bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biological Evidence for Dual Antiangiogenic-Antiaromatase Activity of the VEGFR Inhibitor PTK787/ZK222584In vivo
Authors: Banerjee Susana , A'Hern Roger , Detre Simone , Littlewood-Evans Amanda J. , Evans Dean B. , Dowsett Mitchell , Martin Lesley-Ann 
Published: August 2010

AbstractPurpose: Targeting vascular endothelial growth factor (VEGF) and estrogen receptor signaling pathways concomitantly may enhance benefit in estrogen receptor–positive breast cancer. We had shown previously that the VEGF receptor tyrosine kinase inhibitor PTK787/ZK222584 (PTK/ZK) is a competitive aromatase inhibitor in vitro. Here we investigated (a) whether PTK/ZK shows both antiangiogenic and antiaromatase inhibitory properties in vivo, and (b) whether the combination of PTK/ZK and letrozole is superior to letrozole alone.Experimental Design: Estrogen-dependent human breast cancer cells engineered to express aromatase (MCF7 AROM 1 and BT474 AROM) were used. Mice were treated with vehicle, PTK/ZK (25, 50, or 100 mg/kg), letrozole, or PTK/ZK in combination with letrozole.Results: In MCF7 AROM 1 tumors, all treatments induced growth suppression and were associated with a reduction in cell turnover index, a composite measurement of both proliferation and apoptosis. PTK/ZK significantly reduced vessel density. Whereas letrozole caused tumor regression, PTK/ZK stabilized tumor volumes. The growth suppressive and antiangiogenic effects of PTK/ZK were confirmed in BT474 AROM xenografts. The addition of PTK/ZK did not enhance the growth-suppressive effects of letrozole. However, PTK/ZK decreased progesterone receptor (PgR) and TFF1 expression and uterine weight, indicating that PTK/ZK decreases 17β-estradiol (E2) signaling in vivo.Conclusion: The VEGF receptor inhibitor PTK/ZK showed effects on E2-dependent gene expression consistent with aromatase inhibition as well as antiangiogenesis in xenograft models of breast cancer. The combination with letrozole was not superior to letrozole alone. Overall, these results provide further support for a potential therapeutic approach of dual inhibition of VEGF and E2 signaling using a single agent. Clin Cancer Res; 16(16); 4178–87. ©2010 AACR.
HER2 Fragmentation and Breast Cancer Stratification
Authors: Arribas Joaquín , Parra-Palau Josep Lluís , Pedersen Kim 
Published: August 2010

Abstract
HER2 is a tyrosine kinase receptor whose overexpression in breast cancers correlates with poor prognosis. A subset of HER2-positive tumors also expresses a series of HER2 fragments, collectively known as p95HER2. These fragments are emerging as a valuable biomarker for this subset of patients, who have a particularly poor prognosis. Clin Cancer Res; 16(16); 4071–3. ©2010 AACR.
X-linked Inhibitor of Apoptosis: A Chemoresistance Factor or a Hollow Promise
Authors: Kashkar Hamid 
Published: August 2010

Abstract
The X-linked inhibitor of apoptosis (XIAP) is the only cellular protein that has evolved to potently inhibit the enzymatic activity of mammalian caspases and promotes resistance to apoptosis. Given its role in apoptosis and its frequently elevated expression in malignant cells, XIAP has garnered the most attention as a promising therapeutic target in cancer to overcome drug resistance. Accordingly, XIAP is thought to render tumor cells resistant to chemotherapy through its ability to inhibit caspases, and it is on this basis that XIAP has been proposed as an important adverse biomarker for chemoresistance in cancer patients. Here, the current understanding of the role of XIAP in cancer is reviewed. Further, the notion is explored that the elevated XIAP expression frequently observed in malignant tissues is, at least, not exclusively responsible for the resistance of tumor cells to conventional therapeutic treatment; rather, the function of XIAP seems to be conducive to the process of malignant transformation and/or progression. Clin Cancer Res; 16(18); 4496–502. ©2010 AACR.
Expression of ABCG2 (BCRP) Is Regulated by Nrf2 in Cancer Cells That Confers Side Population and Chemoresistance Phenotype
Authors: Singh Anju , Wu Hailong , Zhang Ping , Happel Christine , Ma Jinfang , Biswal Shyam 
Published: August 2010

