bluuebunny/crossref_metadata_2025_split huggingface dataset:
Agonist Anti-CD137 mAb Act on Tumor Endothelial Cells to Enhance Recruitment of Activated T Lymphocytes
Authors: Palazón Asís , Teijeira Alvaro , Martínez-Forero Iván , Hervás-Stubbs Sandra , Roncal Carmen , Peñuelas Iván , Dubrot Juan , Morales-Kastresana Aizea , Pérez-Gracia José Luis , Ochoa M. Carmen , Ochoa-Callejero Laura , Martínez Alfredo , Luque Alfonso , Dinchuk Joseph , Rouzaut Ana , Jure-Kunkel Maria , Melero Ignacio 
Published: January 2011

Abstract
Agonist monoclonal antibodies (mAb) to the immune costimulatory molecule CD137, also known as 4-1BB, are presently in clinical trials for cancer treatment on the basis of their costimulatory effects on primed T cells and perhaps other cells of the immune system. Here we provide evidence that CD137 is selectively expressed on the surface of tumor endothelial cells. Hypoxia upregulated CD137 on murine endothelial cells. Treatment of tumor-bearing immunocompromised Rag−/− mice with agonist CD137 mAb did not elicit any measurable antiangiogenic effects. In contrast, agonist mAb stimulated tumor endothelial cells, increasing cell surface expression of the adhesion molecules intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and E-selectin. When adoptively transferred into mice, activated T lymphocytes derived from CD137-deficient animals entered more avidly into tumor tissue after treatment with agonist mAb. This effect could be neutralized with anti–ICAM-1 and anti–VCAM-1 blocking antibodies. Thus, stimulation of CD137 not only enhanced T-cell activation but also augmented their trafficking into malignant tissue, through direct actions on the blood vessels that irrigate the tumor. Our findings identify an additional mechanism of action that can explain the immunotherapeutic effects of agonist CD137 antibodies. Cancer Res; 71(3); 801–11. ©2011 AACR.
Hydrophilic Agarose Macrobead Cultures Select for Outgrowth of Carcinoma Cell Populations That Can Restrict Tumor Growth
Authors: Smith Barry H. , Gazda Lawrence S. , Conn Bryan L. , Jain Kanti , Asina Shirin , Levine Daniel M. , Parker Thomas S. , Laramore Melissa A. , Martis Prithy C. , Vinerean Horatiu V. , David Eric M. , Qiu Suizhen , North Alison J. , Couto C. Guillermo , Post Gerald S. , Waters David J. , Cordon-Cardo Carlos , Hall Richard D. , Gordon Bruce R. , Diehl Carolyn H. , Stenzel Kurt H. , Rubin Albert L. 
Published: January 2011

Abstract
Cancer cells and their associated tumors have long been considered to exhibit unregulated proliferation or growth. However, a substantial body of evidence indicates that tumor growth is subject to both positive and negative regulatory controls. Here, we describe a novel property of tumor growth regulation that is neither species nor tumor-type specific. This property, functionally a type of feedback control, is triggered by the encapsulation of neoplastic cells in a growth-restricting hydrogel composed of an agarose matrix with a second coating of agarose to form 6- to 8-mm diameter macrobeads. In a mouse cell model of renal adenocarcinoma (RENCA cells), this process resulted in selection for a stem cell–like subpopulation which together with at least one other cell subpopulation drove colony formation in the macrobeads. Cells in these colonies produced diffusible substances that markedly inhibited in vitro and in vivo proliferation of epithelial-derived tumor cells outside the macrobeads. RENCA cells in monolayer culture that were exposed to RENCA macrobead-conditioned media exhibited cell-cycle accumulation in S phase due to activation of a G2/M checkpoint. At least 10 proteins with known tumor suppression functions were identified by analysis of RENCA macrobead-conditioned media, the properties of which offer opportunities to further dissect the molecular basis for tumor growth control. More generally, macrobead culture may permit the isolation of cancer stem cells and other cells of the stem cell niche, perhaps providing strategies to define more effective biologically based clinical approaches to treat neoplastic disease. Cancer Res; 71(3); 725–35. ©2011 AACR.
EGFR Nuclear Translocation Modulates DNA Repair following Cisplatin and Ionizing Radiation Treatment
Authors: Liccardi Gianmaria , Hartley John A. , Hochhauser Daniel 
Published: January 2011

