bluuebunny/crossref_metadata_2025_split huggingface dataset:
Imaging Pharmacodynamics of the α-Folate Receptor–Targeted Thymidylate Synthase Inhibitor BGC 945
Authors: Pillai Radhakrishna G. , Forster Martin , Perumal Meg , Mitchell Fraser , Leyton Julius , Aibgirhio Franklin I. , Golovko Oksana , Jackman Ann L. , Aboagye Eric O. 
Published: May 2008

Abstract
The assessment of tissue-specific pharmacodynamics is desirable in the development of tumor-targeted therapies. Plasma deoxyuridine (dUrd) levels, a measure of systemic thymidylate synthase (TS) inhibition, has limited application for studying the pharmacodynamics of novel TS inhibitors targeted to the high affinity α-folate receptor (FR). Here, we have evaluated the utility of [18F]fluorothymidine positron emission tomography ([18F]FLT-PET) for imaging the tissue pharmacodynamics of BGC 945, an FR-targeted antifolate TS inhibitor; the nontargeted antifolate BGC 9331 was used for comparison. TS inhibition by both drugs induced a concentration-dependent increase in [3H]thymidine uptake in FR-positive human epidermoid KB cells. Membrane-associated equilibrative nucleoside transporter type 1 levels increased from 55,720 ± 6,101 to 118,700 ± 5,193 and 130,800 ± 10,800 per cell at 100 μg/mL of BGC 9331 and BGC 945, respectively, suggesting this as a potential mechanism of increased nucleoside uptake. In keeping with these in vitro findings, tumor [18F]FLT accumulation in KB xenografts increased by ≥2-fold after drug treatment with maximal levels at 1 to 4 hours and 4 to 24 hours after BGC 9331 and BGC 945 treatment, respectively. Of interest to FR targeting, BGC 9331, but not BGC 945, induced accumulation of [18F]FLT uptake in intestine, a proliferative and TS-responsive tissue. For both drugs, quantitative changes in tumor [18F]FLT uptake were associated with increased tumor dUrd levels. In conclusion, we have validated the utility of [18F]FLT-PET to image TS inhibition induced by antifolates and shown the tumor-specific activity of BGC 945. This imaging biomarker readout will be useful in the early clinical development of BGC 945. [Cancer Res 2008;68(10):3827–34]
Single-Molecule PCR Analysis of Germ Line Mutation Induction by Anticancer Drugs in Mice
Authors: Glen Colin D. , Smith Andrew G. , Dubrova Yuri E. 
Published: May 2008

Abstract
Understanding and estimating the genetic hazards of exposure to chemical mutagens and anticancer drugs in humans requires the development of efficient systems for monitoring germ line mutation. The suitability of a single-molecule PCR–based approach for monitoring mutation induction at the mouse expanded simple tandem repeat (ESTR) locus Ms6-hm by chemical mutagens and anticancer drugs has been validated. The frequency of ESTR mutation was evaluated in the germ line of male mice exposed to the well-characterized alkylating agent and mutagen, ethylnitrosourea, and four widely used anticancer drugs, bleomycin, cyclophosphamide, mitomycin C, and procarbazine. The dose-response of ethylnitrosourea-induced mutation was found to be very close to that previously established using a pedigree-based approach for ESTR mutation detection. Paternal exposure to the clinically relevant doses of bleomycin (15–30 mg/kg), cyclophosphamide (40–80 mg/kg), and mitomycin C (2.5–5 mg/kg) led to statistically significant, dose-dependent increases in ESTR mutation frequencies in the germ line of treated male mice. Exposure to procarbazine led to a maximal increase in mutation frequency at 50 mg/kg, with a plateau at the higher concentrations. The results of this study show that the single-molecule PCR technique provides a new and efficient experimental system for monitoring the genetic effects of anticancer drugs, capable of detecting increases in mutation rates at clinically relevant doses of exposure. In addition, this approach dramatically reduces the number of mice needed for the measurement of germ line mutation induction. [Cancer Res 2008;68(10):3630–6]
Development of an Empirically Calibrated Model of Gastric Cancer in Two High-Risk Countries
Authors: Yeh Jennifer M. , Kuntz Karen M. , Ezzati Majid , Hur Chin , Kong Chung Yin , Goldie Sue J. 
Published: May 2008

