bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ultraviolet B Light‐induced Nitric Oxide/Peroxynitrite Imbalance in Keratinocytes—Implications for Apoptosis and Necrosis
Authors: Wu Shiyong , Wang Lei , Jacoby Adam M. , Jasinski Krystian , Kubant Ruslan , Malinski Tadeusz 
Published: January 2010

AbstractElevation of nitric oxide (NO˙) can either promote or inhibit ultraviolet B light (UVB)‐induced apoptosis. In this study, we determined real‐time concentration of NO˙ and peroxynitrite (ONOO−) and their role in regulation of membrane integrity and apoptosis. Nanosensors (diameter 300–500 nm) were used for direct in situ simultaneous measurements of NO˙ and ONOO− generated by UVB in cultured keratinocytes and mice epidermis. An exposure of keratinocytes to UVB immediately generated ONOO− at maximal concentration of 190 nm followed by NO˙ release with a maximal concentration of 91 nm. The kinetics of UVB‐induced NO˙/ONOO− was in contrast to cNOS agonist stimulated NO˙/ONOO− from keratinocytes. After stimulating cNOS by calcium ionophore (CaI), NO˙ release from keratinocytes was followed by ONOO− production. The [NO˙] to [ONOO−] ratio generated by UVB decreased below 0.5 indicating a serious imbalance between cytoprotective NO˙ and cytotoxic ONOO−—a main component of nitroxidative stress. The NO˙/ONOO− imbalance increased membrane damage and cell apoptosis was partially reversed in the presence of free radical scavenger. The results suggest that UVB‐induced and cNOS‐produced NO˙ is rapidly scavenged by photolytically and enzymatically generated superoxide (O2˙−) to produce high levels of ONOO−, which enhances oxidative injury and apoptosis of the irradiated cells.
The Neovessel Occlusion Efficacy of 151‐Hydroxypurpurin‐7‐Lactone Dimethyl Ester Induced with Photodynamic Therapy
Authors: Lim Siang Hui , Nowak‐Sliwinska Patrycja , Kamarulzaman Fadzly Adzhar , Van Den Bergh Hubert , Wagnières Georges , Lee Hong Boon 
Published: January 2010

AbstractIn this study, the photodynamic therapy (PDT) induced efficacy of a semi‐synthesized analogue 151‐hydroxypurpurin‐7‐lactone dimethyl ester or G2, in terms of chick chorioallantoic membrane blood vessel occlusion was evaluated in reference to verteporfin. Early formulation studies showed that G2 prepared in a system of cremophor EL 2.5% and ethanol 2.5% in saline was biocompatible up to 20 μL volume of injection. Following injection, G2 accumulation peaked within the first minute and its extravasation from intra‐ to extra‐vascular occurred somewhat slower as compared with verteporfin. In the PDT study, closure of capillaries and small neovessels was observed with 4 μg per embryo of G2 and a light dose of 20 J cm−2 at a fluence rate of 40 mW cm−2 filtered at 400–440 nm—a result that may be considered optimum for the treatment of age‐related macular degeneration (AMD). Also, partial occlusion of the large vessels was observed using the same dose of G2 and light—an effect which is desirable for cancer treatment. From this study, we conclude that G2 has the potential to be developed as a therapeutic agent for photodynamic treatment for AMD and cancer.
Controlling a Robot with Intention Derived from Motion
Authors: Crick Christopher , Scassellati Brian 
Published: January 2010

