bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor
Authors: Maira Sauveur-Michel , Pecchi Sabina , Huang Alan , Burger Matthew , Knapp Mark , Sterker Dario , Schnell Christian , Guthy Daniel , Nagel Tobi , Wiesmann Marion , Brachmann Saskia , Fritsch Christine , Dorsch Marion , Chène Patrick , Shoemaker Kevin , De Pover Alain , Menezes Daniel , Martiny-Baron Georg , Fabbro Doriano , Wilson Christopher J. , Schlegel Robert , Hofmann Francesco , García-Echeverría Carlos , Sellers William R. , Voliva Charles F. 
Published: December 2011

Abstract
Following the discovery of NVP-BEZ235, our first dual pan-PI3K/mTOR clinical compound, we sought to identify additional phosphoinositide 3-kinase (PI3K) inhibitors from different chemical classes with a different selectivity profile. The key to achieve these objectives was to couple a structure-based design approach with intensive pharmacologic evaluation of selected compounds during the medicinal chemistry optimization process. Here, we report on the biologic characterization of the 2-morpholino pyrimidine derivative pan-PI3K inhibitor NVP-BKM120. This compound inhibits all four class I PI3K isoforms in biochemical assays with at least 50-fold selectivity against other protein kinases. The compound is also active against the most common somatic PI3Kα mutations but does not significantly inhibit the related class III (Vps34) and class IV (mTOR, DNA-PK) PI3K kinases. Consistent with its mechanism of action, NVP-BKM120 decreases the cellular levels of p-Akt in mechanistic models and relevant tumor cell lines, as well as downstream effectors in a concentration-dependent and pathway-specific manner. Tested in a panel of 353 cell lines, NVP-BKM120 exhibited preferential inhibition of tumor cells bearing PIK3CA mutations, in contrast to either KRAS or PTEN mutant models. NVP-BKM120 shows dose-dependent in vivo pharmacodynamic activity as measured by significant inhibition of p-Akt and tumor growth inhibition in mechanistic xenograft models. NVP-BKM120 behaves synergistically when combined with either targeted agents such as MEK or HER2 inhibitors or with cytotoxic agents such as docetaxel or temozolomide. The pharmacological, biologic, and preclinical safety profile of NVP-BKM120 supports its clinical development and the compound is undergoing phase II clinical trials in patients with cancer. Mol Cancer Ther; 11(2); 317–28. ©2011 AACR.
Potent Inhibition of Angiogenesis by the IGF-1 Receptor-Targeting Antibody SCH717454 Is Reversed by IGF-2
Authors: Bid Hemant K. , Zhan Jun , Phelps Doris A. , Kurmasheva Raushan T. , Houghton Peter J. 
Published: December 2011

AbstractPreviously, we reported that a predominant action of a type-1 insulin-like growth factor receptor (IGF-1R)-targeted antibody was through inhibiting tumor-derived VEGF, and indirectly, angiogenesis. Here, we examined the direct antiangiogenic activity of the IGF-1R-targeted antibody SCH717454 that inhibits ligand-receptor binding and the mechanism by which tumors circumvent its antiangiogenic activity. Inhibition of ligand-stimulated activation of IGF-1R, insulin receptor (IN-R), or downstream signaling [phosphorylation of Akt (Ser473)] was determined by receptor-specific immunoprecipitation and immunoblotting. Inhibition of angiogenesis was determined by proliferation and tube formation using human umbilical vein endothelial cells (HUVEC) in vitro and in Matrigel plugs implanted in mice. SCH717454 blocked IGF-1-stimulated but not IGF-2-stimulated phosphorylation of Akt in sarcoma cells. Immunoprecipitation using anti-IGF-1R and anti-IN-R antibodies revealed that SCH717454 equally blocked IGF-1-stimulated and IGF-2-stimulated IGF-1R phosphorylation, but not IGF-2-stimulated phosphorylation of IN-R. SCH717454 completely blocked VEGF-stimulated proliferation and tube formation of HUVECs, but exogenous IGF-2 and insulin circumvented these inhibitory effects. Coculture of HUVECs with IGF-2-secreting tumor cells completely abrogated SCH717454 inhibition of VEGF-stimulated HUVEC tube formation. In mice, SCH717454 inhibited angiogenesis in VEGF-infused Matrigel plugs, but had no inhibitory activity when plugs contained both VEGF + IGF-2. These results reveal for the first time, a role for IGF-1R signaling in VEGF-mediated angiogenesis in vitro and indicate direct antiangiogenic activity of SCH717454. Both in vitro and in vivo IGF-2 circumvented these effects through IN-R signaling. Many childhood cancers secrete IGF-2, suggesting that tumor-derived IGF-2 in the microenvironment maintains angiogenesis in the presence of IGF-1R-targeted antibodies allowing tumor progression. Mol Cancer Ther; 11(3); 649–59. ©2011 AACR.
TAK-960, a Novel, Orally Available, Selective Inhibitor of Polo-Like Kinase 1, Shows Broad-spectrum Preclinical Antitumor Activity in Multiple Dosing Regimens
Authors: Hikichi Yuichi , Honda Kohei , Hikami Kouki , Miyashita Hitoshi , Kaieda Isao , Murai Saomi , Uchiyama Noriko , Hasegawa Maki , Kawamoto Tomohiro , Sato Takashi , Ichikawa Takashi , Cao Sheldon , Nie Zhe , Zhang Lilly , Yang Johnny , Kuida Keisuke , Kupperman Erik 
Published: December 2011