Abstract
Epidermal growth factor receptor (EGFR) overexpression is associated with resistance to chemotherapy and radiotherapy. It modulates DNA repair after radiation-induced damage through association with the catalytic subunit of DNA protein kinase (DNA-PKcs). We investigated the role of EGFR nuclear import and its association with DNA-PKcs on DNA repair after exposure to cisplatin or ionizing radiation (IR). The model system was based on EGFR-null murine NIH3T3 fibroblasts in which EGFR expression was restored with isoforms that were wild-type (wt), derived from human cancers (L858R, EGFRvIII), or mutated in the nuclear localization signal (NLS) sequence. In cells expressing wtEGFR or EGFRvIII, there was complete unhooking of cisplatin-induced interstrand cross-links and repair of IR-induced strand breaks. In contrast, cells expressing L858R or NLS mutations showed reduced unhooking of interstrand cross-links and repair of strand breaks. Immunoprecipitation showed wtEGFR and EGFRvIII binding to DNA-PKcs, increasing 2-fold 18 hours after cisplatin therapy. Confocal microscopy and proximity ligation assay showed that this interaction in the cytoplasm and nucleus was associated with increased DNA protein kinase complex (DNA-PK) activity. Cells expressing the EGFR L858R mutation, which has constitutive kinase activity, exhibited reduced DNA repair without nuclear localization. EGFR-NLS mutants showed impaired nuclear localization and DNA-PKcs association with reduced DNA repair and DNA-PK kinase activity. In summary, EGFR nuclear localization was required for modulation of cisplatin and IR-induced repair of DNA damage. EGFR–DNA-PKcs binding was induced by cisplatin or IR but not by EGFR nuclear translocation per se. Our findings show that EGFR subcellular distribution can modulate DNA repair kinetics, with implications for design of EGFR-targeted combinational therapies. Cancer Res; 71(3); 1103–14. ©2011 AACR.
HSulf-1 Modulates FGF2- and Hypoxia-Mediated Migration and Invasion of Breast Cancer Cells
Authors: Khurana Ashwani , Liu Peng , Mellone Pasquale , Lorenzon Laura , Vincenzi Bruno , Datta Kaustubh , Yang Bo , Linhardt Robert J. , Lingle Wilma , Chien Jeremy , Baldi Alfonso , Shridhar Viji 
Published: January 2011

Abstract
HSulf-1 modulates the sulfation states of heparan sulfate proteoglycans critical for heparin binding growth factor signaling. In the present study, we show that HSulf-1 is transcriptionally deregulated under hypoxia in breast cancer cell lines. Knockdown of HIF-1α rescued HSulf-1 downregulation imposed by hypoxia, both at the RNA and protein levels. Chromatin immunoprecipitation with HIF-1α and HIF-2α antibodies confirmed recruitment of HIF-α proteins to the two functional hypoxia-responsive elements on the native HSulf-1 promoter. HSulf-1 depletion in breast cancer cells resulted in an increased and sustained bFGF2 (basic fibroblast growth factor) signaling and promoted cell migration and invasion under hypoxic conditions. In addition, FGFR2 (fibroblast growth factor receptor 2) depletion in HSulf-1–silenced breast cancer cells attenuated hypoxia-mediated cell invasion. Immunohistochemical analysis of 53 invasive ductal carcinomas and their autologous metastatic lesions revealed an inverse correlation for the expression of HSulf-1 to CAIX in both the primary tumors (P ≥ 0.0198) and metastatic lesions (P ≥ 0.0067), respectively, by χ2 test. Finally, HSulf-1 expression levels in breast tumors by RNA in situ hybridization showed that high HSulf-1 expression is associated with increased disease-free and overall survival (P ≥ 0.03 and P ≥ 0.0001, respectively). Collectively, these results reveal an important link between loss of HSulf-1 under hypoxic microenvironment and increased growth factor signaling, cell migration, and invasion. Cancer Res; 71(6); 2152–61. ©2011 AACR.
Cancer Stem Cell Niche: The Place to Be
Authors: Borovski Tijana , De Sousa E Melo Felipe , Vermeulen Louis , Medema Jan Paul 
Published: January 2011