AbstractWe present a novel, sophisticated intention‐based control system for a mobile robot built from an extremely inexpensive webcam and radio‐controlled toy vehicle. The system visually observes humans participating in various playground games and infers their goals and intentions through analyzing their spatiotemporal activity in relation to itself and each other, and then builds a coherent narrative out of the succession of these intentional states. Starting from zero information about the room, the rules of the games, or even which vehicle it controls, it learns rich relationships between players, their goals and intentions, probing uncertain situations with its own behavior. The robot is able to watch people playing various playground games, learn the roles and rules that apply to specific games, and participate in the play. The narratives it constructs capture essential information about the observed social roles and types of activity. After watching play for a short while, the system is able to participate appropriately in the games. We demonstrate how the system acts appropriately in scenarios such as chasing, follow‐the‐leader, and variants of tag.
Myocardin Functions as an Effective Inducer of Growth Arrest and Differentiation in Human Uterine Leiomyosarcoma Cells
Authors: Kimura Yasunori , Morita Tsuyoshi , Hayashi Ken'ichiro , Miki Tsuneharu , Sobue Kenji 
Published: January 2010

Abstract
Myocardin is an important transcriptional regulator in smooth and cardiac muscle development. We noticed that the expression of myocardin was markedly downregulated in human uterine leiomyosarcoma cells. Restoration of myocardin expression induced the reexpression of smooth muscle marker proteins and the formation of well-developed actin fibers. A concomitant increase in the expression of a cyclin-dependent kinase inhibitor, p21, led to significantly reduced cell proliferation, via p21's inhibition of the G1-S transition. A p21 promoter-reporter assay showed that myocardin markedly increased p21's promoter activity. Furthermore, a serum response factor (SRF)–binding cis-element CArG box in the p21 promoter region was required for this myocardin effect. Chromatin immunoprecipitation and DNA-protein binding assays showed that myocardin indirectly bound to the CArG box in the p21 promoter through the interaction with SRF. Furthermore, immunohistochemistry revealed that the levels of myocardin and p21 were both lower in leiomyosarcoma samples than in normal smooth muscle tissue. Taken together, our results indicate that the downregulation of myocardin expression facilitates cell cycle progression via the reduction of p21 expression in human leimyosarcomas and suggest that myocardin could be a useful therapeutic target for this disease. Cancer Res; 70(2); 501–11
Modulation of T-Cell Activation by Malignant Melanoma Initiating Cells
Authors: Schatton Tobias , Schütte Ute , Frank Natasha Y. , Zhan Qian , Hoerning André , Robles Susanne C. , Zhou Jun , Hodi F. Stephen , Spagnoli Giulio C. , Murphy George F. , Frank Markus H. 
Published: January 2010

AbstractHighly immunogenic cancers such as malignant melanoma are capable of inexorable tumor growth despite the presence of antitumor immunity. Thus, only a restricted minority of tumorigenic malignant cells may possess the phenotypic and functional characteristics needed to modulate tumor-directed immune activation. Here we provide evidence supporting this hypothesis. Tumorigenic ABCB5+ malignant melanoma initiating cells (MMICs) possessed the capacity to preferentially inhibit IL-2–dependent T-cell activation and to support, in a B7.2-dependent manner, induction of CD4+CD25+FoxP3+ regulatory T cells (Tregs). Compared with melanoma bulk cell populations, ABCB5+ MMICs displayed lower levels of MHC class I, aberrant positivity for MHC class II, and lower expression levels of the melanoma-associated antigens MART-1, ML-IAP, NY-ESO-1, and MAGE-A. Additionally, these tumorigenic ABCB5+ subpopulations preferentially expressed the costimulatory molecules B7.2 and PD-1, both in established melanoma xenografts and in clinical tumor specimens. In immune activation assays, MMICs inhibited mitogen-dependent human peripheral blood mononuclear cell (PBMC) proliferation and IL-2 production more efficiently than ABCB5− melanoma cell populations. Moreover, coculture with ABCB5+ MMICs increased the abundance of Tregs, in a B7.2 signaling-dependent manner, along with IL-10 production by mitogen-activated PBMCs. Consistent with these findings, MMICs also preferentially inhibited IL-2 production and induced IL-10 secretion by cocultured patient-derived, syngeneic PBMCs. Our findings identify novel T-cell modulatory functions of ABCB5+ melanoma subpopulations and suggest specific roles for these MMICs in the evasion of antitumor immunity and in cancer immunotherapeutic resistance. Cancer Res; 70(2); 697–708
Regulation of Breast Cancer Stem Cell Activity by Signaling through the Notch4 Receptor
Authors: Harrison Hannah , Farnie Gillian , Howell Sacha J. , Rock Rebecca E. , Stylianou Spyros , Brennan Keith R. , Bundred Nigel J. , Clarke Robert B. 
Published: January 2010

