bluuebunny/crossref_metadata_2025_split huggingface dataset:
CLOCKin Breast Tumorigenesis: Genetic, Epigenetic, and Transcriptional Profiling Analyses
Authors: Hoffman Aaron E. , Yi Chun-Hui , Zheng Tongzhang , Stevens Richard G. , Leaderer Derek , Zhang Yawei , Holford Theodore R. , Hansen Johnni , Paulson Jennifer , Zhu Yong 
Published: February 2010

AbstractThe transcription factors responsible for maintaining circadian rhythm influence a variety of biological processes. Recently, it has been suggested that the core circadian genes may play a role in breast tumorigenesis, possibly by influencing hormone regulation or other pathways relevant to cancer. To evaluate this hypothesis, we conducted a genetic and epigenetic association study, as well as a transcriptional profiling array and a pathway-based network analysis. We report significant correlations between single nucleotide polymorphisms associated with the central circadian regulator CLOCK and breast cancer risk, with apparent effect modification by estrogen receptor/progesterone receptor status. We also found that hypermethylation in the CLOCK promoter reduced the risk of breast cancer, and lower levels of CLOCK expression were documented in healthy controls relative to normal or tumor tissue from patients with breast cancer. Finally, we silenced CLOCK in vitro and performed a whole-genome expression microarray and pathway analysis, which identified a cancer-relevant network of transcripts with altered expression following CLOCK gene knockdown. Our findings support the hypothesis that circadian genes influence tumorigenesis, and identify a set of circadian gene variants as candidate breast cancer susceptibility biomarkers. Cancer Res; 70(4); 1459–68
Loss of Kelch-Like ECH-Associated Protein 1 Function in Prostate Cancer Cells Causes Chemoresistance and Radioresistance and Promotes Tumor Growth
Authors: Zhang Ping , Singh Anju , Yegnasubramanian Srinivasan , Esopi David , Kombairaju Ponvijay , Bodas Manish , Wu Hailong , Bova Steven G. , Biswal Shyam 
Published: February 2010

AbstractLoss-of-function mutations in the nuclear factor erythroid-2–related factor 2 (Nrf2) inhibitor Kelch-like ECH-associated protein 1 (Keap1) result in increased Nrf2 activity in non–small cell lung cancer and confer therapeutic resistance. We detected point mutations in Keap1 gene, leading to nonconservative amino acid substitutions in prostate cancer cells. We found novel transcriptional and posttranscriptional mechanisms of Keap1 inactivation, such as promoter CpG island hypermethylation and aberrant splicing of Keap1, in DU-145 cells. Very low levels of Keap1 mRNA were detected in DU-145 cells, which significantly increased by treatment with DNA methyltransferase inhibitor 5-aza-deoxycytidine. The loss of Keap1 function led to an enhanced activity of Nrf2 and its downstream electrophile/drug detoxification pathway. Inhibition of Nrf2 expression in DU-145 cells by RNA interference attenuated the expression of glutathione, thioredoxin, and the drug efflux pathways involved in counteracting electrophiles, oxidative stress, and detoxification of a broad spectrum of drugs. DU-145 cells constitutively expressing Nrf2 short hairpin RNA had lower levels of total glutathione and higher levels of intracellular reactive oxygen species. Attenuation of Nrf2 function in DU-145 cells enhanced sensitivity to chemotherapeutic drugs and radiation-induced cell death. In addition, inhibition of Nrf2 greatly suppressed in vitro and in vivo tumor growth of DU-145 prostate cancer cells. Thus, targeting the Nrf2 pathway in prostate cancer cells may provide a novel strategy to enhance chemotherapy and radiotherapy responsiveness and ameliorate the growth and tumorigenicity, leading to improved clinical outcomes. Mol Cancer Ther; 9(2); 336–46
Hydroxyamidine Inhibitors of Indoleamine-2,3-dioxygenase Potently Suppress Systemic Tryptophan Catabolism and the Growth of IDO-Expressing Tumors
Authors: Koblish Holly K. , Hansbury Michael J. , Bowman Kevin J. , Yang Gengjie , Neilan Claire L. , Haley Patrick J. , Burn Timothy C. , Waeltz Paul , Sparks Richard B. , Yue Eddy W. , Combs Andrew P. , Scherle Peggy A. , Vaddi Kris , Fridman Jordan S. 
Published: February 2010