Abstract
Tumors are being increasingly perceived as abnormal organs that, in many respects, recapitulate the outgrowth and differentiation patterns of normal tissues. In line with this idea is the observation that only a small fraction of tumor cells is capable of initiating a new tumor. Because of the features that these cells share with somatic stem cells, they have been termed cancer stem cells (CSC). Normal stem cells reside in a “stem cell niche” that maintains them in a stem-like state. Recent data suggest that CSCs also rely on a similar niche, dubbed the “CSC niche,” which controls their self-renewal and differentiation. Moreover, CSCs can be generated by the microenvironment through induction of CSC features in more differentiated tumor cells. In addition to a role in CSC maintenance, the microenvironment is hypothesized to be involved in metastasis by induction of the epithelial-mesenchymal transition, leading to dissemination and invasion of tumor cells. The localization of secondary tumors also seems to be orchestrated by the microenvironment, which is suggested to form a premetastatic niche. Thus, the microenvironment seems to be of crucial importance for primary tumor growth as well as metastasis formation. Combined with its role in the protection of CSCs against genotoxic insults, these data strongly put forward the niche as an important target for novel therapies. Cancer Res; 71(3); 634–9. ©2011 AACR.
Cyst Fluid Interleukin-1β (IL1β) Levels Predict the Risk of Carcinoma in Intraductal Papillary Mucinous Neoplasms of the Pancreas
Authors: Maker Ajay V. , Katabi Nora , Qin Li-Xuan , Klimstra David S. , Schattner Mark , Brennan Murray F. , Jarnagin William R. , Allen Peter J. 
Published: January 2011

Abstract
Purpose: Biomarkers for high-grade dysplasia in patients with radiographically identified intraductal papillary mucinous neoplasms (IPMN) have not been described. We hypothesized that dysplasia in IPMN invokes an immunogenic/proinflammatory microenvironment that can be identified by cyst fluid cytokine levels.
Experimental Design: Pancreatic cyst fluid aspirates were collected at resection (2005–2009). Samples were grouped into low-risk [low-grade (n = 6) or moderate dysplasia (n = 15)] and high-risk groups [high-grade dysplasia (n = 13) or carcinoma (n = 6)]. Cytokine expression was determined using a multiplex sandwich immunoassay. Differences in cytokine expression were evaluated using the 2-sample t test. Sample classification was performed using a logistic regression adjusting for sample covariates.
Results: IL5 and IL8 concentrations were higher in the cyst fluid from patients in the high-risk group than the low-risk group. Interleukin (IL)-1β concentrations were also higher in the cyst fluid from patients with high-grade dysplasia or cancer (n = 19) than those with low- or moderate-grade dysplasia (n = 21, 539 ± 255 pg/mL vs. 0.2 ± 0.1 pg/mL; P &lt; 0.0001). IL1β remained a significant predictor of high-risk cysts after multivariate analysis. There was no significant difference in levels of IL2, IL4, IL10, IL12, IL13, TNF-α, or IFN-γ between the groups. That IL1β levels identified cysts at a high risk of malignancy was confirmed in an independent validation set.
Conclusions: Cyst fluid levels of IL1β can differentiate low- from high-risk IPMN. This study introduces IL1β as a potential biomarker for validation in larger clinical studies. Clin Cancer Res; 17(6); 1502–8. ©2011 AACR.
Combined Blockade of Src Kinase and Epidermal Growth Factor Receptor with Gemcitabine Overcomes STAT3-Mediated Resistance of Inhibition of Pancreatic Tumor Growth
Authors: Nagaraj Nagathihalli S. , Washington M. Kay , Merchant Nipun B. 
Published: January 2011

