bluuebunny/crossref_metadata_2025_split huggingface dataset:
S110, a 5-Aza-2′-Deoxycytidine–Containing Dinucleotide, Is an Effective DNA Methylation Inhibitor In vivo and Can Reduce Tumor Growth
Authors: Chuang Jody C. , Warner Steven L. , Vollmer David , Vankayalapati Hariprasad , Redkar Sanjeev , Bearss David J. , Qiu Xiangning , Yoo Christine B. , Jones Peter A. 
Published: May 2010

Abstract
Methylation of CpG islands in promoter regions is often associated with gene silencing and aberrant DNA methylation occurs in most cancers, leading to the silencing of some tumor suppressor genes. Reversal of this abnormal hypermethylation by DNA methylation inhibitors is effective in reactivating methylation-silenced tumor suppressor genes both in vitro and in vivo. Several DNA methylation inhibitors have been well studied; the most potent among them is 5-aza-2′-deoxycytidine (5-Aza-CdR), which can induce myelosuppression in patients. S110 is a dinucleotide consisting of 5-Aza-CdR followed by a deoxyguanosine, which we previously showed to be effective in vitro as a DNA methylation inhibitor while being less prone to deamination by cytidine deaminase, making it a promising alternative to 5-Aza-CdR. Here, we show that S110 is better tolerated than 5-Aza-CdR in mice and is as effective in vivo in inducing p16 expression, reducing DNA methylation at the p16 promoter region, and retarding tumor growth in human xenograft. We also show that S110 is effective by both i.p. and s.c. deliveries. S110 therefore is a promising new agent that acts similarly to 5-Aza-CdR and has better stability and less toxicity. Mol Cancer Ther; 9(5); 1443–50. ©2010 AACR.
A Novel Small-Molecule Inhibitor of Protein Kinase D Blocks Pancreatic Cancer GrowthIn vitroandIn vivo
Authors: Harikumar Kuzhuvelil B. , Kunnumakkara Ajaikumar B. , Ochi Nobuo , Tong Zhimin , Deorukhkar Amit , Sung Bokyung , Kelland Lloyd , Jamieson Stephen , Sutherland Rachel , Raynham Tony , Charles Mark , Bagherzadeh Azadeh , Foxton Caroline , Boakes Alexandra , Farooq Muddasar , Maru Dipen , Diagaradjane Parmeswaran , Matsuo Yoichi , Sinnett-Smith James , Gelovani Juri , Krishnan Sunil , Aggarwal Bharat B. , Rozengurt Enrique , Ireson Christopher R. , Guha Sushovan 
Published: May 2010

AbstractProtein kinase D (PKD) family members are increasingly implicated in multiple normal and abnormal biological functions, including signaling pathways that promote mitogenesis in pancreatic cancer. However, nothing is known about the effects of targeting PKD in pancreatic cancer. Our PKD inhibitor discovery program identified CRT0066101 as a specific inhibitor of all PKD isoforms. The aim of our study was to determine the effects of CRT0066101 in pancreatic cancer. Initially, we showed that autophosphorylated PKD1 and PKD2 (activated PKD1/2) are significantly upregulated in pancreatic cancer and that PKD1/2 are expressed in multiple pancreatic cancer cell lines. Using Panc-1 as a model system, we showed that CRT0066101 reduced bromodeoxyuridine incorporation; increased apoptosis; blocked neurotensin-induced PKD1/2 activation; reduced neurotensin-induced, PKD-mediated Hsp27 phosphorylation; attenuated PKD1-mediated NF-κB activation; and abrogated the expression of NF-κB-dependent proliferative and prosurvival proteins. We showed that CRT0066101 given orally (80 mg/kg/d) for 24 days significantly abrogated pancreatic cancer growth in Panc-1 subcutaneous xenograft model. Activated PKD1/2 expression in the treated tumor explants was significantly inhibited with peak tumor concentration (12 μmol/L) of CRT0066101 achieved within 2 hours after oral administration. Further, we showed that CRT0066101 given orally (80 mg/kg/d) for 21 days in Panc-1 orthotopic model potently blocked tumor growth in vivo. CRT0066101 significantly reduced Ki-67–positive proliferation index (P &lt; 0.01), increased terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling–positive apoptotic cells (P &lt; 0.05), and abrogated the expression of NF-κB–dependent proteins including cyclin D1, survivin, and cIAP-1. Our results show for the first time that a PKD-specific small-molecule inhibitor CRT0066101 blocks pancreatic cancer growth in vivo and show that PKD is a novel therapeutic target in pancreatic cancer. Mol Cancer Ther; 9(5); 1136–46. ©2010 AACR.
Metformin in Cancer Therapy: A New Perspective for an Old Antidiabetic Drug?
Authors: Ben Sahra Issam , Le Marchand-Brustel Yannick , Tanti Jean-François , Bost Frédéric 
Published: May 2010

