bluuebunny/crossref_metadata_2025_split huggingface dataset:
Receptor Tyrosine Kinase Genes Amplified in Glioblastoma Exhibit a Mutual Exclusivity in Variable Proportions Reflective of Individual Tumor Heterogeneity
Authors: Little Suzanne E. , Popov Sergey , Jury Alexa , Bax Dorine A. , Doey Lawrence , Al-Sarraj Safa , Jurgensmeier Juliane M. , Jones Chris 
Published: February 2012

Abstract
Intratumoral heterogeneity in human solid tumors represents a major barrier for the development of effective molecular treatment strategies, as treatment efficacies will reflect the molecular variegation in individual tumors. In glioblastoma, the generation of composite genomic profiles from bulk tumor samples has allowed one to map the genomic amplifications of putative genetic drivers and to prioritize therapeutic targeting strategies aimed at eradicating the tumor burden. Notably, amplification of multiple receptor tyrosine kinases (RTK) within a single tumor specimen obtained from patients is frequently observed. In this study, use of a detailed multicolor FISH mapping procedure in pathologic specimens revealed a mutual exclusivity of gene amplification in the majority of glioblastoma tumors examined. In particular, the two most commonly amplified RTK genes, EGFR and PDGFRA, were found to be present in variable proportions across the tumors, with one or the other gene predominating in certain areas of the same specimen. Our findings have profound implications for designing efficacious therapeutic regimens, as it remains unclear that how the cells with different gene amplification events contribute to disease propagation or the response to molecular targeted therapies. Cancer Res; 72(7); 1614–20. ©2012 AACR.
Serum Macrophage Inhibitory Cytokine-1 (MIC-1/GDF15): A Potential Screening Tool for the Prevention of Colon Cancer?
Authors: Brown David A. , Hance Kenneth W. , Rogers Connie J. , Sansbury Leah B. , Albert Paul S. , Murphy Gwen , Laiyemo Adeyinka O. , Wang Zhuoqiao , Cross Amanda J. , Schatzkin Arthur , Danta Mark , Srasuebkul Preeyaporn , Amin Janaki , Law Matthew , Breit Samuel N. , Lanza Elaine 
Published: February 2012

Abstract
Background: Macrophage inhibitory cytokine-1 (MIC-1/GDF15) mediates nonsteroidal anti-inflammatory drug (NSAID) protection from colonic polyps in mice and is linked to the development of colorectal carcinoma in humans. Therefore, changes in serum MIC-1/GDF15 levels could predict the presence of premalignant colonic polyposis and assist in population screening strategies.
Methods: Serum MIC-1/GDF15 levels were measured in subjects in the Polyp Prevention Trial, in which NSAID use and colon cancer risk factors were defined. Subjects had an initial adenoma removed, a repeat colonoscopy removing previously unidentified polyps, and serum MIC-1/GDF15 estimation. Three years later recurrent adenomas were identified and serum MIC-1/GDF15 levels reestimated. The relationship between serum MIC-1/GDF15 levels and adenoma presence or recurrence was examined.
Results: Serum MIC-1/GDF15 levels differed by adenoma status and were significantly related to colon cancer risk factors. In addition, mean serum MIC-1/GDF15 levels rose with increasing numbers of adenomas present and high-risk adenoma recurrence. NSAID users had higher serum MIC-1/GDF15 concentrations, which were related to protection from adenoma recurrence. Furthermore, adjusted serum MIC-1/GDF15 levels at final follow-up were related to adenoma recurrence (highest quartile MIC-1/GDF15; OR = 14.7, 95% CI: 3.0–73).
Conclusions: These data suggest that MIC-1/GDF15 mediates at least some of the protection afforded by NSAIDs against human colonic polyposis. Furthermore, serum MIC-1/GDF15 levels vary with the development of adnenomatous colonic polyps.
Impact: Serum MIC-1/GDF15 determination may hold promise as the first serum screening test to assist the detection of premalignant adenomatous colonic polyposis. Cancer Epidemiol Biomarkers Prev; 21(2); 337–46. ©2011 AACR.
Polymorphic Variation in theGCandCASRGenes and Associations with Vitamin D Metabolite Concentration and Metachronous Colorectal Neoplasia
Authors: Hibler Elizabeth A. , Hu Chengcheng , Jurutka Peter W. , Martinez Maria E. , Jacobs Elizabeth T. 
Published: February 2012

