bluuebunny/crossref_metadata_2025_split huggingface dataset:
NF-κB Regulates Radioresistance Mediated By β1-Integrin in Three-Dimensional Culture of Breast Cancer Cells
Authors: Ahmed Kazi Mokim , Zhang Hui , Park Catherine C. 
Published: April 2013

Abstract
β1-integrin induction enhances breast cancer cell survival after exposure to ionizing radiation (IR), but the mechanisms of this effect remain unclear. Although NF-κB initiates prosurvival signaling pathways post-IR, the molecular function of NF-κB with other key elements in radioresistance, particularly with respect to extracellular matrix-induced signaling, is not known. We discovered a typical NF-κB–binding site in the β1-integrin promoter region, indicating a possible regulatory role for NF-κB. Using three-dimensional laminin-rich extracellular matrix (3D lrECM) culture, we show that NF-κB is required for β1-integrin transactivation in T4-2 breast cancer cells post-IR. Inhibition of NF-κB reduced clonogenic survival and induced apoptosis and cytostasis in formed tumor colonies. In addition, T4-2 tumors with inhibition of NF-κB activity exhibit decreased growth in athymic mice, which was further reduced by IR with downregulated β1-integrin expression. Direct interactions between β1-integrin and NF-κB p65 were induced in nonmalignant breast epithelial cells, but not in malignant cells, indicating context-specific regulation. As β1-integrin also activates NF-κB, our findings reveal a novel forward feedback pathway that could be targeted to enhance therapy. Cancer Res; 73(12); 3737–48. ©2013 AACR.
YAP/TEAD–Mediated Transcription Controls Cellular Senescence
Authors: Xie Qi , Chen Jing , Feng Han , Peng Shengyi , Adams Ursula , Bai Yujie , Huang Li , Li Ji , Huang Junjian , Meng Songshu , Yuan Zengqiang 
Published: April 2013

Abstract
Transcription coactivator Yes-associated protein (YAP) plays an important role in the regulation of cell proliferation and apoptosis. Here, we identify a new role of YAP in the regulation of cellular senescence. We find that the expression levels of YAP proteins decrease following the replication-induced cellular senescence in IMR90 cells. Silencing of YAP inhibits cell proliferation and induces premature senescence. In additional experiments, we observe that cellular senescence induced by YAP deficiency is TEAD- and Rb/p16/p53–dependent. Furthermore, we show that Cdk6 is a direct downstream target gene of YAP in the regulation of cellular senescence, and the expression of Cdk6 is through the YAP–TEAD complex. Ectopic expression of Cdk6 rescued YAP knockdown-induced senescence. Finally, we find that downregulation of YAP in tumor cells increases senescence in response to chemotherapeutic agents, and YAP or Cdk6 expression rescues cellular senescence. Taken together, our findings define the critical role of YAP in the regulation of cellular senescence and provide a novel insight into a potential chemotherapeutic avenue for tumor suppression. Cancer Res; 73(12); 3615–24. ©2013 AACR.
Threshold Levels of ABL Tyrosine Kinase Inhibitors Retained in Chronic Myeloid Leukemia Cells Determine Their Commitment to Apoptosis
Authors: O'Hare Thomas , Eide Christopher A. , Agarwal Anupriya , Adrian Lauren T. , Zabriskie Matthew S. , MacKenzie Ryan J. , LaTocha Dorian H. , Johnson Kara J. , You Huihong , Luo Jenny , Riddle Steven M. , Marks Bryan D. , Vogel Kurt W. , Koop Dennis R. , Apgar John , Tyner Jeffrey W. , Deininger Michael W. , Druker Brian J. 
Published: April 2013