Abstract
Purpose: We previously established a mechanistic rationale for Src inhibition as a novel therapeutic target in pancreatic cancer and have identified activated STAT3 as a potential biomarker of resistance to Src inhibition. The purpose of this study was to translate the current understanding of complementary activated tyrosine kinase signaling pathways by targeting Src kinase and epidermal growth factor receptor (EGFR).
Experimental Design: IC50 values for dasatinib, a Src kinase inhibitor, erlotinib, an EGFR tyrosine kinase inhibitor and gemcitabine were determined and sensitive and resistant pancreatic cancer cell lines were identified. The in vitro and in vivo effects of these agents on multiple signaling pathways and tumorigenicity in pancreatic cancer were investigated.
Results: The combination of dasatinib, erlotinib, and gemcitabine resulted in cooperative inhibition of cell migration and invasion of both sensitive and resistant pancreatic cancer cells as well as cooperative inhibition of multiple signaling pathways including FAK, AKT, ERK, JNK, MAPK, and STAT3 at concentrations that were ineffective as individual agents or as double combinations of agents. The triple combination of agents was also most effective at inhibiting the growth of xenografts of both sensitive and resistant pancreatic cancer cells in vivo without increasing toxicity. Furthermore, combined inhibition of Src and EGFR with gemcitabine inhibited constitutively activated STAT3 in vitro and in vivo.
Conclusions: These results provide evidence that combined targeted biological therapy in addition to cytotoxic chemotherapy can overcome treatment resistance. Such treatment strategies may be used to tailor therapy based on identified biomarkers of resistance to targeted monotherapy. Clin Cancer Res; 17(3); 483–93. ©2011 AACR.
A20, ABIN-1/2, and CARD11 Mutations and Their Prognostic Value in Gastrointestinal Diffuse Large B-Cell Lymphoma
Authors: Dong Gehong , Chanudet Estelle , Zeng Naiyan , Appert Alex , Chen Yun-Wen , Au Wing-Yan , Hamoudi Rifat A. , Watkins A. James , Ye Hongtao , Liu Hongxiang , Gao Zifen , Chuang Shih-Sung , Srivastava Gopesh , Du Ming-Qing 
Published: January 2011

Abstract
Purpose: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of aggressive lymphomas with the activated B-cell–like subtype characterized by constitutive NF-κB activation. Activating mutations of CARD11 and inactivating mutations of A20 are frequent events in DLBCL. However, the full extent of genetic alterations in the NF-κB pathway regulators and their potential prognostic value in DLBCL remain to be investigated. We investigated the genetic abnormalities of CARD11, A20, and ABIN-1/2/3 (the A20 binding inhibitor of NF-κB) and their clinicopathologic correlation in gastrointestinal DLBCL.
Experimental Design: The somatic mutation and copy number changes of CARD11, A20, and ABIN-1/2/3 were investigated in 71 gastrointestinal DLBCLs by PCR/sequencing, and interphase FISH/array comparative genomic hybridization, respectively. The mutations identified were functionally characterized by NF-κB reporter assays and immunoprecipitation experiments.
Results: Recurrent somatic mutations were found in CARD11 (10%), A20 (17%), ABIN-1 (4%), and ABIN-2 (3%), but not in ABIN-3. In comparison with the wild-type, all CARD11 mutants were potent NF-κB activators in vitro. On the basis of the destructive nature of the observed mutations, and the findings by reporter assays and immunoprecipitation studies, most if not all of the somatic mutations that were seen in A20, ABIN-1, and ABIN-2 could impair their normal functions. Among these genetic abnormalities, A20 somatic mutation was significantly associated with both poor overall survival and event-free survival.
Conclusions: We show further evidence of NF-κB pathway genetic abnormalities in DLBCL, which are potentially valuable in the prognosis and design of future therapeutic strategies. Clin Cancer Res; 17(6); 1440–51. ©2011 AACR.
Mechanisms of In-Stent Restenosis After Drug-Eluting Stent Implantation
Authors: Kang Soo-Jin , Mintz Gary S. , Park Duk-Woo , Lee Seung-Whan , Kim Young-Hak , Whan Lee Cheol , Han Ki-Hoon , Kim Jae-Joong , Park Seong-Wook , Park Seung-Jung 
Published: January 2011