Abstract
Although epidemiologic studies have established the relationship between Helicobacter pylori and gastric cancer and promising results that H. pylori treatment can reduce cancer incidence among individuals without preexisting precancerous lesions, there is no consensus on whether screening for H. pylori should be conducted. Our objective was to synthesize the available data to develop and empirically calibrate a mathematical model of gastric cancer and H. pylori in China and Colombia that could be used to provide qualitative insight into the benefits and cost-effectiveness of primary and secondary gastric cancer prevention strategies. The model represents the natural history of noncardia intestinal type gastric adenocarcinomas as a sequence of transitions among health states (e.g., normal gastric mucosa, chronic nonatrophic gastritis, gastric atrophy, intestinal metaplasia, dysplasia, and gastric cancer) stratified by H. pylori status. Initial plausible ranges for each parameter were established using data from published literature. A likelihood-based empirical calibration approach was used to identify multiple good-fitting parameter sets that were consistent with epidemiologic data. We then used these parameter sets to estimate a range of likely outcomes associated with H. pylori screening. This modeling approach allows for parameter uncertainty surrounding the natural history of H. pylori and gastric cancer to be reflected in the results of comparative analyses of different gastric cancer prevention strategies. As better data become available, the model can be refined and recalibrated, and, as such, be used as an iterative tool to assess the likely health and economic outcomes associated with gastric cancer prevention strategies. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1179–87)
FGFR2 Is a Breast Cancer Susceptibility Gene in Jewish and Arab Israeli Populations
Authors: Raskin Leon , Pinchev Mila , Arad Chana , Lejbkowicz Flavio , Tamir Ada , Rennert Hedy S. , Rennert Gad , Gruber Stephen B. 
Published: May 2008

Abstract
Genetic variation in FGFR2 is a newly described risk factor for breast cancer. We estimated the relative risk and contribution of FGFR2 polymorphisms to breast cancer risk in diverse ethnic groups within Jewish and other Middle Eastern populations. We genotyped four FGFR2 single nucleotide polymorphisms (SNP) and tested for association of these SNPs and haplotypes with breast cancer risk in a population-based case-control study of 1,529 women with breast cancer and 1,528 controls. We found significant associations between breast cancer risk and all four studied SNPs in FGFR2 (Ptrend for all SNPs &lt; 0.0001). In ethnicity-specific analysis, all four SNPs were significantly associated with breast cancer risk in Ashkenazi and Sephardi Jews, with a similar but not significant trend in Arabs. Haplotype analysis identified five common haplotypes (&gt;1%). The previously described AAGT risk haplotype was significantly associated with breast cancer risk in Ashkenazi [odds ratio (OR), 1.25; 95% confidence interval (95% CI), 1.07-1.45; P = 0.0059] and Sephardi Jews (OR, 1.46; 95% CI, 1.17-1.80; P = 0.0006) compared with the reference GGAC haplotype. The AAAC haplotype was significantly associated with breast cancer risk in Sephardi Jews (OR, 1.97; 95% CI, 1.16-3.35; P = 0.0125) but not in Ashkenazi Jews (OR, 0.83; 95% CI, 0.41-1.62; P = 0.5613) or in Arabs (OR, 1.31; 95% CI, 0.80-2.14; P = 0.2881). Genetic variation in FGFR2, identified by rs1219648, may account for a substantial fraction of breast cancer in Arab (12%), Ashkenazi (15%), and Sephardi Jewish (22%) populations. The identification of population-specific risk haplotypes in FGFR2 is likely to help identify causal variants for breast cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1060–5)
Efficacy of Gemcitabine in Patients with Non–Small Cell Lung Cancer According to Promoter Polymorphisms of the Ribonucleotide Reductase M1 Gene
Authors: Kim Soo-Ok , Jeong Ju-Yeon , Kim Mi-Ran , Cho Hyun-Ju , Ju Jin-Yung , Kwon Yong-Soo , Oh In-Jae , Kim Kyu-Sik , Kim Yu-Il , Lim Sung-Chul , Kim Young-Chul 
Published: May 2008

Abstract
Purpose: High ribonucleotide reductase M1 (RRM1) expression in resected lung cancers has been associated with better clinical outcomes. However, gemcitabine-treated patients with high tumoral RRM1 expression generally evidence poor prognoses due to the decreased efficacy of gemcitabine therapy. This study was designed in accordance with the hypothesis that polymorphisms (−37 and −524) of the RRM1 promoter gene sequence, which regulate RRM1 expression, could influence the efficacy and prognosis of lung cancer patients treated with gemcitabine-based chemotherapy.
Experimental Design: A retrospective dataset of 97 patients with advanced non–small cell lung cancer treated with gemcitabine regimens as a first-line treatment was studied in this work. The allelotyping of RRM1 promoter polymorphisms was conducted via real-time PCR using genomic DNA obtained from peripheral WBC.
Results: The RRM1 promoter allelotype was RR37CC-R524TT in 58 patients, RR37AC-RR524CT in 29 patients, and other allelotypes in 10 patients. The response rate for gemcitabine-containing chemotherapy was 49.5%. The response rate was significantly higher in the RR37AC-RR524CT group (65.5%) compared with the group containing other allelotypes (42.6%; P = 0.039). Overall survival and progression-free survival did not differ significantly by allelotype.
Conclusions: We detected significant differences in response rates to gemcitabine-based chemotherapy according to the allelotypes of the RRM1 promoter sequence, which could be determined using the germline DNA. Further functional and clinical studies will be required before this can be used as a predictive marker.
Legal Codes and Contemporary Fatawa: Muslim Women and Contesting Paradigms
Authors: Abul-Magd Zeinab , Freyer Stowasser Barbara 
Published: May 2008