AbstractBackground: Vitamin D levels and calcium intake have been associated with risk of colorectal neoplasia, and genetic variation in vitamin D pathway genes may affect circulating vitamin D metabolite concentrations and/or risk for colorectal lesions. This study evaluated associations between polymorphic variation in the Gc-globulin (GC) and calcium-sensing receptor (CASR) and odds for metachronous colorectal neoplasia and vitamin D metabolite concentrations.Methods: Participants from the Ursodeoxycholic Acid (UDCA) and Wheat Bran Fiber (WBF) trials (n = 1,439) were analyzed using a single-nucleotide polymorphism (SNP) tagging approach, with a subset (n = 404) of UDCA trial participants for whom vitamin D metabolite concentrations were also available. A total of 25 GC and 35 CASR tagSNPs were evaluated using multiple statistical methods.Results: Principal components analyses did not reveal gene-level associations between GC or CASR and colorectal neoplasia; however, a significant gene-level association between GC and 25(OH)D concentrations (P &lt; 0.01) was observed. At the individual SNP level and following multiple comparisons adjustments, significant associations were observed between seven GC (rs7041, rs222035, rs842999, rs1155563, rs12512631, rs16846876, and rs1746825) polymorphisms and circulating measures of 25(OH)D (adjusted P &lt; 0.01) and CASR SNP rs1042636 and proximal colorectal neoplasia (adjusted P = 0.01).Conclusions: These results show a possible association between variation in CASR and odds of colorectal neoplasia as well as the potential role of variation in GC with circulating 25(OH)D concentrations.Impact: Additional research is warranted to determine the mechanism of GC genotype in influencing 25(OH)D concentrations and to further elucidate the role of CASR in colorectal neoplasia. Cancer Epidemiol Biomarkers Prev; 21(2); 368–75. ©2011 AACR.
Bony Incorporation of Soft Tissue Anterior Cruciate Ligament Grafts in an Animal Model
Authors: Bhatia Sanjeev , Bell Rebecca , Frank Rachel M. , Rodeo Scott A. , Bach Bernard R. , Cole Brian J. , Chubinskaya Susanna , Wang Vincent M. , Verma Nikhil N. 
Published: February 2012

Background: The effect of low-dose gamma irradiation on healing of soft tissue allografts remains largely unknown. Hypothesis: The authors hypothesized that soft tissue allograft healing to bone would be delayed compared with that of autograft tissue and that low-dose (1.2 Mrad) gamma irradiation would not affect the healing response of allograft tissue after anterior cruciate ligament (ACL) reconstruction. Study Design: Controlled laboratory study. Methods: Forty-eight New Zealand White rabbits underwent bilateral ACL reconstructions with semitendinosus tendon graft. Sixteen rabbits were reconstructed with autografts and the remainder with allografts. The 32 allograft rabbits each received 1 irradiated allograft (1.2 Mrad), with the contralateral leg receiving a nonirradiated allograft. Animals were euthanized at 2 weeks or 8 weeks postoperatively. Tensile stiffness, maximum load, and displacement at maximum load were measured. Tibial and femoral segments were sectioned perpendicular to the tunnel axis allowing for histologic and histomorphometric analyses at the tendon-bone interface. Results: There were no significant differences between the maximum load or stiffness values among all groups at 8 weeks. At 2 weeks, autograft exhibited significantly ( P < .01) lower maximum load than did the nonirradiated grafts. Regarding histology, at both 2- and 8-week time points, autograft tendon displayed more advanced degenerative and remodeling processes in comparison with irradiated allograft and nonirradiated allograft. Discussion: The maximum load and stiffness of a healing tendon allograft in ACL reconstruction appear to be unaltered by low-dose (1.2 Mrad) irradiation. At 8 weeks, there were no biomechanical differences in tendon-bone healing of allografts when compared with autograft controls. Histologic analyses suggested a faster remodeling response in autograft specimens in comparison with allografts at both time points. Clinical Relevance: The findings support the contention that low-dose gamma irradiation is safe for sterilization of ACL soft tissue allografts without compromise of graft properties at early time points.
Viral infection triggers rapid differentiation of human blood monocytes into dendritic cells
Authors: Hou Wanqiu , Gibbs James S. , Lu Xiuju , Brooke Christopher B. , Roy Devika , Modlin Robert L. , Bennink Jack R. , Yewdell Jonathan W. 
Published: February 2012