Background—
We used intravascular ultrasound (IVUS) to (1) clarify the mechanisms of luminal loss after drug-eluting stent (DES) implantation and (2) classify morphological patterns of in-stent restenosis (ISR).

Methods and Results—

On the basis of IVUS-identified luminal narrowing (in-stent minimum lumen area <4 mm
2
), IVUS-defined ISR was classified as focal (luminal narrowing ≤10 mm in length), multifocal (≥1 focal lesions), and diffuse (luminal narrowing >10 mm in length) with or without stent edge involvement. Significant intimal hyperplasia (IH) was defined as IH area >50% of stent. Overall, 76 lesions had IVUS-defined ISR; 32 (42%) had stent underexpansion (minimal stent area <5 mm
2
); and 71 (93%) had IH area >50% of stent. Total stent length negatively correlated with minimal stent area (
r
=−0.613,
P
<0.001) as well as with stent area at the minimum lumen site (
r
=−0.436,
P
<0.001) but not with minimum lumen area (
r
=−0.084,
P
=0.472). Underexpansion was present at the minimum lumen site in 15 of 43 (35%) lesions with stent length >28 mm, even though there was significant IH in 34 (79%) lesions; conversely, in 32 of 33 (97%) lesions with stent length ≤28 mm, the minimum lumen site was not associated with stent underexpansion but significant IH. IVUS-defined focal ISR was most common (47%). Compared with focal ISR, normalized vessel, stent, lumen, and plaque volumes were smaller in diffuse and multifocal than focal ISR, with no difference in IH extent.

Conclusions—
In most DES restenosis, IH was the dominant mechanism of ISR. Nevertheless, underexpansion associated with longer stent length remained an important preventable mechanism of ISR.
Validation of Intravascular Ultrasound–Derived Parameters With Fractional Flow Reserve for Assessment of Coronary Stenosis Severity
Authors: Kang Soo-Jin , Lee Jong-Young , Ahn Jung-Min , Mintz Gary S. , Kim Won-Jang , Park Duk-Woo , Yun Sung-Cheol , Lee Seung-Whan , Kim Young-Hak , Whan Lee Cheol , Park Seong-Wook , Park Seung-Jung 
Published: January 2011

Background—
We assessed optimal intravascular ultrasound (IVUS) criteria for predicting functional significance of intermediate coronary lesions.

Methods and Results—

Overall, 201 patients with 236 coronary lesions underwent IVUS and invasive physiological assessment before intervention. Fractional flow reserve (FFR) was measured at maximal hyperemia induced by intravenous adenosine infusion. FFR <0.80 at maximum hyperemia was seen in 49 (21%) of the overall 236 lesions. The independent determinants of FFR were minimal lumen area (MLA; β=0.020; 95% confidence interval [CI], 0.008 to 0.031;
P
=0.032), plaque burden (β=−0.002; 95% CI, −0.003 to 0.001;
P
=0.001), lesion length with a lumen area <3.0 mm
2
(β=−0.003; 95% CI, −0.005 to −0.001;
P
=0.005), and left anterior descending artery location (β=−0.035; 95% CI, −0.055 to −0.016;
P
=0.001). The best cutoff value (with a maximal accuracy) of the MLA to predict FFR <0.80 was <2.4 mm
2
, with a diagnostic accuracy of 68% (90% sensitivity, 60% specificity, and area under the curve=0.800; 95% CI, 0.742 to 0.848;
P
<0.001). The cutoff value of plaque burden to predict FFR <0.80 was ≥79% (69% sensitivity, 72% specificity, and area under the curve=0.756; 95% CI, 0.696 to 0.810;
P
<0.001). The cutoff value of lesion length with a lumen area <3.0 mm
2
was 3.1 mm (84%sensitivity, 63%specificity, and area under the curve=0.765; 95% CI, 0.706 to 0.818;
P
<0.001). Among 117 lesions with an MLA ≥2.4 mm
2
, 112 (96%) had an FFR ≥0.80,; and all but 1 showed FFR ≥0.75. Conversely, 44 (37%) lesions with an MLA <2.4 mm
2
had an FFR <0.80.