Abstract
Metformin is the most widely used antidiabetic drug in the world, and there is increasing evidence of a potential efficacy of this agent as an anticancer drug. First, epidemiological studies show a decrease in cancer incidence in metformin-treated patients. Second, metformin decreases insulin resistance and indirectly reduces insulin level, a beneficial effect because insulin promotes cancer cell growth. Third, several reports outline a direct inhibitory effect of metformin on cancer cell growth and an antitumoral action. Finally, metformin activates the AMP activated protein kinase (AMPK) pathway, a major sensor of the energetic status of the cell, which has been proposed as a promising therapeutic target in cancer. Mol Cancer Ther; 9(5); 1092–99. ©2010 AACR.
Anticancer Efficacy of a Difluorodiarylidenyl Piperidone (HO-3867) in Human Ovarian Cancer Cells and Tumor Xenografts
Authors: Selvendiran Karuppaiyah , Tong Liyue , Bratasz Anna , Kuppusamy M. Lakshmi , Ahmed Shabnam , Ravi Yazhini , Trigg Nancy J. , Rivera Brian K. , Kálai Tamás , Hideg Kálmán , Kuppusamy Periannan 
Published: May 2010

Abstract
The purpose of this study was to evaluate the anticancer potency and mechanism of a novel difluorodiarylidenyl piperidone (H-4073) and its N-hydroxypyrroline modification (HO-3867) in human ovarian cancer. Studies were done using established human ovarian cancer cell lines (A2870, A2780cDDP, OV-4, SKOV3, PA-1, and OVCAR3) as well as in a murine xenograft tumor (A2780) model. Both compounds were comparably and significantly cytotoxic to A2780 cells. However, HO-3867 showed a preferential toxicity toward ovarian cancer cells while sparing healthy cells. HO-3867 induced G2-M cell cycle arrest in A2780 cells by modulating cell cycle regulatory molecules p53, p21, p27, cyclin-dependent kinase 2, and cyclin, and promoted apoptosis by caspase-8 and caspase-3 activation. It also caused an increase in the expression of functional Fas/CD95 and decreases in signal transducers and activators of transcription 3 (STAT3; Tyr705) and JAK1 phosphorylation. There was a significant reduction in STAT3 downstream target protein levels including Bcl-xL, Bcl-2, survivin, and vascular endothelial growth factor, suggesting that HO-3867 exposure disrupted the JAK/STAT3 signaling pathway. In addition, HO-3867 significantly inhibited the growth of the ovarian xenografted tumors in a dosage-dependent manner without any apparent toxicity. Western blot analysis of the xenograft tumor tissues showed that HO-3867 inhibited pSTAT3 (Tyr705 and Ser727) and JAK1 and increased apoptotic markers cleaved caspase-3 and poly ADP ribose polymerase. HO-3867 exhibited significant cytotoxicity toward ovarian cancer cells by inhibition of the JAK/STAT3 signaling pathway. The study suggested that HO-3867 may be useful as a safe and effective anticancer agent for ovarian cancer therapy. Mol Cancer Ther; 9(5); 1169–79. ©2010 AACR.
Thrombin Regulates the Metastatic Potential of Human Rhabdomyosarcoma Cells: Distinct Role of PAR1 and PAR3 Signaling
Authors: Wysoczynski Marcin , Liu Rui , Kucia Magda , Drukala Justyna , Ratajczak Mariusz Z. 
Published: May 2010