AbstractSurprisingly little is known about the interaction of human blood mononuclear cells with viruses. Here, we show that monocytes are the predominant cell type infected when peripheral blood mononuclear cells are exposed to viruses ex vivo. Remarkably, infection with vesicular stomatitis virus, vaccinia virus, and a variety of influenza A viruses (including circulating swine-origin virus) induces monocytes to differentiate within 18 hours into CD16−CD83+ mature dendritic cells with enhanced capacity to activate T cells. Differentiation into dendritic cells does not require cell division and occurs despite the synthesis of viral proteins, which demonstrates that monocytes counteract the capacity of these highly lytic viruses to hijack host cell biosynthetic capacity. Indeed, differentiation requires infectious virus and viral protein synthesis. These findings demonstrate that monocytes are uniquely susceptible to viral infection among blood mononuclear cells, with the likely purpose of generating cells with enhanced capacity to activate innate and acquired antiviral immunity.
IL-5 promotes induction of antigen-specific CD4+CD25+ T regulatory cells that suppress autoimmunity
Authors: Tran Giang T. , Hodgkinson Suzanne J. , Carter Nicole M. , Verma Nirupama D. , Plain Karren M. , Boyd Rochelle , Robinson Catherine M. , Nomura Masaru , Killingsworth Murray , Hall Bruce M. 
Published: February 2012

AbstractImmune responses to foreign and self-Ags can be controlled by regulatory T cells (Tregs) expressing CD4 and IL-2Rα chain (CD25). Defects in Tregs lead to autoimmunity, whereas induction of Ag-specific CD4+CD25+ Tregs restores tolerance. Ag-specific CD4+CD25+ FOXP3+Tregs activated by the T helper type 2 (Th2) cytokine, IL-4, and specific alloantigen promote allograft tolerance. These Tregs expressed the specific IL-5Rα and in the presence of IL-5 proliferate to specific but not third-party Ag. These findings suggest that recombinant IL-5 (rIL-5) therapy may promote Ag-specific Tregs to mediate tolerance. This study showed normal CD4+CD25+ Tregs cultured with IL-4 and an autoantigen expressed Il-5rα. Treatment of experimental autoimmune neuritis with rIL-5 markedly reduced clinical paralysis, weight loss, demyelination, and infiltration of CD4+ (Th1 and Th17) CD8+ T cells and macrophages in nerves. Clinical improvement was associated with expansion of CD4+CD25+FOXP3+ Tregs that expressed Il-5rα and proliferated only to specific autoantigen that was enhanced by rIL-5. Depletion of CD25+ Tregs or blocking of IL-4 abolished the benefits of rIL-5. Thus, rIL-5 promoted Ag-specific Tregs, activated by autoantigen and IL-4, to control autoimmunity. These findings may explain how Th2 responses, especially to parasitic infestation, induce immune tolerance. rIL-5 therapy may be able to induce Ag-specific tolerance in autoimmunity.
Determinants of insecticide-treated net ownership and utilization among pregnant women in Nigeria
Authors: Ankomah Augustine , Adebayo Samson B , Arogundade Ekundayo D , Anyanti Jennifer , Nwokolo Ernest , Ladipo Olaronke , Meremikwu Martin M 
Published: February 2012

Abstract

Background
Malaria during pregnancy is a major public health problem in Nigeria leading to increase in the risk of maternal mortality, low birth weight and infant mortality. This paper is aimed at highlighting key predictors of the ownership of insecticide treated nets (ITNs) and its use among pregnant women in Nigeria.

Methods
A total of 2348 pregnant women were selected by a multi-stage probability sampling technique. Structured interview schedule was used to elicit information on socio-demographic characteristics, ITN ownership, use, knowledge, behaviour and practices. Logistic regression was used to detect predictors of two indicators: ITN ownership, and ITN use in pregnancy among those who owned ITNs.

Results
ITN ownership was low; only 28.8% owned ITNs. Key predictors of ITN ownership included women who knew that ITNs prevent malaria (OR = 3.85; p < 0001); and registration at antenatal clinics (OR = 1.34; p = 0.003). The use of ITNs was equally low with only 7.5% of all pregnant women, and 25.7% of all pregnant women who owned ITNs sleeping under a net. The predictors of ITN use in pregnancy among women who owned ITNs (N = 677) identified by logistic regression were: urban residence (OR = 1.87; p = 0.001); knowledge that ITNs prevent malaria (OR = 2.93; p < 0001) and not holding misconceptions about malaria prevention (OR = 1.56; p = 0.036). Educational level was not significantly related to any of the two outcome variables. Although registration at ANC is significantly associated with ownership of a bednet (perhaps through free ITN distribution) this does not translate to significant use of ITNs.

