lines that express caspase-8 and, in vivo, may provide long-term control of RMS. Clin Cancer Res; 17(10); 3181–92. ©2011 AACR.
Imaging and Therapy with Rituximab Anti-CD20 Immunotherapy in an Animal Model of Central Nervous System Lymphoma
Authors: Muldoon Leslie L. , Lewin Seth J. , Dósa Edit , Kraemer Dale F. , Pagel Michael A. , Doolittle Nancy D. , Neuwelt Edward A. 
Published: March 2011

Abstract
Purpose: To evaluate the effect of rituximab monoclonal antibody (mAb) on MRI tumor volumetrics and efficacy in a rat model of central nervous system (CNS) lymphoma when delivery to the brain was optimized with osmotic blood–brain barrier disruption (BBBD).
Experimental Design: Female nude rats with intracerebral MC116 human B-cell lymphoma xenografts underwent baseline MRI and were randomized into 5 groups (n = 6 per group): (i) BBBD saline control; (ii) methotrexate with BBBD; (iii) rituximab with BBBD; (iv) rituximab and methotrexate with BBBD; and (v) intravenous rituximab. Tumor volumes were assessed by MRI at 1 week, and rats were followed for survival.
Results: BBBD increased delivery of yttrium-90-radiolabeled mAb in the model of CNS lymphoma. Control rats showed 201 ± 102% increase in tumor volume on MRI 1 week after entering the study and median 14-day survival (range: 6–33). Tumor growth on MRI was slowed in the methotrexate treatment group, but survival time (median: 7 days; range: 5–12) was not different from controls. Among 17 evaluable rats treated with rituximab, 10 showed decreased tumor volume on MRI. All rituximab groups had increased survival compared with control, with a combined median of 43 days (range: 20–60, P &lt; 0.001). There were no differences by route of delivery or combination with methotrexate.
Conclusions: Rituximab was effective at decreasing tumor volume and improving survival in a model of CNS lymphoma and was not affected by combination with methotrexate or by BBBD. We suggest that rituximab warrants further study in human primary CNS lymphoma. Clin Cancer Res; 17(8); 2207–15. ©2011 AACR.
Comparison of Corticotropin-Releasing Factor, Dexamethasone, and Temozolomide: Treatment Efficacy and Toxicity in U87 and C6 Intracranial Gliomas
Authors: Moroz Maxim A. , Huang Ruimin , Kochetkov Tatiana , Shi Weiji , Thaler Howard , de Stanchina Elisa , Gamez Idoia , Ryan Robert P. , Blasberg Ronald G. 
Published: March 2011

Abstract
Purpose/Experimental Design: Treatment of cerebral tumors and peritumoral brain edema remains a clinical challenge and is associated with high morbidity and mortality. Dexamethasone is an effective drug for treating brain edema, but it is associated with well-documented side effects. Corticorelin acetate (Xerecept) or human corticotrophin-releasing factor (hCRF) is a comparatively new drug and has been evaluated in two orthotopic glioma models (U87 and C6), by a direct comparison with dexamethasone and temozolomide.
Results: In vitro combination therapy and monotherapy showed a variable response in 6 different glioma cell lines. In vivo studies showed a dose-dependent effect of hCRF (0.03 and 0.1 mg/kg q12h) on survival of U87 intracranial xenograft–bearing animals [median survival: control – 41 days (95% CI 25–61); “low-hCRF” 74.5 days (95% CI 41–88); “high-hCRF” &gt;130 days (95% CI not reached)]. Dexamethasone treatment had no effect on survival, but significant toxicity was observed. A survival benefit was observed with temozolomide and temozolomide + hCRF-treated animals but with significant temozolomide toxicity. C6-bearing animals showed no survival benefit, but there were similar treatment toxicities. The difference in hCRF treatment response between U87 and C6 intracranial gliomas can be explained by a difference in receptor expression. RT-PCR identified CRF2r mRNA in U87 xenografts; no CRF receptors were identified in C6 xenografts.
Conclusions: hCRF was more effective than either dexamethasone or temozolomide in the treatment of U87 xenografts, and results included improved prognosis with long-term survivors and only mild toxicity. The therapeutic efficacy of hCRF seems to be dependent on tumor hCRF receptor (CRFr) expression. These results support further clinical assessment of the therapeutic efficacy of hCRF and levels of CRFr expression in different human gliomas. Clin Cancer Res; 17(10); 3282–92. ©2011 AACR.
BRAFV600E: Implications for Carcinogenesis and Molecular Therapy
Authors: Cantwell-Dorris Emma R. , O'Leary John J. , Sheils Orla M. 
Published: March 2011