Abstract
Notch receptor signaling pathways play an important role not only in normal breast development but also in breast cancer development and progression. We assessed the role of Notch receptors in stem cell activity in breast cancer cell lines and nine primary human tumor samples. Stem cells were enriched by selection of anoikis-resistant cells or cells expressing the membrane phenotype ESA+/CD44+/CD24low. Using these breast cancer stem cell populations, we compared the activation status of Notch receptors with the status in luminally differentiated cells, and we evaluated the consequences of pathway inhibition in vitro and in vivo. We found that Notch4 signaling activity was 8-fold higher in stem cell–enriched cell populations compared with differentiated cells, whereas Notch1 signaling activity was 4-fold lower in the stem cell–enriched cell populations. Pharmacologic or genetic inhibition of Notch1 or Notch4 reduced stem cell activity in vitro and reduced tumor formation in vivo, but Notch4 inhibition produced a more robust effect with a complete inhibition of tumor initiation observed. Our findings suggest that Notch4-targeted therapies will be more effective than targeting Notch1 in suppressing breast cancer recurrence, as it is initiated by breast cancer stem cells. Cancer Res; 70(2); 709–18
Natural Killer Cell Cytotoxicity Is Suppressed by Exposure to the Human NKG2D Ligand MICA*008 That Is Shed by Tumor Cells in Exosomes
Authors: Ashiru Omodele , Boutet Philippe , Fernández-Messina Lola , Agüera-González Sonia , Skepper Jeremy N. , Valés-Gómez Mar , Reyburn Hugh T. 
Published: January 2010

Abstract
The MHC class I–related chain (MIC) A and MICB ligands for the activating receptor NKG2D can be shed from tumor cells, and the presence of these soluble molecules in sera is related with compromised immune response and progression of disease. Recently, thiol disulphide isomerases and members of the ADAM (a disintegrin and metalloproteinase) gene family were identified as key enzymes in mediating MICA/B shedding from cells. Here, we report shedding of the most frequently expressed MICA allele in human populations (MICA*008) into exosomes, small membrane vesicles that are secreted upon fusion with the plasma membrane. Although similar to other MICA/B molecules in the extracellular domain, the predicted transmembrane and cytoplasmic domains of MICA*008 are quite different, and this difference seemed to be critical for the mode of release from tumor cells. Treatment of natural killer (NK) cells with exosomes containing MICA*008 molecules not only triggered downregulation of NKG2D from the cell surface but also provoked a marked reduction in NK cytotoxicity that is independent of NKG2D ligand expression by the target cell. Our findings reveal a mechanism of NK suppression in cancer that may facilitate immune escape and progression. Cancer Res; 70(2); 481–9
Opposing Effects of Toll-like Receptor (TLR3) Signaling in Tumors Can Be Therapeutically Uncoupled to Optimize the Anticancer Efficacy of TLR3 Ligands
Authors: Conforti Rosa , Ma Yuting , Morel Yannis , Paturel Carine , Terme Magali , Viaud Sophie , Ryffel Bernard , Ferrantini Maria , Uppaluri Ravindra , Schreiber Robert , Combadière Christophe , Chaput Nathalie , André Fabrice , Kroemer Guido , Zitvogel Laurence 
Published: January 2010