Abstract
Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase involved in key processes during mitosis. Human PLK1 has been shown to be overexpressed in various human cancers, and elevated levels of PLK1 have been associated with poor prognosis, making it an attractive target for anticancer therapy. TAK-960 [4-[(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino]-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl) benzamide] is a novel, investigational, orally bioavailable, potent, and selective PLK1 inhibitor that has shown activity in several tumor cell lines, including those that express multidrug-resistant protein 1 (MDR1). Consistent with PLK1 inhibition, TAK-960 treatment caused accumulation of G2–M cells, aberrant polo mitosis morphology, and increased phosphorylation of histone H3 (pHH3) in vitro and in vivo. TAK-960 inhibited proliferation of multiple cancer cell lines, with mean EC50 values ranging from 8.4 to 46.9 nmol/L, but not in nondividing normal cells (EC50 &gt;1,000 nmol/L). The mutation status of TP53 or KRAS and MDR1 expression did not correlate with the potency of TAK-960 in the cell lines tested. In animal models, oral administration of TAK-960 increased pHH3 in a dose-dependent manner and significantly inhibited the growth of HT-29 colorectal cancer xenografts. Treatment with once daily TAK-960 exhibited significant efficacy against multiple tumor xenografts, including an adriamycin/paclitaxel-resistant xenograft model and a disseminated leukemia model. TAK-960 has entered clinical evaluation in patients with advanced cancers. Mol Cancer Ther; 11(3); 700–9. ©2011 AACR.
Pancreatic Cancer Cells and Normal Pancreatic Duct Epithelial Cells Express an Autocrine Catecholamine Loop that Is Activated by Nicotinic Acetylcholine Receptors α3, α5, and α7
Authors: Al-Wadei Mohammed H. , Al-Wadei Hussein A.N. , Schuller Hildegard M. 
Published: December 2011

Abstract
Pancreatic cancer is the fourth leading cause of cancer deaths in developed countries. Smoking is an established risk factor for this malignancy but the underlying mechanisms are poorly understood. Previous reports have provided evidence that nicotinic acetylcholine receptors (nAChR) and beta adrenergic receptors (β-AR) stimulate the growth and migration of pancreatic cancer cells. However, a potential cooperation of these two receptor families in the regulation of pancreatic cancer has not been studied to date. Using two pancreatic cancer cell lines and immortalized pancreatic duct epithelia in vitro, our current data show that all three cell lines synthesized and released the catecholamine neurotransmitters noradrenaline and adrenaline upon exposure to nicotine and that this activity was regulated by α3, α5, and α7-nAChRs. In accordance with the established function of these catecholamines as β-AR agonists, nicotine-induced cell proliferation was blocked by the β-AR antagonist propranolol. Nicotine-induced proliferation was also abolished by the α7-nAChR antagonist α-bungarotoxin, whereas catecholamine production in response to nicotine was blocked by gene knockdown of the α3, α5, and α7-nAChRs. The nicotinic agonists acetylcholine, nicotine, and its nitrosated carcinogenic derivative NNK induced the phosphorylation of CREB, ERK, Src, and AKT and these responses were inhibited by propranolol. Our findings identify this hitherto unknown autocrine catecholamine loop as an important regulatory cascade in pancreatic cancer that may prove a promising new target for cancer intervention. Mol Cancer Res; 10(2); 239–49. ©2011 AACR.
Topological characterisation and identification of critical domains within glucosyltransferase IV (GtrIV) of Shigella flexneri
Authors: Nair Anesh , Korres Haralambos , Verma Naresh K 
Published: December 2011