Conclusions
ITN use lagged well behind ITN ownership. This seems to suggest that the current mass distribution of ITNs at antenatal facilities and community levels may not necessarily lead to use unless it is accompanied by behaviour change interventions that address the community level perceptions, misconceptions and positively position ITN as an effective prevention device to prevent malaria
Effects of sterol regulatory element-binding protein (SREBP) in chickens
Authors: Alipour Fahimeh , Hassanabadi Ahmad 
Published: February 2012

Abstract
Sterol regulatory element binding protein- 1 and -2 (SREBP-1 and -2) are key transcription factors involved in the biosynthesis of cholesterol and fatty acids. The SREBP have mostly been studied in rodents in which lipogenesis is regulated in both liver and adipose tissue. There is, though, a paucity of information on birds, in which lipogenesis occurs essentially in the liver as in humans. Since a prelude to the investigation of the role of SREBP in lipid metabolism regulation in chicken, we review Size and Tissue expression Pattern of SREBP and role of this protein in chickens.
Clara cell protein in nasal lavage fluid and nasal nitric oxide - biomarkers with anti-inflammatory properties in allergic rhinitis
Authors: Irander Kristina , Palm Jörgen P , Borres Magnus P , Ghafouri Bijar 
Published: February 2012

Abstract

Background
Clara cell protein (CC16) is ascribed a protective and anti-inflammatory role in airway inflammation. Lower levels have been observed in asthmatic subjects as well as in subjects with intermittent allergic rhinitis than in healthy controls. Nasal nitric oxide (nNO) is present in high concentrations in the upper airways, and considered a biomarker with beneficial effects, due to inhibition of bacteria and viruses along with stimulation of ciliary motility. The aim of this study was to evaluate the presumed anti-inflammatory effects of nasal CC16 and nNO in subjects with allergic rhinitis.

Methods
The levels of CC16 in nasal lavage fluids, achieved from subjects with persistent allergic rhinitis (n = 13), intermittent allergic rhinitis in an allergen free interval (n = 5) and healthy controls (n = 7), were analyzed by Western blot. The levels of nNO were measured by the subtraction method using NIOX®. The occurrences of effector cells in allergic inflammation, i.e. metachromatic cells (MC, mast cells and basophiles) and eosinophils (Eos) were analyzed by light microscopy in samples achieved by nasal brushing.

Results
The levels of CC16 correlated with nNO levels (r2 = 0.37; p = 0.02) in allergic subjects.
The levels of both biomarkers showed inverse relationships with MC occurrence, as higher levels of CC16 (p = 0.03) and nNO (p = 0.05) were found in allergic subjects with no demonstrable MC compared to the levels in subjects with demonstrable MC. Similar relationships, but not reaching significance, were observed between the CC16 and nNO levels and Eos occurrence. The levels of CC16 and nNO did not differ between the allergic and the control groups.

Conclusions
The correlation between nasal CC16 and nNO levels in patients with allergic rhinitis, along with an inverse relationship between their levels and the occurrences of MC in allergic inflammation, may indicate that both biomarkers have anti-inflammatory effects by suppression of cell recruitment. The mechanisms behind these observations warrant further analyses.
Polo-like kinase 1 (Plk1): an Unexpected Player in DNA Replication
Authors: Song Bing , Liu X Shawn , Liu Xiaoqi 
Published: February 2012

Abstract
Regulation of cell cycle progression is important for the maintenance of genome integrity, and Polo-like kinases (Plks) have been identified as key regulators of this process. It is well established that Polo-like kinase 1 (Plk1) plays critical roles in mitosis but little is known about its functions at other stages of the cell cycle. Here we summarize the functions of Plk1 during DNA replication, focusing on the molecular events related to Origin Recognition Complex (ORC), the complex that is essential for the initiation of DNA replication. Within the context of Plk1 phosphorylation of Orc2, we also emphasize regulation of Orc2 in different organisms. This review is intended to provide some insight into how Plk1 coordinates DNA replication in S phase with chromosome segregation in mitosis, and orchestrates the cell cycle as a whole.
Caenorhabditis elegans Muscleblind homolog mbl-1 functions in neurons to regulate synapse formation
Authors: Spilker Kerri A , Wang George J , Tugizova Madina S , Shen Kang 
Published: February 2012

Abstract

Background
The sequestration of Muscleblind splicing regulators results in myotonic dystrophy. Previous work on Muscleblind has largely focused on its roles in muscle development and maintenance due to the skeletal and cardiac muscle degeneration phenotype observed in individuals with the disorder. However, a number of reported nervous system defects suggest that Muscleblind proteins function in other tissues as well.