AbstractWe observed that human rhabdomyosarcoma (RMS) cells highly express a tissue factor that promotes thrombin formation, which indirectly and directly affects RMS progression. First, we found that thrombin activates platelets to generate microvesicles (PMV), which transfer to RMS cells' α2β3 integrin and increase their adhesiveness to endothelial cells. Accordingly, RMS cells covered with PMVs showed higher metastatic potential after i.v. injection into immunodeficient mice. Furthermore, PMVs activate mitogen-activated protein kinase (MAPK)p42/44 and AKT to chemoattract RMS cells. We also found that RMS cells express functional protease-activated receptor-1 (PAR1) and PAR3 and respond to thrombin stimulation by MAPKp42/44 and MAPKp38 phosphorylation. To our surprise, thrombin did not affect RMS proliferation or survival; it inhibited the chemotactic and adhesive properties of RMS cells. However, when PAR1-specific agonist thrombin receptor–activating peptide 6 was used, which does not activate PAR3, selective PAR1 stimulation enhanced RMS proliferation. To learn more on the role of PAR1 and PAR3 antagonism in RMS proliferation and metastasis, we knocked down both receptors by using a short hairpin RNA strategy. We found that although thrombin does not affect growth of PAR1−/− cells, it stimulated the proliferation of PAR3−/− cells. More importantly, PAR3−/− cells, in contrast to PAR1−/− ones, formed larger tumors in immunodeficient mice. We conclude that thrombin is a novel underappreciated modulator of RMS metastasis and that we have identified a novel role for PAR3 in thrombin signaling. Mol Cancer Res; 8(5); 677–90. ©2010 AACR.
Bortezomib Sensitizes Human Renal Cell Carcinomas to TRAIL Apoptosis through Increased Activation of Caspase-8 in the Death-Inducing Signaling Complex
Authors: Brooks Alan D. , Jacobsen Kristen M. , Li Wenqing , Shanker Anil , Sayers Thomas J. 
Published: May 2010

Abstract
Bortezomib (VELCADE) could sensitize certain human renal cell carcinoma (RCC) lines to the apoptotic effects of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL). Analysis of seven human RCC showed a clear increase in the sensitivity of four of the RCC to TRAIL cytotoxicity following bortezomib (5-20 nmol/L) treatment, whereas the remaining three remained resistant. Tumor cell death following sensitization had all the features of apoptosis. The enhanced antitumor activity of the bortezomib and TRAIL combination was confirmed in long-term (6 days) cancer cell outgrowth assays. The extent of proteasome inhibition by bortezomib in the various RCC was equivalent. Following bortezomib treatment, neither changes in the intracellular protein levels of various Bcl-2 and IAP family members, nor minor changes in expression of TRAIL receptors (DR4, DR5), correlated well with the sensitization or resistance of RCC to TRAIL-mediated apoptosis. However, enhanced procaspase-8 activation following bortezomib pretreatment and subsequent TRAIL exposure was only observed in the sensitized RCC in both cell extracts and death-inducing signaling complex immunoprecipitates. These data suggest that the molecular basis for bortezomib sensitization of RCC to TRAIL primarily involves early amplification of caspase-8 activity. In the absence of this increased caspase-8 activation, other bortezomib-induced changes are not sufficient to sensitize RCC to TRAIL-mediated apoptosis. Mol Cancer Res; 8(5); 729–38. ©2010 AACR.
Development of a Novel Prohealing Stent Designed to Deliver Sirolimus From a Biodegradable Abluminal Matrix
Authors: Granada Juan F. , Inami Shigenobu , Aboodi Michael S. , Tellez Armando , Milewski Krzysztof , Wallace-Bradley David , Parker Sherry , Rowland Steve , Nakazawa Gaku , Vorpahl Marc , Kolodgie Frank D. , Kaluza Greg L. , Leon Martin B. , Virmani Renu 
Published: May 2010

Background—
We aimed to demonstrate that, by separating endothelial progenitor cell capture from sirolimus delivery through the application of drug to the abluminal surface of the stent, the degree of endothelialization can be enhanced.