Abstract

Background
The three bacteriophage genes gtrA, gtrB and gtr

(type)
are responsible for O-antigen glucosylation in Shigella flexneri. Both gtrA and gtrB have been demonstrated to be highly conserved and interchangeable among serotypes while gtr

(type)
was found to be specific to each serotype, leading to the hypothesis that the Gtr(type) proteins are responsible for attaching glucosyl groups to the O-antigen in a site- and serotype- specific manner. Based on the confirmed topologies of GtrI, GtrII and GtrV, such interaction and attachment of the glucosyl groups to the O-antigen has been postulated to occur in the periplasm.

Results
In this study, the topology of GtrIV was experimentally determined by creating different fusions between GtrIV and a dual-reporter protein, PhoA/LacZ. This study shows that GtrIV consists of 8 transmembrane helices, 2 large periplasmic loops, 2 small cytoplasmic N- and C- terminal ends and a re-entrant loop that occurs between transmembrane helices III and IV. Though this topology differs from that of GtrI, GtrII, GtrV and GtrX, it is very similar to that of GtrIc. Furthermore, both the N-terminal periplasmic and the C-terminal periplasmic loops are important for GtrIV function as shown via a series of loop deletion experiments and the creation of chimeric proteins between GtrIV and its closest structural homologue, GtrIc.

Conclusion
The current study provides the basis for elucidating the structure and mechanism of action of this important O-antigen modifying glucosyltransferase.
A pilot study for channel catfish whole genome sequencing and de novo assembly
Authors: Jiang Yanliang , Lu Jianguo , Peatman Eric , Kucuktas Huseyin , Liu Shikai , Wang Shaolin , Sun Fanyue , Liu Zhanjiang 
Published: December 2011

Abstract

Background
Recent advances in next-generation sequencing technologies have drastically increased throughput and significantly reduced sequencing costs. However, the average read lengths in next-generation sequencing technologies are short as compared with that of traditional Sanger sequencing. The short sequence reads pose great challenges for de novo sequence assembly. As a pilot project for whole genome sequencing of the catfish genome, here we attempt to determine the proper sequence coverage, the proper software for assembly, and various parameters used for the assembly of a BAC physical map contig spanning approximately a million of base pairs.

Results
A combination of low sequence coverage of 454 and Illumina sequencing appeared to provide effective assembly as reflected by a high N50 value. Using 454 sequencing alone, a sequencing depth of 18 X was sufficient to obtain the good quality assembly, whereas a 70 X Illumina appeared to be sufficient for a good quality assembly. Additional sequencing coverage after 18 X of 454 or after 70 X of Illumina sequencing does not provide significant improvement of the assembly. Considering the cost of sequencing, a 2 X 454 sequencing, when coupled to 70 X Illumina sequencing, provided an assembly of reasonably good quality. With several software tested, Newbler with a seed length of 16 and ABySS with a K-value of 60 appear to be appropriate for the assembly of 454 reads alone and Illumina paired-end reads alone, respectively. Using both 454 and Illumina paired-end reads, a hybrid assembly strategy using Newbler for initial 454 sequence assembly, Velvet for initial Illumina sequence assembly, followed by a second step assembly using MIRA provided the best assembly of the physical map contig, resulting in 193 contigs with a N50 value of 13,123 bp.

Conclusions
A hybrid sequencing strategy using low sequencing depth of 454 and high sequencing depth of Illumina provided the good quality assembly with high N50 value and relatively low cost. A combination of Newbler, Velvet, and MIRA can be used to assemble the 454 sequence reads and the Illumina reads effectively. The assembled sequence can serve as a resource for comparative genome analysis. Additional long reads using the third generation sequencing platforms are needed to sequence through repetitive genome regions that should further enhance the sequence assembly.
Chronic disease knowledge and its determinants among chronically ill adults in rural areas of Shanxi Province in China: a cross-sectional study
Authors: Tian Miaomiao , Chen Yingchun , Zhao Rui , Chen Li , Chen Xi , Feng Da , Feng Zhanchun 
Published: December 2011

Abstract

Background
Chronic disease knowledge is an important prerequisite for an individual to implement behavioural changes towards the prevention and control of chronic diseases (CDs). Limited information is available about the relationship between different levels of health services and CD knowledge among rural residents with CDs. This research explores the distribution characteristics of CD knowledge and its determinants among chronically ill adults in rural China according to the aspects of patients and health service providers.