AbstractIn this paper we wish to explore the legal notion of the family in contemporary legal codes and fatwa literature, and how it differs from legal stipulations regarding the nature and purpose of the marriage contract in the pre-modern Sunni fiqh. We are pursuing this brief comparative study by focusing on the issue of tahlil marriage as a legal construct that all of the four classical Sunni madhahib (law schools) did embrace, even though at least one of them tried to restrict its validity. By contrast, its role in the modern family codes is that of an awkward relic of the past, and some modern muftis in their fatwas even attempt to get away from it altogether.
Truncation in CCND1 mRNA alters miR-16-1 regulation in mantle cell lymphoma
Authors: Chen Robert W. , Bemis Lynne T. , Amato Carol M. , Myint Han , Tran Hung , Birks Diane K. , Eckhardt S. Gail , Robinson William A. 
Published: May 2008

AbstractCyclin D1 (CCND1) is a well-known regulator of cell-cycle progression. It is overexpressed in several types of cancer including breast, lung, squamous, neuroblastoma, and lymphomas. The most well-known mechanism of overexpression is the t(11;14)(q13;q32) translocation found in mantle cell lymphoma (MCL). It has previously been shown that truncated CCND1 mRNA in MCL correlates with poor prognosis. We hypothesized that truncations of the CCND1 mRNA alter its ability to be down-regulated by microRNAs in MCL. MicroRNAs are a new class of abundant small RNAs that play important regulatory roles at the posttranscriptional level by binding to the 3′ untranslated region (UTR) of mRNAs blocking either their translation or initiating their degradation. In this study, we have identified the truncation in CCND1 mRNA in MCL cell lines. We also found that truncated CCND1 mRNA leads to increased CCND1 protein expression and increased S-phase cell fraction. Furthermore, we demonstrated that this truncation alters miR-16-1 binding sites, and through the use of reporter constructs, we were able to show that miR-16-1 regulates CCND1 mRNA expression. This study introduces the role of miR-16-1 in the regulation of CCND1 in MCL.
Pulmonary cryptococcosis induces chitinase in the rat
Authors: Vicencio Alfin G , Narain Swati , Du Zhongfang , Zeng Wang Yong , Ritch James , Casadevall Arturo , Goldman David L 
Published: May 2008

Abstract

Background
We previously demonstrated that chronic pulmonary infection with Cryptococcus neoformans results in enhanced allergic inflammation and airway hyperreactivity in a rat model. Because the cell wall of C. neoformans consists of chitin, and since acidic mammalian chitinase (AMCase) has recently been implicated as a novel mediator of asthma, we sought to determine whether such infection induces chitinase activity and expression of AMCase in the rat.

Methods
We utilized a previously-established model of chronic C. neoformans pulmonary infection in the rat to analyze the activity, expression and localization of AMCase.

Results
Our studies indicate that intratracheal inoculation of C. neoformans induces chitinase activity within the lung and bronchoalveolar lavage fluid of infected rats. Chitinase activity is also elicited by pulmonary infection with other fungi (e.g. C. albicans), but not by the inoculation of dead organisms. Enhanced chitinase activity reflects increased AMCase expression by airway epithelial cells and alveolar macrophages. Systemic cryptococcosis is not associated with increased pulmonary chitinase activity or AMCase expression.