Methods and Results—

Stainless steel R Stents, with biodegradable SynBiosys polymer coating with sirolimus abluminally applied and surface modified with anti-CD34 antibody were prepared at 2 dosages (low-dose sirolimus [LD-Combo, 2.5 μg sirolimus/mm] and full-dose sirolimus [Combo, 5 μg sirolimus/mm). These Combo stents and the Cypher stent (10 μg sirolimus/mm) were deployed in 98 normal porcine arteries and harvested for pharmacokinetic analysis at 0.25, 1, 3, 7, 14, 28, and 35 days. The LD-Combo stents showed faster early release (50%total dose in 72 hours) than the Combo and Cypher. At 30 days, drug release was near complete with both Combo stents, whereas 20% of drug remained on the Cypher stents. To assess efficacy, a total of 50 stents (Xience V=8, Cypher=8, Genous bioengineered R stent=6, LD-Combo=14, and Combo=14) were implanted in 18 pigs for 14 and 28 days. Optical coherence tomography was performed, and stents were harvested for histology. At 28 days, there was less neointimal thickness with Combo (0.173±0.088 mm) compared with Cypher (0.358±0.225 mm), LD-Combo (0.316±0.228 mm), and Xience V (0.305±0.252 mm;
P
<0.00001). Immunohistochemical analysis of endothelialization showed that Genous bioengineered R stent had the highest degree of platelet endothelial cell adhesion molecule expression (87%) followed by the Combo (75%), LD-Combo (65%), and Cypher (58%).

Conclusions—
Both optical coherence tomography and histology demonstrate that anti-CD34 sirolimus-eluting stents promote endothelialization while reducing neointimal formation and inflammation.
University students’ views of obesity and weight management strategies
Authors: Okonkwo Ononuju , While Alison 
Published: May 2010

Objective: To investigate the knowledge and views of university students regarding obesity and weight management strategies. Design: Online questionnaire-based survey of undergraduate and postgraduate university students in a large London university with a diverse student population. Method: The survey was administered online and circulated through the university’s email. The questionnaire sought the following data: demographic data; knowledge and beliefs regarding obesity, weight management strategies, barriers to weight management and perceived responsibility for tackling obesity Results: The sample comprised: female (73.0 per cent), white (80.6 per cent), mean age of 25.4 years (SD 7.66), undergraduates (59.9 per cent), studying health-related courses (65.2 per cent). About half of the participants (49.3 per cent) reported that their body shape was normal with a minority (3.3 per cent) indicating that they were obese. Obesity (68.1 per cent) was viewed as being the most important public health issue, with most participants (94.1 per cent) reporting that obesity had increased over the last 10 years. Lack of physical exercise and poor diet were identified by more than 90 per cent of the participants as causes of obesity. Most management strategies were supported by the majority of the participants. Conclusions: The findings demonstrate that the complex nature of obesity is generally understood, suggesting that health education has been partially successful. Overall, there was support for obesity management strategies which can be built on.
Folic acid promotion for Hispanic women in Florida: A vitamin diary study
Authors: Thomas Kamilah B , Hauser Kimberlea , Rodriguez Nydia Y , Quinn Gwendolyn P 
Published: May 2010

Objective: To assess the barriers and benefits of taking multivitamins among Hispanic women exposed to a folic acid social marketing campaign in Florida, USA. Design and setting: Evaluation of non-pregnant women aged 18—35 from multiple Hispanic subgroups. Method: For 6 months, participants exposed to social marketing campaign educational materials were given a supply of vitamins and reported, on a daily basis, how often they took a multivitamin with folic acid and reasons why they may not have taken the multivitamin. Results: Forty-one women participated in the study and 65 per cent missed 10 days or less of taking the supplement. The most common reason for not taking the vitamin was forgetting. Conclusion: Compliance with multivitamin intake has numerous barriers.Therefore, continued educational efforts by public health practitioners are necessary in order to reach Hispanic/Latino populations known to have a high risk of neural tube defects.
A tale of two cities: A study of access to food, lessons for public health practice
Authors: Caraher Martin , Lloyd Susan , Lawton Julie , Singh Gulab , Horsley Kayt , Mussa Fozia 
Published: May 2010