Conclusions—

IVUS-derived MLA ≥2.4 mm
2
may be useful to exclude FFR <0.80, but poor specificity limits its value for physiological assessment of lesions with MLA <2.4 mm
2
. Thus, FFR or stress tests may be necessary to accurately identify ischemia-inducible intermediate stenoses.
Network Dynamics Mediating Ipsilateral Motor Cortex Activity during Unimanual Actions
Authors: Verstynen Timothy , Ivry Richard B. 
Published: January 2011

Abstract
Executing difficult actions with the left hand results in bilateral activity of motor areas along the precentral gyrus. Using TMS and fMRI, we explored the functional relationship between primary (M1) and premotor areas during unimanual actions, focusing on M1 activity in the ipsilateral hemisphere. Single-pulse TMS revealed that the amplitude of motor-evoked potentials (MEPs), elicited in the stationary right-hand muscles following left M1 stimulation, fluctuated with the state of homologous muscles in the moving left hand. This ipsilateral excitability was pronounced when the left-hand movements were more complex. We used fMRI to visualize the cortical dynamics during unimanual actions. Trial-by-trial fluctuations in ipsilateral M1 activity were correlated with contralateral M1 responses and this correlation increased with movement complexity. Consistent with previous studies, the left caudal precentral premotor area (pcPM) was engaged during movements of either hand. Following low-frequency rTMS over left pcPM, the correlation between the activity level in the two M1s increased. This finding indicates that left pcPM may regulate the unintentional mirroring of motor commands in M1 during unilateral movement.
The Continuity Illusion Does Not Depend on Attentional State: fMRI Evidence from Illusory Vowels
Authors: Heinrich Antje , Carlyon Robert P. , Davis Matthew H. , Johnsrude Ingrid S. 
Published: January 2011

Abstract
We investigate whether the neural correlates of the continuity illusion, as measured using fMRI, are modulated by attention. As we have shown previously, when two formants of a synthetic vowel are presented in an alternating pattern, the vowel can be identified if the gaps in each formant are filled with bursts of plausible masking noise, causing the illusory percept of a continuous vowel (“Illusion” condition). When the formant-to-noise ratio is increased so that noise no longer plausibly masks the formants, the formants are heard as interrupted (“Illusion Break” condition) and vowels are not identifiable. A region of the left middle temporal gyrus (MTG) is sensitive both to intact synthetic vowels (two formants present simultaneously) and to Illusion stimuli, compared to Illusion Break stimuli. Here, we compared these conditions in the presence and absence of attention. We examined fMRI signal for different sound types under three attentional conditions: full attention to the vowels; attention to a visual distracter; or attention to an auditory distracter. Crucially, although a robust main effect of attentional state was observed in many regions, the effect of attention did not differ systematically for the illusory vowels compared to either intact vowels or to the Illusion Break stimuli in the left STG/MTG vowel-sensitive region. This result suggests that illusory continuity of vowels is an obligatory perceptual process, and operates independently of attentional state. An additional finding was that the sensitivity of primary auditory cortex to the number of sound onsets in the stimulus was modulated by attention.