Abstract
ATP-binding cassette, subfamily G, member 2 (ABCG2) is expressed in both normal and cancer cells and plays a crucial role in side population (SP) formation and efflux of xenobiotics and drugs. Nrf2, a redox-sensing transcription factor, on constitutive activation in non–small-cell lung cancer cells upregulates a wide spectrum of genes involved in redox balance, glutathione metabolism, and drug detoxification, which contribute to chemoresistance and tumorigenicity. This study examined the mechanism underlying Nrf2-dependent expression of ABCG2 and its role in the multidrug resistance phenotype. In silico analysis of the 5′-promoter flanking region of ABCG2 identified an antioxidant response element (ARE) at −431 to −420 bp. A detailed promoter analysis using luciferase reporter assays showed that ARE at −431 to −420 bp is critical for the Nrf2-mediated expression in lung cancer cells. Electrophoretic mobility shift assays and chromatin immunoprecipitation assays revealed that Nrf2 interacts with the ABCG2 ARE element at −431 to −420 bp in vitro and in vivo. Disruption of Nrf2 expression in lung and prostate cancer cells, by short hairpin RNA, attenuated the expression of ABCG2 transcript and protein, and dramatically reduced the SP fraction in Nrf2-depleted cancer cells. Moreover, depleted levels of ABCG2 in these Nrf2 knockdown cells sensitized them to mitoxantrone and topotecan, two chemotherapy drugs detoxified mainly by ABCG2. As expected, overexpression of Nrf2 cDNA in lung epithelial cells led to an increase in ABCG2 expression and a 2-fold higher SP fraction. Thus, Nrf2-mediated regulation of ABCG2 expression maintains the SP fraction and confers chemoresistance. Mol Cancer Ther; 9(8); 2365–76. ©2010 AACR.
Dual Targeting of CDK and Tropomyosin Receptor Kinase Families by the Oral Inhibitor PHA-848125, an Agent with Broad-Spectrum Antitumor Efficacy
Authors: Albanese Clara , Alzani Rachele , Amboldi Nadia , Avanzi Nilla , Ballinari Dario , Brasca Maria Gabriella , Festuccia Claudio , Fiorentini Francesco , Locatelli Giuseppe , Pastori Wilma , Patton Veronica , Roletto Fulvia , Colotta Francesco , Galvani Arturo , Isacchi Antonella , Moll Jurgen , Pesenti Enrico , Mercurio Ciro , Ciomei Marina 
Published: August 2010

Abstract
Altered expression and activity of cyclin-dependent kinase (CDK) and tropomyosin receptor kinase (TRK) families are observed in a wide variety of tumors. In those malignancies with aberrant CDK activation, the retinoblastoma protein (pRb) pathway is deregulated, leading to uncontrolled cell proliferation. Constitutive activation of TRKs is instead linked to cancer cell survival and dissemination. Here, we show that the novel small-molecule PHA-848125, a potent dual inhibitor of CDKs and TRKs, possesses significant antitumor activity. The compound inhibits cell proliferation of a wide panel of tumoral cell lines with submicromolar IC50. PHA-848125–treated cells show cell cycle arrest in G1 and reduced DNA synthesis, accompanied by inhibition of pRb phosphorylation and modulation of other CDK-dependent markers. The compound additionally inhibits phosphorylation of TRKA and its substrates in cells, which functionally express this receptor. Following oral administration, PHA-848125 has significant antitumor activity in various human xenografts and carcinogen-induced tumors as well as in disseminated primary leukemia models, with plasma concentrations in rodents in the same range as those found active in inhibiting cancer cell proliferation. Mechanism of action was also confirmed in vivo as assessed in tumor biopsies from treated mice. These results show that the dual CDK-TRK inhibitor PHA-848125 has the potential for being a novel and efficacious targeted drug for cancer treatment. Mol Cancer Ther; 9(8); 2243–54. ©2010 AACR.
γ-Tocotrienol Promotes TRAIL-Induced Apoptosis through Reactive Oxygen Species/Extracellular Signal-Regulated Kinase/p53–Mediated Upregulation of Death Receptors
Authors: Kannappan Ramaswamy , Ravindran Jayaraj , Prasad Sahdeo , Sung Bokyung , Yadav Vivek R. , Reuter Simone , Chaturvedi Madan M. , Aggarwal Bharat B. 
Published: August 2010

Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor superfamily, is in clinical trials for cancer therapy, but its anticancer potential is limited by the development of resistance. We investigated the ability of tocotrienol (T3), an unsaturated vitamin E present in palm oil, rice bran, barley, oats, and wheat germ, to sensitize tumor cells to TRAIL. Results from esterase staining, colony formation, caspase activation, and sub-G1 cell cycle arrest revealed that γ-T3 can sensitize human colon cancer cells to TRAIL. When examined for the mechanism, we found that γ-T3 significantly downregulated the expression of antiapoptotic proteins (c-IAP2 and Bcl-xL). We also found that γ-T3, but not tocopherol, induced the expression of the TRAIL receptors death receptor (DR)-4 and DR5. This induction was not cell type specific, as upregulation was also found in pancreatic, kidney, and leukemic cells. Upregulation of DRs by γ-T3 required the production of reactive oxygen species (ROS), and sequestering of ROS abolished both upregulation of the receptors and potentiation of TRAIL-induced apoptosis. Induction of DRs by γ-T3 also required activation of extracellular signal-regulated kinase 1 (ERK1), as silencing of ERK1 by specific siRNA abrogated the upregulation of TRAIL receptors. Further, induction of DRs by γ-T3 required the expression of p53 and Bax, as no induction of the receptors was found in colon cancer cells with deletion of these genes. Overall, our results show that γ-T3 sensitizes tumor cells to TRAIL by upregulating DRs through the ROS/ERK/p53 pathway and by downregulating cell survival proteins. Mol Cancer Ther; 9(8); 2196–207. ©2010 AACR.
Combinations of DNA Methyltransferase and Histone Deacetylase Inhibitors Induce DNA Damage in Small Cell Lung Cancer Cells: Correlation of Resistance with IFN-Stimulated Gene Expression
Authors: Luszczek Wioleta , Cheriyath Venugopalan , Mekhail Tarek M. , Borden Ernest C. 
Published: August 2010

Abstract
Because epigenetic inhibitors can reduce cancer cell proliferation, we tested the hypothesis that concurrent inhibition of histone acetylation and DNA methylation could synergistically reduce the viability of small cell lung cancer (SCLC) cells. Sub-IC50 concentrations of the DNA methyltransferase (DNMT) inhibitor decitabine (5-AZA-dC) and the histone deacetylase (HDAC) inhibitors (LBH589 or MGCD0103) synergistically reduced the proliferation of five of nine SCLC cell lines. Loss of viability of sensitive SCLC cells did not correlate with the inhibition of either DNMT1 or HDACs, suggesting nonepigenetic mechanisms for synergy between these two classes of epigenetic modulators. Because combinations of 5-AZA-dC and HDAC inhibitors had marginal effects on the apoptosis index, Comet assay was undertaken to assess DNA damage. MGCD0103 and 5AZA-dC cotreatment augmented DNA damage in SCLC cells, resulting in increased tail length and moment in Comet assays by 24 hours in sensitive cell lines (P &lt; 0.01). Consistent with augmented DNA damage, combination of a DNMT and HDAC inhibitor markedly increased the levels of phospho-H2A.X in sensitive cells but not in resistant ones. Comparison of basal gene expression between resistant and sensitive cells identified markedly higher basal expression of IFN-stimulated genes in the resistant cell lines, suggesting that IFN-stimulated gene expression may determine SCLC cell sensitivity to epigenetic modulators or other DNA damaging agents. Mol Cancer Ther; 9(8); 2309–21. ©2010 AACR.
Epidermal Growth Factor Receptor–Targeted Radioimmunotherapy of Human Head and Neck Cancer Xenografts Using 90Y-Labeled Fully Human Antibody Panitumumab
Authors: Liu Zhaofei , Liu Yan , Jia Bing , Zhao Huiyun , Jin Xiaona , Li Fang , Chen Xiaoyuan , Wang Fan 
Published: August 2010