Conclusion
Our findings indicate a possible link between respiratory fungal infections, including C. neoformans, and asthma through the induction of AMCase.
Complementation of a phycocyanin-bilin lyase from Synechocystis sp. PCC 6803 with a nucleomorph-encoded open reading frame from the cryptophyte Guillardia theta
Authors: Bolte Kathrin , Kawach Oliver , Prechtl Julia , Gruenheit Nicole , Nyalwidhe Julius , Maier Uwe-G 
Published: May 2008

Abstract

Background
Cryptophytes are highly compartmentalized organisms, expressing a secondary minimized eukaryotic genome in the nucleomorph and its surrounding remnant cytoplasm, in addition to the cell nucleus, the mitochondrion and the plastid. Because the members of the nucleomorph-encoded proteome may contribute to essential cellular pathways, elucidating nucleomorph-encoded functions is of utmost interest. Unfortunately, cryptophytes are inaccessible for genetic transformations thus far. Therefore the functions of nucleomorph-encoded proteins must be elucidated indirectly by application of methods in genetically accessible organisms.

Results
Orf222, one of the uncharacterized nucleomorph-specific open reading frames of the cryptophyte Guillardia theta, shows homology to slr1649 of Synechocystis sp. PCC 6803. Recently a further homolog from Synechococcus sp. PCC 7002 was characterized to encode a phycocyanin-β155-bilin lyase. Here we show by insertion mutagenesis that the Synechocystis sp. PCC 6803 slr1649-encoded protein also acts as a bilin lyase, and additionally contributes to linker attachment and/or stability of phycobilisomes. Finally, our results indicate that the phycocyanin-β155-bilin lyase of Synechocystis sp. PCC 6803 can be complemented in vivo by the nucleomorph-encoded open reading frame orf222.

Conclusion
Our data show that the loss of phycocyanin-lyase function causes pleiotropic effects in Synechocystis sp. PCC 6803 and indicate that after separating from a common ancestor protein, the phycoerythrin lyase from Guillardia theta has retained its capacity to couple a bilin group to other phycobiliproteins. This is a further, unexpected example of the universality of phycobiliprotein lyases.
Heritability of cardiovascular risk factors in a Brazilian population: Baependi Heart Study
Authors: de Oliveira Camila M , Pereira Alexandre C , de Andrade Mariza , Soler Júlia M , Krieger José E 
Published: May 2008

Abstract

Background
The heritability of cardiovascular risk factors is expected to differ between populations because of the different distribution of environmental risk factors, as well as the genetic make-up of different human populations.

Methods
The purpose of this analysis was to evaluate genetic and environmental influences on cardiovascular risk factor traits, using a variance component approach, by estimating the heritability of these traits in a sample of 1,666 individuals in 81 families ascertained randomly from a highly admixed population of a city in a rural area in Brazil.

Results
Before adjustment for sex, age, age2, and age × sex interaction, polygenic heritability of systolic (SBP) and diastolic (DBP) blood pressure were 15.0% and 16.4%, waist circumference 26.1%, triglycerides 25.7%, fasting glucose 32.8%, HDL-c 31.2%, total cholesterol 28.6%, LDL-c 26.3%, BMI 39.1%. Adjustment for covariates increased polygenic heritability estimates for all traits mainly systolic and diastolic blood pressure (25.9 and 26.2%, respectively), waist circumference (40.1%), and BMI (51.0%).

Conclusion
Heritability estimates for cardiovascular traits in the Brazilian population are high and not significantly different from other studied worldwide populations. Mapping efforts to identify genetic loci associated with variability of these traits are warranted.
Effect of iron content on the tolerability of prenatal multivitamins in pregnancy
Authors: Nguyen Patricia , Nava-Ocampo Alejandro , Levy Amalia , O'Connor Deborah L , Einarson Tom R , Taddio Anna , Koren Gideon 
Published: May 2008

Abstract

Background
Gastrointestinal irritability can deter pregnant women from starting or continuing prenatal multivitamin supplementation. In a previous study, suboptimal tolerability was observed among pregnant women taking a large tablet (18 mm × 8 mm × 8 mm) multivitamin with high elemental iron content (60 mg as ferrous fumarate). The objective of the present study was to compare rates of adherence and reported adverse events among pregnant women who were randomized to commence supplementation with a small-tablet prenatal multivitamin, containing either low or high iron content.

Methods
Pregnant women who called the Motherisk Program (Hospital for Sick Children, Toronto) and had not started taking or had discontinued any multivitamin due to adverse events were included in this prospective, randomized, open-label, 2-arm study. Women were randomized to take a small-size (16 mm × 9 mm × 4 mm), low elemental iron content (35 mg as ferrous fumarate) multivitamin ('35 mg' group); or a small-size (5 mm radius, 5 mm thickness), high elemental iron content (60 mg as ferrous sulphate) multivitamin ('60 mg' group). Follow-up interviews documented pill intake and adverse events. Rates of adherence and adverse events were compared between groups using chi-squared tests and Kaplan-Meier survival curves.