AbstractMalignant tumors arise, in part, because the immune system does not adequately recognize and destroy them. Expression of indoleamine-2,3-dioxygenase (IDO; IDO1), a rate-limiting enzyme in the catabolism of tryptophan into kynurenine, contributes to this immune evasion. Here we describe the effects of systemic IDO inhibition using orally active hydroxyamidine small molecule inhibitors. A single dose of INCB023843 or INCB024360 results in efficient and durable suppression of Ido1 activity in the plasma of treated mice and dogs, the former to levels seen in Ido1-deficient mice. Hydroxyamidines potently suppress tryptophan metabolism in vitro in CT26 colon carcinoma and PAN02 pancreatic carcinoma cells and in vivo in tumors and their draining lymph nodes. Repeated administration of these IDO1 inhibitors impedes tumor growth in a dose- and lymphocyte-dependent fashion and is well tolerated in efficacy and preclinical toxicology studies. Substantiating the fundamental role of tumor cell–derived IDO expression, hydroxyamidines control the growth of IDO-expressing tumors in Ido1-deficient mice. These activities can be attributed, at least partially, to the increased immunoreactivity of lymphocytes found in tumors and their draining lymph nodes and to the reduction in tumor-associated regulatory T cells. INCB024360, a potent IDO1 inhibitor with desirable pharmaceutical properties, is poised to start clinical trials in cancer patients. Mol Cancer Ther; 9(2); 489–98
ALK1-Fc Inhibits Multiple Mediators of Angiogenesis and Suppresses Tumor Growth
Authors: Mitchell Dianne , Pobre Eileen G. , Mulivor Aaron W. , Grinberg Asya V. , Castonguay Roselyne , Monnell Travis E. , Solban Nicolas , Ucran Jeffrey A. , Pearsall R. Scott , Underwood Kathryn W. , Seehra Jasbir , Kumar Ravindra 
Published: February 2010

Abstract
Activin receptor–like kinase-1 (ALK1) is a type I, endothelial cell–specific member of the transforming growth factor-β superfamily of receptors known to play an essential role in modulating angiogenesis and vessel maintenance. In the present study, we sought to examine the angiogenic and tumorigenic effects mediated upon the inhibition of ALK1 signaling using a soluble chimeric protein (ALK1-Fc). Of 29 transforming growth factor-β–related ligands screened by surface plasmon resonance, only bone morphogenetic protein (BMP9) and BMP10 displayed high-affinity binding to ALK1-Fc. In cell-based assays, ALK1-Fc inhibited BMP9-mediated Id-1 expression in human umbilical vein endothelial cells and inhibited cord formation by these cells on a Matrigel substrate. In a chick chorioallantoic membrane assay, ALK1-Fc reduced vascular endothelial growth factor–, fibroblast growth factor–, and BMP10-mediated vessel formation. The growth of B16 melanoma explants was also inhibited significantly by ALK1-Fc in this assay. Finally, ALK1-Fc treatment reduced tumor burden in mice receiving orthotopic grafts of MCF7 mammary adenocarcinoma cells. These data show the efficacy of chimeric ALK1-Fc proteins in mitigating vessel formation and support the view that ALK1-Fc is a powerful antiangiogenic agent capable of blocking vascularization. Mol Cancer Ther; 9(2); 379–
Restoration of p53 Functions Protects Cells from Concanavalin A–Induced Apoptosis
Authors: Amin A.R.M. Ruhul , Thakur Vijay S. , Gupta Kalpana , Jackson Mark W. , Harada Hisashi , Agarwal Mukesh K. , Shin Dong M. , Wald David N. , Agarwal Munna L. 
Published: February 2010

Abstract
A great majority of human cancers encounter disruption of the p53 network. Identification and characterization of molecular components important in both p53-dependent and p53-independent apoptosis might be useful in developing novel therapies. Previously, we reported that concanavalin A (Con A) induced p73-dependent apoptosis of cells lacking functional p53. In the present study, we investigated the mechanism and role of p53 in protection from apoptosis induced by Con A. Treatment with Con A resulted in apoptosis of p53-null ovarian cancer, SKOV3, or Li-Fraumeni syndrome, MDAH041 (041), cells. However, their isogenic pairs, SKP53 and TR9-7, expressing wild-type p53 were much less sensitive and were protected by G1 arrest. Inhibition of p53 function rendered these cells sensitive to Con A. Con A–induced apoptosis was accompanied by upregulation of forkhead box O1a (FOXO1a) and Bcl-2–interacting mediator (Bim), which were strongly inhibited after p53 expression and rescued after p53 ablation. Moreover, ablation of Bim by short hairpin RNA protected cells from apoptosis. Taken together, our study suggests that Con A induces apoptosis of cells lacking p53 by activating FOXO1a-Bim signaling and that expression of p53 protects these cells by inducing G1 arrest and by downregulating the expression of both FOXO1a and Bim, identifying a novel cross-talk between FOXO1a and p53 transcription factors. Mol Cancer Ther; 9(2); 471–9
ATM Deficiency Sensitizes Mantle Cell Lymphoma Cells to Poly(ADP-Ribose) Polymerase-1 Inhibitors
Authors: Williamson Chris T. , Muzik Huong , Turhan Ali G. , Zamò Alberto , O'Connor Mark J. , Bebb D. Gwyn , Lees-Miller Susan P. 
Published: February 2010