Abstract
The mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway is frequently mutated in human cancer. This pathway consists of a small GTP protein of the RAS family that is activated in response to extracellular signaling to recruit a member of the RAF kinase family to the cell membrane. Active RAF signals through MAP/ERK kinase to activate ERK and its downstream effectors to regulate a wide range of biological activities including cell differentiation, proliferation, senescence, and survival. Mutations in the v-raf murine sarcoma viral oncogenes homolog B1 (BRAF) isoform of the RAF kinase or KRAS isoform of the RAS protein are found as activating mutations in approximately 30% of all human cancers. The BRAF pathway has become a target of interest for molecular therapy, with promising results emerging from clinical trials. Here, the role of the most common BRAF mutation BRAFV600E in human carcinogenesis is investigated through a review of the literature, with specific focus on its role in melanoma, colorectal, and thyroid cancers and its potential as a therapeutic target. Mol Cancer Ther; 10(3); 385–94. ©2011 AACR.
Apoptosis Is the Essential Target of Selective Pressure against p53, whereas Loss of Additional p53 Functions Facilitates Carcinoma Progression
Authors: Lu Xiangdong , Yang Chunyu , Yin Chaoying , Van Dyke Terry , Simin Karl 
Published: March 2011

Abstract
The high frequency of p53 mutation in human cancers indicates the important role of p53 in suppressing tumorigenesis. It is well established that the p53 regulates multiple, distinct cellular functions such as cell-cycle arrest and apoptosis. Despite intensive studies, little is known about which function is essential, or if multiple pathways are required, for p53-dependent tumor suppression in vivo. Using a mouse brain carcinoma model that shows high selective pressure for p53 inactivation, we found that even partially abolishing p53-dependent apoptosis by Bax inactivation was sufficient to significantly reduce the selective pressure for p53 loss. This finding is consistent with previous reports that apoptosis is the primary p53 function selected against during Eμ-myc–induced mouse lymphoma progression. However, unlike observed in the Eμ-myc–induced lymphoma model, attenuation of apoptosis is not sufficient to phenocopy the aggressive tumor progression associated with complete loss of p53 activity. We conclude that apoptosis is the primary tumor suppressive p53 function and the ablation of additional p53 pleiotropic effects further exacerbates tumor progression. Mol Cancer Res; 9(4); 430–9. ©2011 AACR.
Hypoxia and Senescence: The Impact of Oxygenation on Tumor Suppression
Authors: Welford Scott M. , Giaccia Amato J. 
Published: March 2011

Abstract
Cellular senescence has emerged as a biological response to two major pathophysiological states of our being: cancer and aging. In the course of the transformation of a normal cell to a cancerous cell, senescence is frequently induced to suppress tumor development. In aged individuals, senescence is found in cells that have exhausted their replication potential. The similarity in these responses suggests that understanding how senescence is mediated can provide insight into both cancer and aging. One environmental factor that is implicated in both of these states is tissue hypoxia, which increases with aging and can inhibit senescence. Hypoxia is particularly important in normal physiology to maintain the stem cell niche; but at the same time, hypoxic inhibition of an essential tumor suppressor response can theoretically contribute to cancer initiation. Mol Cancer Res; 9(5); 538–44. ©2011 AACR.
Procedure-Type Risk Categories for Pediatric and Congenital Cardiac Catheterization
Authors: Bergersen Lisa , Gauvreau Kimberlee , Marshall Audrey , Kreutzer Jacqueline , Beekman Robert , Hirsch Russel , Foerster Susan , Balzer David , Vincent Julie , Hellenbrand William , Holzer Ralf , Cheatham John , Moore John , Lock James , Jenkins Kathy 
Published: March 2011