Results
Of 167 randomized women, 92 in the '35 mg' group and 75 in the '60 mg' group were included in the analysis. Despite ideal conditions and regular follow-ups, mean adherence based on pill intake recall, in both groups was approximately 50%. No statistically significant difference was detected in proportions of women who actually started taking either multivitamin. Among those who started, no difference was detected in rates of adherence or reported adverse events.

Conclusion
The present results suggest that iron content is not a major determinant of adherence to prenatal multivitamins. Combined with our previous study, tablet size may be the more definitive factor affecting adherence.
Importance of dose-schedule of 5-aza-2'-deoxycytidine for epigenetic therapy of cancer
Authors: Lemaire Maryse , Chabot Guy G , Raynal Noël JM , Momparler Louise F , Hurtubise Annie , Bernstein Mark L , Momparler Richard L 
Published: May 2008

AbstractBackgroundThe inactivation of tumor suppressor genes (TSGs) by aberrant DNA methylation plays an important role in the development of malignancy. Since this epigenetic change is reversible, it is a potential target for chemotherapeutic intervention using an inhibitor of DNA methylation, such as 5-aza-2'-deoxycytidine (DAC). Although clinical studies show that DAC has activity against hematological malignancies, the optimal dose-schedule of this epigenetic agent still needs to be established.MethodsClonogenic assays were performed on leukemic and tumor cell lines to evaluate thein vitroantineoplastic activity of DAC. The reactivation of TSGs and inhibition of DNA methylation by DAC were investigated by reverse transcriptase-PCR and Line-1 assays. Thein vivoantineoplastic activity of DAC administered as an i.v. infusion was evaluated in mice with murine L1210 leukemia by measurement of survival time, and in mice bearing murine EMT6 mammary tumor by excision of tumor after chemotherapy for anin vitroclonogenic assay.ResultsIncreasing the DAC concentration and duration of exposure produced a greater loss of clonogenicity for both human leukemic and tumor cell lines. The reactivation of the TSGs (p57KIP2in HL-60 leukemic cells andp16CDKN2Ain Calu-6 lung carcinoma cells) and the inhibition of global DNA methylation in HL-60 leukemic cells increased with DAC concentration. In mice with L1210 leukemia and in mice bearing EMT6 tumors, the antineoplastic action of DAC also increased with the dose. The plasma level of DAC that produced a very potent antineoplastic effect in mice with leukemia or solid tumors was > 200 ng/ml (> 1 μM).ConclusionWe have shown that intensification of the DAC dose markedly increased its antineoplastic activity in mouse models of cancer. Our data also show that there is a good correlation between the concentrations of DAC that reducein vitroclonogenicity, reactivate TSGs and inhibit DNA methylation. These results suggest that the antineoplastic action of DAC is related to its epigenetic action. Our observations provide a strong rationale to perform clinical trials using dose intensification of DAC to maximize the chemotherapeutic potential of this epigenetic agent in patients with cancer.
Viral vectors based on bidirectional cell-specific mammalian promoters and transcriptional amplification strategy for use in vitro and in vivo
Authors: Liu Beihui , Paton Julian F , Kasparov Sergey 
Published: May 2008

Abstract

Background
Using cell-type-specific promoters to restrict gene expression to particular cells is an attractive approach for gene therapy, but often hampered by insufficient transcriptional activity of these promoters. Previous studies have shown that transcriptional amplification strategy (TAS) can be used to enhance the activity of such promoters without loss of cell type specificity. Originally TAS involved the use of two copies of a cell-specific promoter leading to generation of large expression cassettes, which can be hard to use given the space limitations of the conventional viral gene expression vectors.

Results
We have now developed a new bidirectional lentiviral vector system, based on TAS that can enhance the transcriptional activity of human synapsin-1 (SYN) promoter and the compact glial fibrillary acidic protein (GfaABC1D) promoter. In the opposite orientation, a minimal core promoter (65 bp) derived from the human cytomegalovirus (CMV) was joined upstream of the SYN promoter or GfaABC1D promoter. This led to the formation of synthetic bidirectional promoters which were flanked with two gene expression cassettes. The 5' cassette transcribed the artificial transcriptional activator. The downstream cassette drove the synthesis of the gene of interest. Studies in both cell cultures and in vivo showed that the new bidirectional promoters greatly increased the expression level of the reporter gene. In vivo studies also showed that transgene expression was enhanced without loss of cell specificity of both SYN and GfaABC1D promoters.

Conclusion
This work establishes a novel approach for creating compact TAS-amplified cell-specific promoters, a feature important for their use in viral backbones. This improved approach should prove useful for the development of powerful gene expression systems based on weak cell-specific promoters.