Abstract
The imatinib paradigm in chronic myelogenous leukemia (CML) established continuous BCR-ABL inhibition as a design principle for ABL tyrosine kinase inhibitors (TKI). However, clinical responses seen in patients treated with the ABL TKI dasatinib despite its much shorter plasma half-life and the apparent rapid restoration of BCR-ABL signaling activity following once-daily dosing suggested acute, potent inhibition of kinase activity may be sufficient to irrevocably commit CML cells to apoptosis. To determine the specific requirements for ABL TKI-induced CML cell death for a panel of clinically important ABL TKIs (imatinib, nilotinib, dasatinib, ponatinib, and DCC-2036), we interrogated response of CML cell lines and primary CML cells following acute drug exposure using intracellular fluorescence-activated cell sorting and immunoblot analyses of BCR-ABL signaling, apoptosis measurements, liquid chromatography/tandem mass spectrometry of intracellular drug levels, and biochemical TKI dissociation studies. Importantly, significant intracellular TKI stores were detected following drug washout, levels of which tracked with onset of apoptosis and incomplete return of BCR-ABL signaling, particularly pSTAT5, to baseline. Among TKIs tested, ponatinib showed the most robust capacity for apoptotic commitment showing sustained suppression of BCR-ABL signaling even at low intracellular levels following extensive washout, consistent with high-affinity binding and slow dissociation from ABL kinase. Together, our findings suggest commitment of CML cells to apoptosis requires protracted incomplete restoration of BCR-ABL signaling mediated by intracellular retention of TKIs above a quantifiable threshold. These studies refine our understanding of apoptotic commitment in CML cells and highlight parameters important to design of therapeutic kinase inhibitors for CML and other malignancies. Cancer Res; 73(11); 3356–70. ©2013 AACR.
Hedgehog Signaling Alters Reliance on EGF Receptor Signaling and Mediates Anti-EGFR Therapeutic Resistance in Head and Neck Cancer
Authors: Keysar Stephen B. , Le Phuong N. , Anderson Ryan T. , Morton J. Jason , Bowles Daniel W. , Paylor Jeramiah J. , Vogler Brian W. , Thorburn Jackie , Fernandez Pamela , Glogowska Magdalena J. , Takimoto Sarah M. , Sehrt Daniel B. , Gan Gregory N. , Eagles-Soukup Justin R. , Serracino Hilary , Hirsch Fred R. , Lucia M. Scott , Thorburn Andrew , Song John I. , Wang Xiao-Jing , Jimeno Antonio 
Published: April 2013

Abstract
The EGF receptor (EGFR)-directed monoclonal antibody cetuximab is the only targeted therapy approved for the treatment of squamous cell carcinoma of the head and neck (HNSCC) but is only effective in a minority of patients. Epithelial-to-mesenchymal transition (EMT) has been implicated as a drug resistance mechanism in multiple cancers, and the EGFR and Hedgehog pathways (HhP) are relevant to this process, but the interplay between the two pathways has not been defined in HNSCC. Here, we show that HNSCC cells that were naturally sensitive to EGFR inhibition over time developed increased expression of the HhP transcription factor GLI1 as they became resistant after long-term EGFR inhibitor exposure. This robustly correlated with an increase in vimentin expression. Conversely, the HhP negatively regulated an EGFR-dependent, EMT-like state in HNSCC cells, and pharmacologic or genetic inhibition of HhP signaling pushed cells further into an EGFR-dependent phenotype, increasing expression of ZEB1 and VIM. In vivo treatment with cetuximab resulted in tumor shrinkage in four of six HNSCC patient-derived xenografts; however, they eventually regrew. Cetuximab in combination with the HhP inhibitor IPI-926 eliminated tumors in two cases and significantly delayed regrowth in the other two cases. Expression of EMT genes TWIST and ZEB2 was increased in sensitive xenografts, suggesting a possible resistant mesenchymal population. In summary, we report that EGFR-dependent HNSCC cells can undergo both EGFR-dependent and -independent EMT and HhP signaling is a regulator in both processes. Cetuximab plus IPI-926 forces tumor cells into an EGFR-dependent state, delaying or completely blocking tumor recurrence. Cancer Res; 73(11); 3381–92. ©2013 AACR.
Dual Role of the Antioxidant Enzyme Peroxiredoxin 6 in Skin Carcinogenesis
Authors: Rolfs Frank , Huber Marcel , Gruber Florian , Böhm Friederike , Pfister Herbert J. , Bochkov Valery N. , Tschachler Erwin , Dummer Reinhard , Hohl Daniel , Schäfer Matthias , Werner Sabine 
Published: April 2013