Objectives: To map food access in the city of Preston in the north-west of England in order to determine access, availability and affordability of healthy food options. Design and methodology: The research design employed a number of distinct methods including: surveys of shops; interviews with local people and shopkeepers; a cost and availability survey of shops in two deprived areas of Preston —Deepdale and Ingol — the former with a majority South Asian population; and the use of geographical information systems to map access and availability. Results: • Preston had more fast food outlets (186) [not including restaurants who operate takeaways] than general groceries outlets (165). • There were more local shops selling affordable food in the area with the high South Asian population than in Ingol with its white working class population. There were clear gaps in provision and access in the white working class area (Ingol), with shops being more than 500 metres away from where people lived. Shops in this area stocked more familiar ‘British foods’ and less specialist or fresh produce. • Analysis of the availability of some healthy options such as brown bread, wholemeal pasta and brown rice showed that they were not widely available within shops in the two areas. • The price of the ‘White British’ basket in Ingol was £70.61 (cheapest price). For comparable goods in Deepdale, using the most expensive shopping basket, the price for the same basket was £42.47. • A South Asian family shopping at a major national supermarket outlet in Deepdale would pay £47.05. Using local shops they could pay between £38.59 and £44.28 by seeking out the best bargains in five shops (including some top-up items from a national supermarket). • At the time of the research a mother with two children, entitled to income support and child allowance, would have to spend 28—32 per cent of her income in local shops and 34 per cent in a supermarket to buy a basket of healthy goods. Conclusions: There is a need to engage proactively with the location of shops in urban areas, to ensure they offer a healthy range of options and are sited near to where people live. The number of fast food outlets needs to be controlled and the food they offer improved.This latter issue of the number of outlets and quality of fast food contributes to an overall obesogenic environment. Access to food is heavily dependent on having access to a car; local shopping and the quality of food on offer are important for key groups such as those on benefits, the elderly, single parents and others with limited access to a car. Proactive policy solutions may lie with the engagement of health agencies with the planning processes in local authorities to ensure that the food retail environment reflects a healthy choice. Local area agreements between health agencies and local authorities offer a way forward, in that they can take into account the expressed needs of local residents.
A tale of two localities
Authors: Lloyd Susan , Lawton Julie , Caraher Martin , Singh Gulab , Horsley Kayt , Mussa Fozia 
Published: May 2010

Objective: To determine the availability and affordability of a healthy food basket and to model how those on low-incomes might manage. Design and methodology: After determining access and availability of key items from shops in two localities, called Deepdale and Ingol, a healthy food basket was developed. From this a week’s healthy menu was devised for a mother and two children, then availability of the ingredients was checked using data collected from the shops and costed. The baskets represented the cultural preferences of White British and South Asian families informed by participatory work with both these groups. We chose the income level for a family entitled to income support and child allowance. Results: Analysis of the availability of some healthy options such as brown bread, wholemeal pasta, and brown rice showed they were not widely available within shops in the two areas. The price of the ‘White British’ basket in the area of Ingol was £70.61 (lowest price). For comparable goods in the area of Deepdale, using the most expensive shopping basket, the price for the same basket was £42.47. A South Asian family shopping at a major supermarket outlet in Deepdale would pay £47.05. Using local shops they could pay between £38.59 and £44.28 by seeking out the best bargains in five shops (including some top-up items from a national supermarket). At the time of the research a mother with two children entitled to income support and child allowance would have to spend 28–32 per cent of her income in local shops and 34 per cent in a supermarket to buy a basket of healthy goods. This compared to the national average of 10–12 per cent of income being spent on food purchases. Conclusions: Prices varied enormously between the two areas. Local shops in one area offered a comparable price to shopping in the supermarkets. The Ingol area, with a large white working class population, was particularly poorly served for those on low incomes and the range of choices restricted. The percentages spent on food to meet the requirements of our healthy baskets and menus show that more than the national average – in both absolute and relative terms – would have to be spent to eat healthily. For the vulnerable and price dependent poor in Preston this will mean having to spend more on food and possibly more on travel to access basics, a healthy diet will cost more, while proportionally an unhealthy diet, as can be found in fast food outlets, may not be as expensive when other costs such as cooking are taken into account. An overall rise in food prices of 5 per cent will reduce living standards among high-income consumers by approximately 3 per cent; for low-income consumers this reduction in an already poor diet could be as high as 20 per cent. What we have demonstrated is the usefulness of local studies to highlight micro-differences in relatively small areas (Preston city) and the different experiences of groups in accessing healthy foods, and thus the need to refine interventions at a local level.