Background—
The Congenital Cardiac Catheterization Project on Outcomes (C3PO) was established to develop outcome assessment methods for pediatric catheterization.

Methods and Results—
Six sites have been recording demographic, procedural and immediate outcome data on all cases, using a web-based system since February 2007. A sample of data was independently audited for validity and data completeness. In 2006, participants categorized 84 procedure types into 6 categories by anticipated risk of an adverse event (AE). Consensus and empirical methods were used to determine final procedure risk categories, based on the outcomes: any AE (level 1 to 5); AE level 3, 4, or 5; and death or life-threatening event (level 4 or 5). The final models were then evaluated for validity in a prospectively collected data set between May 2008 and December 31, 2009. Between February 2007 and April 2008, 3756 cases were recorded, 558 (14.9%) with any AE; 226 (6.0%) level 3, 4, or 5; and 73 (1.9%) level 4 or 5. General estimating equations models using 6 consensus-based risk categories were moderately predictive of AE occurrence (c-statistics: 0.644, 0.664, and 0.707). The participant panel made adjustments based on the collected empirical data supported by clinical judgment. These decisions yielded 4 procedure risk categories; the final models had improved discrimination, with c-statistics of 0.699, 0.725, and 0.765. Similar discrimination was observed in the performance data set (n=7043), with c-statistics of 0.672, 0.708, and 0.721.

Conclusions—
Procedure-type risk categories are associated with different complication rates in our data set and could be an important variable in risk adjustment models for pediatric catheterization.
Pharmacodynamic Effects of Different Aspirin Dosing Regimens in Type 2 Diabetes Mellitus Patients With Coronary Artery Disease
Authors: Capodanno Davide , Patel Aasita , Dharmashankar Kodlipet , Ferreiro José Luis , Ueno Masafumi , Kodali Murali , Tomasello Salvatore D. , Capranzano Piera , Seecheran Naveen , Darlington Andrew , Tello-Montoliu Antonio , Desai Bhaloo , Bass Theodore A. , Angiolillo Dominick J. 
Published: March 2011

Background—
Patients with type 2 diabetes mellitus (T2DM) have reduced aspirin-induced pharmacodynamic effects. This may be attributed to increased platelet turnover rates resulting in an increased proportion of non–aspirin-inhibited platelets during the daily dosing interval. The hypothesis of this study was that an increase in the frequency of drug administration [twice daily (bid) versus once daily (od)] may provide more effective platelet inhibition in T2DM patients.

Methods and Results—

T2DM patients with stable coronary artery disease were prospectively recruited. Patients modified their aspirin regimen on a weekly basis according to the following scheme: 81 mg/od, 81 mg/bid, 162 mg/od, 162 mg/bid, and 325 mg/od. Pharmacodynamic assessments included light-transmittance aggregometry after arachidonic acid, collagen and adenosine diphosphate stimuli; VerifyNow-Aspirin assay; and serum thromboxane B
2
(TXB
2
) levels. Twenty patients were analyzed. All patients were sensitive and compliant to aspirin irrespective of dose, as assessed by arachidonic acid–induced aggregation. When aspirin was administered once daily, there was no significant effect on platelet reactivity by increasing the once-daily dosing using aspirin-sensitive assays (collagen-induced aggregation and VerifyNow-Aspirin). An increase in aspirin dose by means of a second daily administration was associated with a significant reduction in platelet reactivity assessed by collagen-induced aggregation and VerifyNow-Aspirin between 81 mg/od and 81 mg/bid (
P
<0.05 for both assays) and between 81 mg/od and 162 mg/bid (
P
<0.05 for both assays). There was no impact of aspirin dosing regimens on adenosine diphosphate–induced aggregation. A dose-dependent effect of aspirin was observed on serum TXB
2
levels (
P
=0.003).