Abstract
The antioxidant enzyme peroxiredoxin 6 (Prdx6) is a key regulator of the cellular redox balance, particularly under stress conditions. We identified Prdx6 as an important player in different phases of skin carcinogenesis. Loss of Prdx6 in mice enhanced the susceptibility to skin tumorigenesis, whereas overexpression of Prdx6 in keratinocytes of transgenic mice had the opposite effect. The tumor-preventive effect of Prdx6, which was observed in a human papilloma virus 8–induced and a chemically induced tumor model, was not due to alterations in keratinocyte proliferation, apoptosis, or in the inflammatory response. Rather, endogenous and overexpressed Prdx6 reduced oxidative stress as reflected by the lower levels of oxidized phospholipids in the protumorigenic skin of Prdx6 transgenic mice and the higher levels in Prdx6-knockout mice than in control animals. In contrast to its beneficial effect in tumor prevention, overexpression of Prdx6 led to an acceleration of malignant progression of existing tumors, revealing a dual function of this enzyme in the pathogenesis of skin cancer. Finally, we found strong expression of PRDX6 in keratinocytes of normal human skin and in the tumor cells of squamous cell carcinomas, indicating a role of Prdx6 in human skin carcinogenesis. Taken together, our data point to the potential usefulness of Prdx6 activators or inhibitors for controlling different stages of skin carcinogenesis. Cancer Res; 73(11); 3460–9. ©2013 AACR.
Gankyrin Activates IL-8 to Promote Hepatic Metastasis of Colorectal Cancer
Authors: Bai Zhaofang , Tai Yanhong , Li Weihua , Zhen Cheng , Gu Weiting , Jian Zhao , Wang Qianyi , Lin Jieru E. , Zhao Qing , Gong Weili , Liang Bing , Wang Chenguang , Zhou Tao 
Published: April 2013

Abstract
Hepatic metastasis is responsible for the majority of colorectal cancer (CRC)-related mortalities. Although Gankyrin (PSMD10) has been implicated in cancer metastasis, its exact role and underlying mechanisms of CRC hepatic metastasis remain largely unknown. Herein, we showed that the expression of Gankyrin was higher in primary CRC with hepatic metastasis compared with CRC without metastasis. RNAi-mediated silencing of Gankyrin expression in highly metastatic human CRC cells impaired their migratory and metastatic capacity in vivo. Genome-wide transcriptome profiling revealed activation of the interleukin (IL)-8 signaling pathway by Gankyrin. Protein levels of IL-8 and cyclin D1 (CCND1), the two important molecules in the IL-8 pathway, were positively correlated with Gankyrin expression in human CRC specimens. Furthermore, genetic deletion of cyclin D1 showed its requirement in Gankyrin-mediated cell migration. Finally, administration of recombinant IL-8 rescued the migratory defect of CRC cells where Gankyrin expression was silenced. Together, our findings highlight the importance of Gankyrin in hepatic metastasis of CRC and point out its candidature as a potential prognostic marker and therapeutic target to improve the clinical management of metastatic CRC. Cancer Res; 73(14); 4548–58. ©2013 AACR.
Early Diagnostic Biomarkers for Esophageal Adenocarcinoma—The Current State of Play
Authors: Shah Alok Kishorkumar , Saunders Nicholas A. , Barbour Andrew P. , Hill Michelle M. 
Published: April 2013

AbstractEsophageal adenocarcinoma (EAC) is one of the two most common types of esophageal cancer with alarming increase in incidence and very poor prognosis. Aiming to detect EAC early, currently high-risk patients are monitored using an endoscopic-biopsy approach. However, this approach is prone to sampling error and interobserver variability. Diagnostic tissue biomarkers related to genomic and cell-cycle abnormalities have shown promising results, although with current technology these tests are difficult to implement in the screening of high-risk patients for early neoplastic changes. Differential miRNA profiles and aberrant protein glycosylation in tissue samples have been reported to improve performance of existing tissue-based diagnostic biomarkers. In contrast to tissue biomarkers, circulating biomarkers are more amenable to population-screening strategies, due to the ease and low cost of testing. Studies have already shown altered circulating glycans and DNA methylation in BE/EAC, whereas disease-associated changes in circulating miRNA remain to be determined. Future research should focus on identification and validation of these circulating biomarkers in large-scale trials to develop in vitro diagnostic tools to screen population at risk for EAC development. Cancer Epidemiol Biomarkers Prev; 22(7); 1185–209. ©2013 AACR.
Translation Initiation Factor eIF3b Expression in Human Cancer and Its Role in Tumor Growth and Lung Colonization
Authors: Wang Hong , Ru Yuanbin , Sanchez-Carbayo Marta , Wang Xuejiao , Kieft Jeffrey S. , Theodorescu Dan 
Published: April 2013