Abstract
Many cancer cells express Toll-like receptors (TLR) that offer possible therapeutic targets. Polyadenylic-polyuridylic acid [poly(A:U)] is an agonist of the Toll-like receptor TLR3 that displays anticancer properties. In this study, we illustrate how the immunostimulatory and immunosuppressive effects of this agent can be uncoupled to therapeutic advantage. We took advantage of two TLR3-expressing tumor models that produced large amounts of CCL5 (a CCR5 ligand) and CXCL10 (a CXCR3 ligand) in response to type I IFN and poly(A:U), both in vitro and in vivo. Conventional chemotherapy or in vivo injection of poly(A:U), alone or in combination, failed to reduce tumor growth unless an immunochemotherapeutic regimen of vaccination against tumor antigens was included. CCL5 blockade improved the efficacy of immunochemotherapy, whereas CXCR3 blockade abolished its beneficial effects. These findings show how poly(A:U) can elicit production of a range of chemokines by tumor cells that reinforce immunostimulatory or immunosuppressive effects. Optimizing the anticancer effects of TLR3 agonists may require manipulating these chemokines or their receptors. Cancer Res; 70(2); 490–500
Beyond Rapalog Therapy: Preclinical Pharmacology and Antitumor Activity of WYE-125132, an ATP-Competitive and Specific Inhibitor of mTORC1 and mTORC2
Authors: Yu Ker , Shi Celine , Toral-Barza Lourdes , Lucas Judy , Shor Boris , Kim Jae Eun , Zhang Wei-Guo , Mahoney Robert , Gaydos Christine , Tardio LuAnna , Kim Sung Kyoo , Conant Roger , Curran Kevin , Kaplan Joshua , Verheijen Jeroen , Ayral-Kaloustian Semiramis , Mansour Tarek S. , Abraham Robert T. , Zask Arie , Gibbons James J. 
Published: January 2010

Abstract
The mammalian target of rapamycin (mTOR) is a major component of the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway that is dysregulated in 50% of all human malignancies. Rapamycin and its analogues (rapalogs) partially inhibit mTOR through allosteric binding to mTOR complex 1 (mTORC1) but not mTOR complex 2 (mTORC2), an emerging player in cancer. Here, we report WYE-125132 (WYE-132), a highly potent, ATP-competitive, and specific mTOR kinase inhibitor (IC50: 0.19 ± 0.07 nmol/L; &gt;5,000-fold selective versus PI3Ks). WYE-132 inhibited mTORC1 and mTORC2 in diverse cancer models in vitro and in vivo. Importantly, consistent with genetic ablation of mTORC2, WYE-132 targeted P-AKT(S473) and AKT function without significantly reducing the steady-state level of the PI3K/PDK1 activity biomarker P-AKT(T308), highlighting a prominent and direct regulation of AKT by mTORC2 in cancer cells. Compared with the rapalog temsirolimus/CCI-779, WYE-132 elicited a substantially stronger inhibition of cancer cell growth and survival, protein synthesis, cell size, bioenergetic metabolism, and adaptation to hypoxia. Oral administration of WYE-132 to tumor-bearing mice showed potent single-agent antitumor activity against MDA361 breast, U87MG glioma, A549 and H1975 lung, as well as A498 and 786-O renal tumors. An optimal dose of WYE-132 achieved a substantial regression of MDA361 and A549 large tumors and caused complete regression of A498 large tumors when coadministered with bevacizumab. Our results further validate mTOR as a critical driver for tumor growth, establish WYE-132 as a potent and profound anticancer agent, and provide a strong rationale for clinical development of specific mTOR kinase inhibitors as new cancer therapy. Cancer Res; 70(2); 621–31
Predicting Outcomes in Cervical Cancer: A Kinetic Model of Tumor Regression during Radiation Therapy
Authors: Huang Zhibin , Mayr Nina A. , Yuh William T.C. , Lo Simon S. , Montebello Joseph F. , Grecula John C. , Lu Lanchun , Li Kaile , Zhang Hualin , Gupta Nilendu , Wang Jian Z. 
Published: January 2010