Abstract
Poly(ADP-ribose) polymerase-1 (PARP-1) inhibition is toxic to cells with mutations in the breast and ovarian cancer susceptibility genes BRCA1 or BRCA2, a concept termed synthetic lethality. However, whether this approach is applicable to other human cancers with defects in other DNA repair genes has yet to be determined. The ataxia telangiectasia mutated (ATM) gene is altered in several human cancers including mantle cell lymphoma (MCL). Here, we characterize a panel of MCL cell lines for ATM status and function and investigate the potential for synthetic lethality in MCL in the presence of small-molecule inhibitors of PARP-1. We show that Granta-519 and UPN2 cells have low levels of ATM protein, are defective in DNA damage-induced ATM-dependent signaling, are radiation sensitive, and have cell cycle checkpoint defects: all characteristics of defective ATM function. Significantly, Granta-519 and UPN2 cells were more sensitive to PARP-1 inhibition than were the ATM-proficient MCL cell lines examined. Furthermore, the PARP-1 inhibitor olaparib (known previously as AZD2281/KU-0059436) significantly decreased tumor growth and increased overall survival in mice bearing s.c. xenografts of ATM-deficient Granta-519 cells while producing only a modest effect on overall survival of mice bearing xenografts of the ATM-proficient cell line, Z138. Thus, PARP inhibitors have therapeutic potential in the treatment of MCL, and the concept of synthetic lethality extends to human cancers with ATM alterations. Mol Cancer Ther; 9(2); 347–57
Deregulated E2F and the AAA+ Coregulator ANCCA Drive Proto-Oncogene ACTR/AIB1 Overexpression in Breast Cancer
Authors: Hsia Elaine Y.C. , Kalashnikova Ekaterina V. , Revenko Alexey S. , Zou June X. , Borowsky Alexander D. , Chen Hong-Wu 
Published: February 2010

Abstract
The proto-oncogene ACTR/AIB1, a coactivator for transcription factors such as the nuclear receptors and E2Fs, is frequently overexpressed in various cancers including breast cancers. However, the underlying mechanism is poorly understood. Here, we identified several functional, noncanonical E2F binding sites in the ACTR first exon and intron that are critical for ACTR gene activation. We also found that the newly identified AAA+ coregulator AAA+ nuclear coregulator cancer associated (ANCCA) is recruited to the ACTR promoter and directly controls ACTR expression in breast cancer cells. Importantly, immunohistochemistry analysis indicated that ACTR overexpression is highly correlated with the expression of E2F1 and ANCCA in a cohort of human primary and lymph node–metastasized breast cancer specimens. Along with previous findings from us and others that ACTR is involved in its own gene regulation, these results suggest that one major mechanism of ACTR overexpression in cancer is the concerted, aberrant function of the nuclear coregulators such as ANCCA and ACTR, and they point to therapeutic strategies that target the Rb-E2F axis and/or the coregulator ANCCA for ACTR-overexpressing cancers. Mol Cancer Res; 8(2); 183–93
Prognostic role of PET scanning before and after reduced-intensity allogeneic stem cell transplantation for lymphoma
Authors: Lambert Jonathan R. , Bomanji Jamshed B. , Peggs Karl S. , Thomson Kirsty J. , Chakraverty Ronjon K. , Fielding Adele K. , Kottaridis Panagiotis D. , Roughton Michael , Morris Emma C. , Goldstone Anthony H. , Linch David C. , Ell Peter J. , Mackinnon Stephen 
Published: February 2010