Abstract
Purpose: Discovery transcriptomic analyses suggest eukaryotic initiation factor 3b (eIF3b) is elevated in human bladder and prostate cancer, yet its role as a prognostic factor or its requirement in the maintenance or progression of human cancer is not established. Here, we determine the therapeutic potential of eIF3b by examining the clinical relevance of its expression in human cancer tissues and its role in experimental tumor models.
Experimental Design: We examined mRNA expression of eIF3b in bladder (N = 317) and prostate (N = 566) tissue samples and protein expression by immunohistochemistry in 143 bladder tumor samples as a function of clinicopathologic features. The impact of eIF3b depletion by siRNA in human cancer lines was evaluated in regard to in vitro cell growth, cell cycle, migration, in vivo subcutaneous tumor growth, and lung colonization.
Results: eIF3b mRNA expression correlated to tumor grade, stage, and survival in human bladder and prostate cancer. eIF3b protein expression stratified survival in human bladder cancer. eIF3b depletion reduced in vitro cancer cell growth; inhibited G1–S cell-cycle transition by changing protein but not RNA expression of cyclin A, E, Rb, and p27Kip1; inhibited migration; and disrupted actin cytoskeleton and focal adhesions. These changes were associated with decreased protein expression of integrin α5. Integrin α5 depletion phenocopied effects observed with eIF3b. eIF3b-depleted bladder cancer cells formed fewer subcutaneous tumors that grew more slowly and had reduced lung colonization.
Conclusion: eIF3b expression relates to human bladder and prostate cancer prognosis, is required for tumor growth, and thus a candidate therapeutic target. Clin Cancer Res; 19(11); 2850–60. ©2013 AACR.
Discovery and Prevalidation of Salivary Extracellular microRNA Biomarkers Panel for the Noninvasive Detection of Benign and Malignant Parotid Gland Tumors
Authors: Matse Johannes H. , Yoshizawa Janice , Wang Xiaoyan , Elashoff David , Bolscher Jan G.M. , Veerman Enno C.I. , Bloemena Elisabeth , Wong David T.W. 
Published: April 2013

AbstractPurpose: This study was conducted to explore the differences in salivary microRNA (miRNA) profiles between patients with malignant or benign parotid gland tumors as a potential preoperative diagnostic tool of tumors in the salivary glands.Experimental Design: Whole saliva samples from patients with malignant (n = 38) or benign (n = 29) parotid gland tumors were obtained from the Salivary Gland Tumor Biorepository (SGTB). After total RNA isolation, human miRNA cards were used for miRNA profiling. The differential miRNA expression was analyzed using two-sided Wilcoxon test. Quantitative real-time PCR (qRT-PCR) was used to validate selected miRNAs in an independent sample set. Receiver-operating characteristics curve and probability of malignancy was exploited to evaluate the diagnostic power of the validated miRNAs.Results: With miRNA profiling, 57 of 750 investigated miRNAs were differently expressed, of which 54 showed higher miRNA expression in samples from patients with malignant tumors than those from patients with benign tumors. Validating the expression in an independent sample set of 9 miRNAs revealed indeed higher expression of miRNAs in malignant samples compared with benign samples. The expression of 6 validated miRNAs was statistically significantly different between the two groups (P &lt; 0.05). A four miRNA combination was able to discriminate between saliva samples from patients with malignant tumors from those of patients with benign parotid gland tumors (sensitivity 69%, specificity 95%).Conclusions: Salivary miRNA profiles differ in saliva from patients with malignant from saliva from patients with a benign parotid gland tumor. These preliminary results are promising to develop a noninvasive diagnostic tool for diagnosing tumors in the salivary glands. Clin Cancer Res; 19(11); 3032–8. ©2013 AACR.
Sedentary Behavior, Physical Activity, and Likelihood of Breast Cancer among Black and White Women: A Report from the Southern Community Cohort Study
Authors: Cohen Sarah S. , Matthews Charles E. , Bradshaw Patrick T. , Lipworth Loren , Buchowski Maciej S. , Signorello Lisa B. , Blot William J. 
Published: April 2013

Abstract
Increased physical activity has been shown to be protective for breast cancer although few studies have examined this association in Black women. In addition, limited evidence to date indicates that sedentary behavior may be an independent risk factor for breast cancer. We examined sedentary behavior and physical activity in relation to subsequent incident breast cancer in a nested case–control study within 546 cases (374 among Black women) and 2,184 matched controls enrolled in the Southern Community Cohort Study. Sedentary and physically active behaviors were assessed via self-report at study baseline (2002–2009) using a validated physical activity questionnaire. Conditional logistic regression was used to estimate mutually adjusted ORs and corresponding 95% confidence intervals (CI) for quartiles of sedentary and physical activity measures in relation to breast cancer risk. Being in the highest versus lowest quartile of total sedentary behavior (≥12 vs. &lt;5.5 h/d) was associated with increased odds of breast cancer among White women [OR, 1.94 (95% CI, 1.01–3.70); Ptrend = 0.1] but not Black women [OR, 1.23 (95% CI, 0.82–1.83); Ptrend = 0.6] after adjustment for physical activity. After adjustment for sedentary activity, greater physical activity was associated with reduced odds for breast cancer among White women (Ptrend = 0.03) only. In conclusion, independent of one another, sedentary behavior and physical activity are risk factors for breast cancer among White women. Differences in these associations between Black and White women require further investigation. Reducing sedentary behavior and increasing physical activity are potentially independent targets for breast cancer prevention interventions. Cancer Prev Res; 6(6); 566–76. ©2013 AACR.
A Model for Primary Melanoma of the CNS Implicates NRAS
Authors: Ciarlo Christie A. , Zon Leonard I. 
Published: April 2013