Abstract
Panitumumab (ABX-EGF or Vectibix), the first fully human monoclonal antibody targeting epidermal growth factor receptor (EGFR), was approved by the Food and Drug Administration for treatment of patients with metastatic colorectal cancer. Here, we report for the first time the radioimmunotherapy (RIT) of EGFR-positive human head and neck cancer in a nude mouse model using pure β− emitter 90Y-labeled panitumumab. Biodistribution and planar γ-imaging studies were carried out with 111In-DOTA-panitumumab. The RIT efficacy of 90Y-DOTA-panitumumab was evaluated in UM-SCC-22B tumor model. CD31, Ki67, terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling, and H&E staining were done on UM-SCC-22B tumor sections after treatment. The tumor uptake of 111In-DOTA-panitumumab in UM-SCC-22B tumor-bearing nude mice was 26.10 ± 4.93, 59.11 ± 7.22, 44.57 ± 9.80, 40.38 ± 7.76, and 14.86 ± 7.23 % injected dose per gram of tissue at 4, 24, 72, 120, and 168 hours after injection, respectively. Immunotherapy with cold panitumumab (four doses of 10 mg/kg) did not cause significant antitumor effect. RIT with a single dose of 100 μCi 90Y-DOTA-panitumumab caused significant tumor growth delay and improved the survival in UM-SCC-22B tumor model. A single dose of 200 μCi 90Y-DOTA-panitumumab led to almost complete tumor regression (tumor volumes were 34.83 ± 11.11 mm3 and 56.02 ± 39.95 mm3 on days 0 and 46 after treatment, respectively). Histopathologic analysis of tumors and normal organs further validated the therapeutic efficacy and limited systemic toxicity of 90Y-DOTA-panitumumab. The high tumor uptake and prolonged tumor retention, as well as effective therapy, reveal that 90Y-DOTA-panitumumab may be a promising radioimmunotherapeutic agent to treat EGFR-positive solid tumors. Mol Cancer Ther; 9(8); 2297–308. ©2010 AACR.
Re-evaluating Dissociations between Implicit and Explicit Category Learning: An Event-related fMRI Study
Authors: Gureckis Todd M. , James Thomas W. , Nosofsky Robert M. 
Published: August 2010

AbstractRecent fMRI studies have found that distinct neural systems may mediate perceptual category learning under implicit and explicit learning conditions. In these previous studies, however, different stimulus-encoding processes may have been associated with implicit versus explicit learning. The present design was aimed at decoupling the influence of these factors on the recruitment of alternate neural systems. Consistent with previous reports, following incidental learning in a dot-pattern classification task, participants showed decreased neural activity in occipital visual cortex (extrastriate region V3, BA 19) in response to novel exemplars of a studied category compared to members of a foil category, but did not show this decreased neural activity following explicit learning. Crucially, however, our results show that this pattern was primarily modulated by aspects of the stimulus-encoding instructions provided at the time of study. In particular, when participants in an implicit learning condition were encouraged to evaluate the overall shape and configuration of the stimuli during study, we failed to find the pattern of brain activity that has been taken to be a signature of implicit learning, suggesting that activity in this area does not uniquely reflect implicit memory for perceptual categories but instead may reflect aspects of processing or perceptual encoding strategies.
Formation of the Philippine Twin Tropical Cyclones during the 2008 Summer Monsoon Onset
Authors: Chen Tsing-Chang , Tsay Jenq-Dar , Yen Ming-Cheng , Cayanan Esperanza O. 
Published: August 2010

Abstract
Stretched from Indochina, across the South China Sea, to the Philippine Sea, a monsoon cyclonic shear flow was formed by easterlies of the cold surge-like flow in the north and monsoon westerlies in the south before the onset of the tropical Southeast Asian monsoon on 12 May 2008. On this date, two named tropical cyclones (Halong and Matmo) evolved with a 12-h lag from a closed vortex adjacent to the coast of central Vietnam and another closed vortex near Palawan Island (Philippines) within this shear flow. These two cyclones, named the twin Philippine tropical cyclones, moved almost on the same track, along the anomalous shear line (departure from the climatological one) across the Philippines, and turned northeastward to the ocean south of Japan. It was revealed from synoptic analysis that the cold surge-like flow was coupled with the midlatitude eastward-propagating short wave in northeast Asia, and part of the monsoon westerlies were fed by the cross-equatorial flow, the downstream flow of easterlies around the northern rim of the Southern Hemisphere subtropical high. The environment favorable for the formation of the twin cyclones was developed from the tropics–midlatitude interaction between synoptic systems in these two latitudinal zones. Formations of these cyclones were a result of drastic spinups of the two closed vortices (within the monsoon shear flow) following the surge of monsoon westerlies, which coincided with those of easterlies of the cold surge-like flow, and the cross-equatorial flow originating from easterlies between the Southern Hemisphere subtropical high and the Southern Hemisphere shear flow.
Perioperative Rehabilitation Using a Knee Extension Device and Arthroscopic Debridement in the Treatment of Arthrofibrosis
Authors: Biggs-Kinzer Angie , Murphy Brian , Shelbourne K. Donald , Urch Scott 
Published: August 2010