Abstract
Allogeneic stem cell transplantation (SCT) is an established therapy for patients with relapsed lymphoma, but the role of positron emission tomography (PET) scanning preallogeneic and postallogeneic SCT is uncertain. We investigated whether pretransplantation PET status predicted outcome after allogeneic SCT and whether PET surveillance after transplantation provided additional information compared with computed tomography (CT) scanning. Eighty consecutive patients with lymphoma who received a reduced-intensity allogeneic SCT were entered onto a prospective trial. PET and CT scans were performed before transplantation and up to 36 months after transplantation. Forty-two patients were PET-positive before transplantation. Pretransplantation PET status had no significant impact on either relapse rate or overall survival. Thirty-four relapses were observed, of which 17 were PET-positive with a normal CT scan at relapse. Donor lymphocyte infusion (DLI) was administered in 26 episodes of relapse and was guided by PET alone in 14 patients. These findings suggest that, in contrast to autologous SCT, pretransplantation PET status is not predictive of relapse and survival after allogeneic SCT for lymphoma. Posttransplantation surveillance by PET detected relapse before CT in half of episodes, often allowing earlier administration of DLI in patients with recurrent lymphoma, and permitted withholding of potentially harmful DLI in those with PET-negative masses on CT scans.
The impact of parental migration on health status and health behaviours among left behind adolescent school children in China
Authors: Gao Yang , Li Li Ping , Kim Jean Hee , Congdon Nathan , Lau Joseph , Griffiths Sian 
Published: February 2010

Abstract

Background
One out of ten of China's population are migrants, moving from rural to urban areas. Many leave their families behind resulting in millions of school children living in their rural home towns without one or both their parents. Little is known about the health status of these left behind children (LBC). This study compares the health status and health-related behaviours of left behind adolescent school children and their counterparts in a rural area in Southern China.

Methods
A cross-sectional study was conducted among middle school students in Fuyang Township, Guangdong, China (2007-2008). Information about health behaviours, parental migration and demographic characteristics was collected using a self-administered questionnaire. Overweight/obesity and stunting were defined based on measurements of height and weight. Univariate and multivariate analyses were used to estimate the differences in health outcomes between LBC and non-LBC.

Results
18.1% of the schoolchildren had one or both parents working away from home. Multivariate analysis showed that male LBC were at higher risk of skipping breakfast, higher levels of physical inactivity, internet addiction, having ever smoked tobacco, suicide ideation, and being overweight. LBC girls were more likely to drink excessive amounts of sweetened beverage, to watch more TV, to have ever smoked or currently smoke tobacco, to have ever drunk alcohol and to binge drinking. They were also more likely to be unhappy, to think of planning suicide and consider leaving home.

Conclusions
Our findings suggest that parental migration is a risk factor for unhealthy behaviours amongst adolescent school children in rural China. Further research is required in addition to the consideration of the implications for policies and programmes to protect LBC.
Identifying type and determinants of missing items in quality of life questionnaires: Application to the SF-36 French version of the 2003 Decennial Health Survey
Authors: Peyre Hugo , Coste Joël , Leplège Alain 
Published: February 2010

Abstract

Background
Missing items are common in quality of life (QoL) questionnaires and present a challenge for research in this field. The development of sound strategies of replacement and prevention requires accurate knowledge of their type and determinants.

Methods
We used the 2003 French Decennial Health Survey of a representative sample of the general population -- including 22,620 adult subjects who completed the SF-36 questionnaire-- to test various socio-demographic, health status and QoL variables as potential predictors of missingness. We constructed logistic regression models for each SF-36 item to identify independent predictors and classify them according to Little and Rubin ("missing completely at random", "missing at random" and "missing not at random").

Results
The type of missingness was missing at random for half of the items of the SF-36 and missing not at random for the others. None of the items were missing completely at random. Independent predictors of missingness were age, female sex, low scores on the SF-36 subscales and in some cases low educational level, occupation, nationality and poor health status.

Conclusion
This study of the SF-36 shows that imputation of missing items is necessary and emphasizes several factors for missingness that should be considered in prevention strategies of missing data. Similar methodologies could be applied to item missingness in other QoL questionnaires.
Unchanged triclabendazole kinetics after co-administration with ivermectin and methimazole: failure of its therapeutic activity against triclabendazole-resistant liver flukes
Authors: Ceballos Laura , Moreno Laura , Alvarez Luis , Shaw Laura , Fairweather Ian , Lanusse Carlos 
Published: February 2010