Abstract
Summary: In this issue of Cancer Discovery, Pedersen and colleagues present the first mouse model of primary CNS melanoma, which arises when oncogenic NRAS is expressed from the endogenous Nras promoter in melanocytes during embryogenesis. In support of this model, two pediatric cases of NRAS-mutant primary melanoma of the CNS are identified. Cancer Discov; 3(4); 382–3. ©2013 AACR.
See related article by Pedersen et al., p. 458
Action Concepts in the Brain: An Activation Likelihood Estimation Meta-analysis
Authors: Watson Christine E. , Cardillo Eileen R. , Ianni Geena R. , Chatterjee Anjan 
Published: April 2013

AbstractMany recent neuroimaging studies have investigated the representation of semantic memory for actions in the brain. We used activation likelihood estimation (ALE) meta-analyses to answer two outstanding questions about the neural basis of action concepts. First, on an “embodied” view of semantic memory, evidence to date is unclear regarding whether visual motion or motor systems are more consistently engaged by action concepts. Second, few studies have directly investigated the possibility that action concepts accessed verbally or nonverbally recruit different areas of the brain. Because our meta-analyses did not include studies requiring the perception of dynamic depictions of actions or action execution, we were able to determine whether conceptual processing alone recruits visual motion and motor systems. Significant concordance in brain regions within or adjacent to visual motion areas emerged in all meta-analyses. By contrast, we did not observe significant concordance in motor or premotor cortices in any analysis. Neural differences between action images and action verbs followed a gradient of abstraction among representations derived from visual motion information in the left lateral temporal and occipital cortex. The consistent involvement of visual motion but not motor brain regions in representing action concepts may reflect differences in the variability of experience across individuals with perceiving versus performing actions.
NEW TECHNIQUES FOR THE ANATOMICAL STUDY OF CHARCOALIFIED WOOD
Authors: Angeles Guillermo 
Published: April 2013

Studies of charcoalified wood have followed two main approaches: observation of fractured surfaces, either under the dissecting or SE microscope, and observation of thin slices of epoxy-embedded samples with the light microscope. I introduce here a combination of techniques overcoming some of the problems these typical methods have presented, related to trouble with the high reflectance of fractured surfaces when observations are made using light microscopy, unavailability of equipment, and time-consuming, sample-altering methodologies. I used transverse surfaces painted with correction fluid for determination of vessel grouping and distribution, and indirect replicas of transverse and longitudinal surfaces made of nail polish for observation of other features including intervessel pit apertures, and ray size and composition. Good results are obtained even with a routine light microscope.
APPLICATION OF NEAR INFRARED SPECTROSCOPY TO A DIVERSE RANGE OF SPECIES DEMONSTRATING WIDE DENSITY AND STIFFNESS VARIATION
Authors: Schimleck Laurence , Evans Robert , Ilic Jugo 
Published: April 2013

The application of near infrared (NIR) spectroscopy to a large number of mixed species that display extremely wide variations in wood chemistry, anatomy and physical properties, is described. The mixed species samples were characterized in terms of density, longitudinal modulus of elasticity and microfibril angle. NIR spectra were obtained from the radial / longitudinal face of each sample and used to generate calibrations for the measured physical properties. The calibrations developed for density and longitudinal modulus of elasticity had the highest coefficients of determination (R2) and demonstrated that it is possible to develop general calibrations for these important wood properties across a wide range of species.
The mixed species calibrations were used to estimate wood properties of two species, Eucalyptus delegatensis R.T. Baker and Pinus radiata D.Don. The results obtained for density and longitudinal modulus of elasticity indicated that mixed species calibrations can be used to rank trees. In practice the extreme variation of samples selected for this study would not be required. It is expected that refinement of calibrations, through sample selection, would provide more accurate prediction of physical properties.