Abstract
Applications of mathematical modeling can improve outcome predictions of cancer therapy. Here we present a kinetic model incorporating effects of radiosensitivity, tumor repopulation, and dead-cell resolving on the analysis of tumor volume regression data of 80 cervical cancer patients (stages 1B2-IVA) who underwent radiation therapy. Regression rates and derived model parameters correlated significantly with clinical outcome (P &lt; 0.001; median follow-up: 6.2 years). The 6-year local tumor control rate was 87% versus 54% using radiosensitivity (2-Gy surviving fraction S2 &lt; 0.70 vs. S2 ≥ 0.70) as a predictor (P = 0.001) and 89% vs. 57% using dead-cell resolving time (T1/2 &lt; 22 days versus T1/2 ≥ 22 days, P &lt; 0.001). The 6-year disease-specific survival was 73% versus 41% with S2 &lt; 0.70 versus S2 ≥ 0.70 (P = 0.025), and 87% vs. 52% with T1/2 &lt; 22 days versus T1/2 ≥ 22 days (P = 0.002). Our approach illustrates the promise of volume-based tumor response modeling to improve early outcome predictions that can be used to enable personalized adaptive therapy. Cancer Res; 70(2); 463–70
p38 Mitogen-Activated Protein Kinase–Driven MAPKAPK2 Regulates Invasion of Bladder Cancer by Modulation of MMP-2 and MMP-9 Activity
Authors: Kumar Binod , Koul Sweaty , Petersen Jane , Khandrika Lakshmipathi , Hwa Jeong S. , Meacham Randall B. , Wilson Shandra , Koul Hari K. 
Published: January 2010

Abstract
In transitional cell carcinoma, the most common form of bladder cancer, overexpression of the matrix metalloproteinases MMP-2 and MMP-9 offers prognostic value as markers of disease-specific survival. These molecules have been implicated in metastasis of bladder cancer, but the underlying mechanisms through which they are controlled are poorly defined. In this study, we investigated a role of p38 mitogen-activated protein kinase (MAPK) in this process, using bladder cancer cell lines HTB9 and HTB5 that were derived from different tumor stages. p38 MAPK modulated MMP-2/9 mRNA levels at the levels of transcript stability and MMP-2/9 activity along with invasive capacity. We defined a downstream effector of p38 MAPK, MAPK-activated protein kinase 2 (MAPKAPK2), that was associated with MMP-2/9 activation. Ectopic expression of wild-type or constitutively active forms of MAPKAPK2 increased MMP-2/9 activities and invasive capacity. Conversely, p38 MAPK inhibition blocked the MAPKAPK2-mediated increase in MMP-2/9 activities and the invasive capacity of the cancer cells. Our findings implicate p38 MAPK and MAPKAPK2 in mediating bladder cancer invasion via regulation of MMP-2 and MMP-9 at the level of mRNA stability. Cancer Res; 70(2); 832–41
Defective Mismatch Repair, Microsatellite Mutation Bias, and Variability in Clinical Cancer Phenotypes
Authors: Shah Sandeep N. , Hile Suzanne E. , Eckert Kristin A. 
Published: January 2010

Abstract
Microsatellite instability is associated with 10% to 15% of colorectal, endometrial, ovarian, and gastric cancers, and has long been used as a diagnostic tool for hereditary nonpolyposis colorectal carcinoma–related cancers. Tumor-specific length alterations within microsatellites are generally accepted to be a consequence of strand slippage events during DNA replication, which are uncorrected due to a defective postreplication mismatch repair (MMR) system. Mutations arising within microsatellites associated with critical target genes are believed to play a causative role in the evolution of MMR-defective tumors. In this review, we summarize current evidence of mutational biases within microsatellites arising as a consequence of intrinsic DNA sequence effects as well as variation in MMR efficiency. Microsatellite mutational biases are generally not considered during clinical testing; however, we suggest that such biases may be clinically significant as a factor contributing to phenotypic variation among microsatellite instability–positive tumors. Cancer Res; 70(2); 431–5
Discovery and Mechanistic Characterization of a Novel Selective Nuclear Androgen Receptor Exporter for the Treatment of Prostate Cancer
Authors: Narayanan Ramesh , Yepuru Muralimohan , Szafran Adam T. , Szwarc Maria , Bohl Casey E. , Young Natalie L. , Miller Duane D. , Mancini Michael A. , Dalton James T. 
Published: January 2010