Results
We have identified a mutation in the Caenorhabditis elegans homolog of Muscleblind, mbl-1, that is required for proper formation of neuromuscular junction (NMJ) synapses. mbl-1 mutants exhibit selective loss of the most distal NMJ synapses in a C. elegans motorneuron, DA9, visualized using the vesicle-associated protein RAB-3, as well as the active zone proteins SYD-2/liprin-α and UNC-10/Rim. The proximal NMJs appear to have normal pre- and postsynaptic specializations. Surprisingly, expressing a mbl-1 transgene in the presynaptic neuron is sufficient to rescue the synaptic defect, while muscle expression has no effect. Consistent with this result, mbl-1 is also expressed in neurons.

Conclusions
Based on these results, we conclude that in addition to its functions in muscle, the Muscleblind splice regulators also function in neurons to regulate synapse formation.
targetTB: A target identification pipeline for Mycobacterium tuberculosis through an interactome, reactome and genome-scale structural analysis
Authors: Raman Karthik , Yeturu Kalidas , Chandra Nagasuma 
Published: February 2012

Abstract

Background
Tuberculosis still remains one of the largest killer infectious diseases, warranting the identification of newer targets and drugs. Identification and validation of appropriate targets for designing drugs are critical steps in drug discovery, which are at present major bottle-necks. A majority of drugs in current clinical use for many diseases have been designed without the knowledge of the targets, perhaps because standard methodologies to identify such targets in a high-throughput fashion do not really exist. With different kinds of 'omics' data that are now available, computational approaches can be powerful means of obtaining short-lists of possible targets for further experimental validation.

Results
We report a comprehensive in silico target identification pipeline, targetTB, for Mycobacterium tuberculosis. The pipeline incorporates a network analysis of the protein-protein interactome, a flux balance analysis of the reactome, experimentally derived phenotype essentiality data, sequence analyses and a structural assessment of targetability, using novel algorithms recently developed by us. Using flux balance analysis and network analysis, proteins critical for survival of M. tuberculosis are first identified, followed by comparative genomics with the host, finally incorporating a novel structural analysis of the binding sites to assess the feasibility of a protein as a target. Further analyses include correlation with expression data and non-similarity to gut flora proteins as well as 'anti-targets' in the host, leading to the identification of 451 high-confidence targets. Through phylogenetic profiling against 228 pathogen genomes, shortlisted targets have been further explored to identify broad-spectrum antibiotic targets, while also identifying those specific to tuberculosis. Targets that address mycobacterial persistence and drug resistance mechanisms are also analysed.

Conclusion
The pipeline developed provides rational schema for drug target identification that are likely to have high rates of success, which is expected to save enormous amounts of money, resources and time in the drug discovery process. A thorough comparison with previously suggested targets in the literature demonstrates the usefulness of the integrated approach used in our study, highlighting the importance of systems-level analyses in particular. The method has the potential to be used as a general strategy for target identification and validation and hence significantly impact most drug discovery programmes.
Hemoglobin Q-Iran detected in family members from Northern Iran: a case report
Authors: Khorshidi Mohammad , Roshan Payam , Bayat Nooshin , Mahdavi Mohammad Reza , Najmabadi Hossein 
Published: February 2012

Abstract

Introduction
Hemoglobin Q-Iran (α75Asp→His) is an important member of the hemoglobin Q family, molecularly characterized by the replacement of aspartic acid by histidine. The first report of hemoglobin Q-Iran and the nomenclature of this hemoglobinopathy dates back to 1970. Iran is known as a country with a high prevalence of α- and β-thalassemia and different types of hemoglobinopathy. Many of these variants are yet to be identified as the practice of molecular laboratory techniques is limited in this part of the world. Applying such molecular methods, we report the first hemoglobin Q-Iran cases in Northern Iran.

Case presentation
An unusual band was detected in an isoelectric focusing test and cellulose acetate electrophoresis of a sample from a 22-year-old Iranian man from Mazandaran Province. Capillary zone electrophoresis analysis identified this band as hemoglobin Q. A similar band was also detected in his mother's electrophoresis (38 years, Iranian ethnicity). The cases underwent molecular investigation and the presence of a hemoglobin Q-Iran mutation was confirmed by the amplification refractory mutation system polymerase chain reaction method. Direct conventional sequencing revealed a single guanine to cytosine missense mutation (c.226G > C; G AC > C AC) at codon 75 in the α-globin gene in both cases.

Conclusion
The wide spectrum and high frequency of nondeletional α-globin mutations in Mazandaran Province is remarkable and seem to differ considerably from what has been found in Mediterranean populations. This short communication reports the first cases of patients with hemoglobin Q found in that region.