Abstract

Background
The reduced drug accumulation based on enhanced drug efflux and metabolic capacity, identified in triclabendazole (TCBZ)-resistant Fasciola hepatica may contribute to the development of resistance to TCBZ. The aim of this work was to evaluate the pharmacokinetics and clinical efficacy of TCBZ administered alone or co-administered with ivermectin (IVM, efflux modulator) and methimazole (MTZ, metabolic inhibitor) in TCBZ-resistant F. hepatica-parasitized sheep. Sheep infected with TCBZ-resistant F. hepatica (Sligo isolate) were divided into three groups (n = 4): untreated control, TCBZ-treated (i.r. at 10 mg/kg) and TCBZ+IVM+MTZ treated sheep (10 i.r., 0.2 s.c. and 1.5 i.m. mg/kg, respectively). Plasma samples were collected and analysed by HPLC. In the clinical efficacy study, the animals were sacrificed at 15 days post-treatment to evaluate the comparative efficacy against TCBZ-resistant F. hepatica.

Results
The presence of IVM and MTZ did not affect the plasma disposition kinetics of TCBZ metabolites after the i.r. administration of TCBZ. The AUC value of TCBZ.SO obtained after TCBZ administration (653.9 ± 140.6 μg.h/ml) was similar to that obtained after TCBZ co-administered with IVM and MTZ (650.7 ± 122.8 μg.h/ml). Efficacy values of 56 and 38% were observed for TCBZ alone and for the combined treatment, respectively. No statistical differences (P > 0.05) were observed in fluke counts between treated groups and untreated control, which confirm the resistant status of the Sligo isolate.

Conclusions
The presence of IVM and MTZ did not affect the disposition kinetics of TCBZ and its metabolites. Thus, the combined drug treatment did not reverse the poor efficacy of TCBZ against TCBZ-resistant F. hepatica.
Inferring the functions of longevity genes with modular subnetwork biomarkers of Caenorhabditis elegansaging
Authors: Fortney Kristen , Kotlyar Max , Jurisica Igor 
Published: February 2010

AbstractA central goal of biogerontology is to identify robust gene-expression biomarkers of aging. Here we develop a method where the biomarkers are networks of genes selected based on age-dependent activity and a graph-theoretic property called modularity. Tested on Caenorhabditis elegans, our algorithm yields better biomarkers than previous methods - they are more conserved across studies and better predictors of age. We apply these modular biomarkers to assign novel aging-related functions to poorly characterized longevity genes.
Salmonella inhibits monocyte differentiation into CD11chiMHC-IIhi cells in a MyD88-dependent fashion
Authors: Rydström Anna , Wick Mary Jo 
Published: February 2010

Abstract
“Inflammatory” monocytes develop into CD11chiMHC-IIhi cells with poor antigen presentation capacity; exposure to Salmonella inhibits their differentiation into CD11chiMHC-IIhi cells in a MyD88-dependent fashion.
Monocytes and DCs originate from a shared precursor in the bone marrow, and steady-state DCs in lymphoid organs develop directly from the precursor rather than via a monocyte intermediate. However, monocytes can differentiate into DCs in tissues such as the lung and gut mucosa and into macrophages in most tissues. As Ly6Chi monocytes accumulate in lymphoid organs during oral Salmonella infection, we investigated their ability to develop into potential DCs, identified as CD11chiMHC-IIhi cells, in infected hosts. Ly6Chi monocytes, isolated from the blood of Salmonella-infected mice, developed into CD11chiMHC-IIhi cells after culture with GM-CSF or Flt3L. In contrast, the same monocytes cultured in the presence of GM-CSF and heat-killed Salmonella did not differentiate into CD11chiMHC-IIhi cells. The bacteria-induced differentiation block was dependent on TLRs, as monocytes from MyD88−/− mice converted into CD11chiMHC-IIhi cells even in the presence of bacteria. We hypothesized that Salmonella-activated wild-type monocytes secreted mediators that inhibited differentiation of MyD88−/−-derived monocytes. However, IL-6, IL-10, TNF-α, or IL-12p70 did not account for the inhibition. Finally, monocyte-derived CD11chiMHC-IIhi cells pulsed with OVA peptide or protein did not induce proliferation of antigen-specific CD4+ T cells but rather, suppressed the ability of DCs to activate CD4+ T cells. Overall, the data show that Ly6Chi monocytes from Salmonella-infected mice develop into CD11chiMHC-IIhi cells with poor antigen-presentation capacity when cultured ex vivo, and that monocyte exposure to Salmonella inhibits their differentiation into CD11chiMHC-IIhi cells in a MyD88-dependent fashion.