Conclusions—

Aspirin dosing regimens are associated with different pharmacodynamic effects in platelets from T2DM patients and stable coronary artery disease, with a twice-daily, low-dose aspirin administration resulting in greater platelet inhibition than once-daily administration as assessed by aspirin-sensitive assays and a dose-dependent effect on serum TXB
2
levels. The clinical implications of a modified aspirin regimen tailored to T2DM patients warrant further investigation.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01201785.
The Effectiveness of Ultrabrief and Brief Educational Videos for Training Lay Responders in Hands-Only Cardiopulmonary Resuscitation
Authors: Bobrow Bentley J. , Vadeboncoeur Tyler F. , Spaite Daniel W. , Potts Jerald , Denninghoff Kurt , Chikani Vatsal , Brazil Paula R. , Ramsey Bob , Abella Benjamin S. 
Published: March 2011

Background—
Bystander cardiopulmonary resuscitation (CPR) improves survival from out-of-hospital cardiac arrest (OHCA) but often is not performed. We hypothesized that subjects viewing very short Hands-Only CPR videos will (1) be more likely to attempt CPR in a simulated OHCA scenario and (2) demonstrate better CPR skills than untrained individuals.

Methods and Results—

This study is a prospective trial of 336 adults without recent CPR training randomized into 4 groups: (1) control (no training) (n=51); (2) 60-second video training (n=95); (3) 5-minute video training (n=99); and (4) 8-minute video training, including manikin practice (n=91). All subjects were tested for their ability to perform CPR during an adult OHCA scenario using a CPR-sensing manikin and Laerdal PC SkillReporting software. One half of the trained subjects were randomly assigned to testing immediately and the other half after a 2-month delay. Twelve (23.5%) controls did not even attempt CPR, which was true of only 2 subjects (0.7%;
P
=0.01) from any of the experimental groups. All experimental groups had significantly higher average compression rates (closer to the recommended 100/min) than the control group (
P
<0.001), and all experimental groups had significantly greater average compression depth (>38 mm) than the control group (
P
<0.0001).

Conclusions—
Laypersons exposed to very short Hands-Only CPR videos are more likely to attempt CPR and show superior CPR skills than untrained laypersons.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01191736.
West African Monsoon Dynamics and Eastern Equatorial Atlantic and Pacific SST Anomalies (1970–88)
Authors: Janicot Serge , Harzallah Ali , Fontaine Bernard , Moron Vincent 
Published: March 2011

Abstract
The Laboratoire de Météorologie Dynamique atmospheric GCM is used to investigate relationships between West African monsoon dynamics and SST anomalies in the eastern equatorial Atlantic and Pacific for the period 1970–88. Positive SST anomalies in the eastern equatorial Pacific, mainly associated with a larger east–west divergent circulation over the tropical Atlantic, are found to coincide with negative rainfall anomalies over West Africa. This is the case for the composite ENSO warm episodes of 1972, 1976, 1982, and 1983. By contrast, positive SST anomalies in the eastern equatorial Atlantic are accompanied by a southward shift of the intertropical convergence zone along with negative rainfall anomalies in the Sahel and positive rainfall anomalies in the Guinean region. This was the case in 1987. The ENSO warm event during this year had apparently no significant impact on West African monsoon dynamics. A zonal atmospheric coupling associated with differences of SST anomalies between the eastern equatorial Pacific and the Atlantic is evident in the period 1970–88. Positive (negative) phases of this coupling could enhance the impact of ENSO warm (cold) events on West African monsoon dynamics.