Methods
A cross-sectional study was undertaken to estimate distribution characteristics of CD knowledge and collect data of socio-demographic characteristics, healthcare institutions attendances, duration of illness, and family history of CDs. Participants were 1060 rural adults with hypertension or type II diabetes. Correct responses to 12 questions were summed into a total knowledge score, and participants were divided into an adequate health knowledge group (score ≥ 6) or an inadequate health knowledge group (score < 5). Logistic regression was used determine the predictors of adequate CD health knowledge.

Results
The mean age of participants was 61.34 years (SD = 10 years). Out of a possible 12, the median score on the CD knowledge questionnaire was 3.0. About 25% of participants were classified as having adequate CD knowledge. Those who had a family history and/or long duration of CDs were more likely to have adequate health knowledge. Participants who received CD health information and self-care instructions from their physicians had 2.67 and 13.34 times greater odds of possessing adequate health knowledge than those who received no information, respectively. Adequate CD knowledge was strongly associated with regular check-ups, especially for those who attended township hospitals (OR = 40.17).

Conclusions
Having regular check-ups at a fixed healthcare institution and receiving health information from physicians are important measures for increasing CD knowledge among rural adults with CDs. Township hospitals are the most effective settings for health education. It is important to develop an effective community-based prevention and control mechanism for CDs. This requires township hospitals to take a leading role in improving CD knowledge among chronically ill patients, and enhancing implementation of health education in rural China.
Structural adaptation of extreme halophilic proteins through decrease of conserved hydrophobic contact surface
Authors: Siglioccolo Alessandro , Paiardini Alessandro , Piscitelli Maria , Pascarella Stefano 
Published: December 2011

Abstract

Background
Halophiles are extremophilic microorganisms growing optimally at high salt concentrations. There are two strategies used by halophiles to maintain proper osmotic pressure in their cytoplasm: accumulation of molar concentrations of potassium and chloride with extensive adaptation of the intracellular macromolecules ("salt-in" strategy) or biosynthesis and/or accumulation of organic osmotic solutes ("osmolyte" strategy). Our work was aimed at contributing to the understanding of the shared molecular mechanisms of protein haloadaptation through a detailed and systematic comparison of a sample of several three-dimensional structures of halophilic and non-halophilic proteins. Structural differences observed between the "salt-in" and the mesophilic homologous proteins were contrasted to those observed between the "osmolyte" and mesophilic pairs.

Results
The results suggest that haloadaptation strategy in the presence of molar salt concentration, but not of osmolytes, necessitates a weakening of the hydrophobic interactions, in particular at the level of conserved hydrophobic contacts. Weakening of these interactions counterbalances their strengthening by the presence of salts in solution and may help the structure preventing aggregation and/or loss of function in hypersaline environments.

Conclusions
Considering the significant increase of biotechnology applications of halophiles, the understanding of halophilicity can provide the theoretical basis for the engineering of proteins of great interest because stable at concentrations of salts that cause the denaturation or aggregation of the majority of macromolecules.
Effects of particulate air pollution on blood pressure in a highly exposed population in Beijing, China: a repeated-measure study
Authors: Baccarelli Andrea , Barretta Francesco , Dou Chang , Zhang Xiao , McCracken John P , Díaz Anaité , Bertazzi Pier Alberto , Schwartz Joel , Wang Sheng , Hou Lifang 
Published: December 2011

Abstract

Background
Particulate Matter (PM) exposure is critical in Beijing due to high population density and rapid increase in vehicular traffic. PM effects on blood pressure (BP) have been investigated as a mechanism mediating cardiovascular risks, but results are still inconsistent. The purpose of our study is to determine the effects of ambient and personal PM exposure on BP.

Methods
Before the 2008 Olympic Games (June 15-July 27), we examined 60 truck drivers and 60 office workers on two days, 1-2 weeks apart (n = 240). We obtained standardized measures of post-work BP. Exposure assessment included personal PM2.5 and Elemental Carbon (EC, a tracer of traffic particles) measured using portable monitors during work hours; and ambient PM10 averaged over 1-8 days pre-examination. We examined associations of exposures (exposure group, personal PM2.5/EC, ambient PM10) with BP controlling for multiple covariates.