Abstract
Despite the success of medical strategies to reduce androgen levels in the treatment of prostate cancer, this disease invariably relapses to a castrate-resistant state that is generally fatal. Although it had been thought that androgen-insensitive cancers no longer relied on the androgen receptor (AR) for growth and survival, it is now clear that this is not the case. Because relapses are known to occur by many mechanisms that keep the AR functionally active, strategies to block AR accumulation in the nucleus may be therapeutically useful. Here, we report the discovery of a selective nuclear androgen receptor exporter (SNARE) that functions to exclude AR from the nucleus. SNARE-1 binds wild-type and mutant ARs and efficiently inhibits their transactivation activity and ability to induce PSA gene expression. SNARE-1 inhibits the androgen-sensitive growth of LNCaP cells and tumor xenografts. Quantitative subcellular localization studies suggest that SNARE-1 inhibits nuclear translocation of AR, but also facilitates export of nuclear AR that has been translocated by an agonist. Mechanistic studies indicate that SNARE-1 rapidly phosphorylates p38 mitogen-activated protein kinase (MAPK) and Ser650 of the AR. Additionally, SNARE-1 was found to promote ubiquitination of AR in LNCaP cells. Lastly, SNARE-1 functions as a tissue-selective AR inhibitor, as it fails to phosphorylate p38 MAPK in U2OS bone cells that are stably transfected with AR. In summary, SNARE-1 inhibits AR function by a mechanism that is distinct from clinically available antiandrogens, such that it might inform novel methods to block AR function in androgen-independent prostate cancer. Cancer Res; 70(2); 842–51
Multivitamins, Folate, and Green Vegetables Protect against Gene Promoter Methylation in the Aerodigestive Tract of Smokers
Authors: Stidley Christine A. , Picchi Maria A. , Leng Shuguang , Willink Randy , Crowell Richard E. , Flores Kristina G. , Kang Huining , Byers Tim , Gilliland Frank D. , Belinsky Steven A. 
Published: January 2010

Abstract
One promising approach for early detection of lung cancer is by monitoring gene promoter hypermethylation events in sputum. Epidemiologic studies suggest that dietary fruits and vegetables and the micronutrients they contain may reduce risk of lung cancer. In this study, we evaluated whether diet and multivitamin use influenced the prevalence of gene promoter methylation in cells exfoliated from the aerodigestive tract of current and former smokers. Members (N = 1,101) of the Lovelace Smokers Cohort completed the Harvard Food Frequency Questionnaire and provided a sputum sample that was assessed for promoter methylation of eight genes commonly silenced in lung cancer and associated with risk for this disease. Methylation status was categorized as low (fewer than two genes methylated) or high (two or more genes methylated). Logistic regression models were used to identify associations between methylation status and 21 dietary variables hypothesized to affect the acquisition of gene methylation. Significant protection against methylation was observed for leafy green vegetables [odds ratio (OR) = 0.83 per 12 monthly servings; 95% confidence interval (95% CI), 0.74–0.93] and folate (OR, 0.84 per 750 μg/d; 95% CI, 0.72–0.99). Protection against gene methylation was also seen with current use of multivitamins (OR, 0.57; 95% CI, 0.40–0.83). This is the first cohort-based study to identify dietary factors associated with reduced promoter methylation in cells exfoliated from the airway epithelium of smokers. Novel interventions to prevent lung cancer should be developed based on the ability of diet and dietary supplements to affect reprogramming of the epigenome. Cancer Res; 70(2); 568–74