Background: Arthrofibrosis is a postoperative complication of intra-articular knee surgery that can be difficult to treat. Evidence suggests that maximizing knee range of motion may improve outcomes in patients with arthrofibrosis who undergo arthroscopic debridement. Hypothesis: Patients who achieve greater knee range of motion will have better subjective scores. Study Design: Retrospective case series analysis. Methods: A review of records was performed for 33 patients with arthrofibrosis who underwent knee arthroscopy and scar resection coupled with perioperative rehabilitation to maximize knee range of motion. Patient demographics and preoperative and postoperative range of motion measurements were extracted from the records. The International Knee Documentation Committee (IKDC) Subjective Knee Form was administered to assess pain, activity, and knee function. Patients performed a preoperative and postoperative rehabilitation program utilizing a knee extension device to maximize knee extension. Results: According to the IKDC range of motion criteria, 27 of 33 patients achieved normal knee extension, and 14 of 33 achieved normal knee flexion at a mean of 8.6 months after surgery. Patients with normal knee motion had a mean IKDC Subjective Knee Form score of 72.6 ± 13.6, which was significantly higher than patients who did not achieve normal motion ( P = .04). Overall, mean IKDC Subjective Knee Form scores improved from 45.3 ± 16.7 preoperatively to 67.1 ± 18.0 postoperatively ( P < .01) at a mean of 14.7 months after surgery. Conclusions: Perioperative rehabilitation that emphasizes restoration of normal knee range of motion appears to improve outcomes in patients with arthrofibrosis who undergo arthroscopic scar resection. In support of our hypothesis, patients who achieved greater knee range of motion had better subjective knee scores.
Short rare hTERT-VNTR2-2nd alleles are associated with prostate cancer susceptibility and influence gene expression
Authors: Yoon Se-Lyun , Jung Se-Il , Do Eun-Ju , Lee Se-Ra , Lee Sang-Yeop , Chu In-Sun , Kim Wun-Jae , Jung Jaeil , Kim Choung Soo , Cheon Sang-Hyeon , Leem Sun-Hee 
Published: August 2010

Abstract

Background
The hTERT (human telomerase reverse transcriptase) gene contains five variable number tandem repeats (VNTR) and previous studies have described polymorphisms for hTERT-VNTR2-2nd. We investigated how allelic variation in hTERT-VNTR2-2nd may affect susceptibility to prostate cancer.

Methods
A case-control study was performed using DNA from 421 cancer-free male controls and 329 patients with prostate cancer. In addition, to determine whether the VNTR polymorphisms have a functional consequence, we examined the transcriptional levels of a reporter gene linked to these VNTRs and driven by the hTERT promoter in cell lines.

Results
Three new rare alleles were detected from this study, two of which were identified only in cancer subjects. A statistically significant association between rare hTERT-VNTR2-2nd alleles and risk of prostate cancer was observed [OR, 5.17; 95% confidence interval (CI), 1.09-24.43; P = 0.021]. Furthermore, the results indicated that these VNTRs inserted in the enhancer region could influence the expression of hTERT in prostate cancer cell lines.

Conclusions
This is the first study to report that rare hTERT VNTRs are associated with prostate cancer predisposition and that the VNTRs can induce enhanced levels of hTERT promoter activity in prostate cancer cell lines. Thus, the hTERT-VNTR2-2nd locus may function as a modifier of prostate cancer risk by affecting gene expression.
The impact of universal National Health Insurance on population health: the experience of Taiwan
Authors: Lee Yue-Chune , Huang Yu-Tung , Tsai Yi-Wen , Huang Shiuh-Ming , Kuo Ken N , McKee Martin , Nolte Ellen 
Published: August 2010

Abstract

Background
Taiwan established a system of universal National Health Insurance (NHI) in March, 1995. Today, the NHI covers more than 98% of Taiwan's population and enrollees enjoy almost free access to healthcare with small co-payment by most clinics and hospitals. Yet while this expansion of coverage will almost inevitably have improved access to health care, however, it cannot be assumed that it will necessarily have improved the health of the population. The aim of this study was to determine whether the introduction of National Health Insurance (NHI) in Taiwan in 1995 was associated with a change in deaths from causes amenable to health care.

Methods
Identification of discontinuities in trends in mortality considered amenable to health care and all other conditions (non-amenable mortality) using joinpoint regression analysis from 1981 to 2005.

Results
Deaths from amenable causes declined between 1981 and 1993 but slowed between 1993 and 1996. Once NHI was implemented, the decline accelerated significantly, falling at 5.83% per year between 1996 and 1999. In contrast, there was little change in non-amenable causes (0.64% per year between 1981 and 1999). The effect of NHI was highest among the young and old, and lowest among those of working age, consistent with changes in the pattern of coverage. NHI was associated with substantial reductions in deaths from circulatory disorders and, for men, infections, whilst an earlier upward trend in female cancer deaths was reversed.

Conclusions
NHI was associated in a reduction in deaths considered amenable to health care; particularly among those age groups least likely to have been insured previously.