Results
Mean personal PM2.5 was 94.6 μg/m3 (SD = 64.9) in office workers and 126.8 (SD = 68.8) in truck drivers (p-value < 0.001). In all participants combined, a 10 μg/m3 increase in 8-day ambient PM10 was associated with BP increments of 0.98 (95%CI 0.34; 1.61; p-value = 0.003), 0.71 (95%CI 0.18; 1.24; p-value = 0.01), and 0.81 (95%CI 0.31; 1.30; p-value = 0.002) mmHg for systolic, diastolic, and mean BP, respectively. BP was not significantly different between the two groups (p-value > 0.14). Personal PM2.5 and EC during work hours were not associated with increased BP.

Conclusions
Our results indicate delayed effects of ambient PM10 on BP. Lack of associations with exposure groups and personal PM2.5/EC indicates that PM effects are related to background levels of pollution in Beijing, and not specifically to work-related exposure.
Fitness and health-related quality of life dimensions in community-dwelling middle aged and older adults
Authors: Olivares Pedro R , Gusi Narcis , Prieto Josue , Hernandez-Mocholi Miguel A 
Published: December 2011

Abstract

Background
The aim of the present study was to identify the physical fitness (PF) tests of a multi-component battery more related to the perception of problems in each dimension of the health-related quality of life (HRQoL) assessed by the EuroQol 5 dimensions 3 level questionnaire (EQ-5D-3L) in community-dwelling middle-aged and older adults

Methods
A cross-sectional study was conducted with 7104 participants (6243 females and 861 males aged 50-99 years) who were recruited in the framework of the Exercise Looks After You Program, which is a public health program designed to promote physical activity (PA) in community-dwelling middle-aged and older adults. Participants were assessed by the EQ-5D-3L questionnaire and a battery of fitness tests. The responses to each EQ-5D-3L dimension were collapsed into a two-tier variable consisting of «perceive problems» and «do not perceive problems». Correlation coefficients for the relationships between the HRQoL variables, between the PF variables, and between the HRQoL and PF variables were obtained. Two logistic regression models, one adjusted and one unadjusted, were developed for each EQ-5D-3L dimension.

Results
There were significant correlations between all variables except anxiety/depression and the back scratch test. The PF tests that correlated best with the HRQoL dimensions were the Timed Up-and-Go Test (TUG) and the 6-min walk; pain/discomfort and anxiety/depression correlated less well. All PF tests correlated, especially the TUG and 6-min walk tests. Unadjusted logistic models showed significant goodness of fit for the mobility and pain/discomfort dimensions only. Adjusted logistic models showed significant goodness of fit for all dimensions when the following potential confounding variables were included: age, gender, weekly level of PA, smoking and alcohol habits, body mass index, and educational level. For all dimensions, the highest odds ratios for the association with PF tests were with the TUG; this was observed with both the unadjusted and adjusted models.

Conclusions
The perception of problems, as measured by the EQ-5D-3L dimensions, was associated with a lower level of fitness, particularly for those dimensions that relate more closely to physical components. The PF tests that associated most closely with the perception of problems in the HRQoL dimensions were the TUG and the 6-min walk. This information will aid the design and assessment of PA programs that aim to improve HRQoL.
Reductions in abortion-related mortality following policy reform: evidence from Romania, South Africa and Bangladesh
Authors: Benson Janie , Andersen Kathryn , Samandari Ghazaleh 
Published: December 2011

Abstract
Unsafe abortion is a significant contributor to worldwide maternal mortality; however, abortion law and policy liberalization could lead to drops in unsafe abortion and related deaths. This review provides an analysis of changes in abortion mortality in three countries where significant policy reform and related service delivery occurred. Drawing on peer-reviewed literature, population data and grey literature on programs and policies, this paper demonstrates the policy and program changes that led to declines in abortion-related mortality in Romania, South Africa and Bangladesh. In all three countries, abortion policy liberalization was followed by implementation of safe abortion services and other reproductive health interventions. South Africa and Bangladesh trained mid-level providers to offer safe abortion and menstrual regulation services, respectively, Romania improved contraceptive policies and services, and Bangladesh made advances in emergency obstetric care and family planning. The findings point to the importance of multi-faceted and complementary reproductive health reforms in successful implementation of abortion policy reform.