bluuebunny/crossref_metadata_2025_split huggingface dataset:
Canonical Wnt signaling in megakaryocytes regulates proplatelet formation
Authors: Macaulay Iain C. , Thon Jonathan N. , Tijssen Marloes R. , Steele Brian M. , MacDonald Bryan T. , Meade Gerardene , Burns Philippa , Rendon Augusto , Salunkhe Vishal , Murphy Ronan P. , Bennett Cavan , Watkins Nicholas A. , He Xi , Fitzgerald Desmond J. , Italiano Joseph E. , Maguire Patricia B. 
Published: November 2012

AbstractWnt signaling is involved in numerous aspects of vertebrate development and homeostasis, including the formation and function of blood cells. Here, we show that canonical and noncanonical Wnt signaling pathways are present and functional in megakaryocytes (MKs), with several Wnt effectors displaying MK-restricted expression. Using the CHRF288-11 cell line as a model for human MKs, the canonical Wnt3a signal was found to induce a time and dose-dependent increase in β-catenin expression. β-catenin accumulation was inhibited by the canonical antagonist dickkopf-1 (DKK1) and by the noncanonical agonist Wnt5a. Whole genome expression analysis demonstrated that Wnt3a and Wnt5a regulated distinct patterns of gene expression in MKs, and revealed a further interplay between canonical and noncanonical Wnt pathways. Fetal liver cells derived from low-density-lipoprotein receptor-related protein 6-deficient mice (LRP6−/−), generated dramatically reduced numbers of MKs in culture of lower ploidy (2N and 4N) than wild-type controls, implicating LRP6-dependent Wnt signaling in MK proliferation and maturation. Finally, in wild-type mature murine fetal liver-derived MKs, Wnt3a potently induced proplatelet formation, an effect that could be completely abrogated by DKK1. These data identify novel extrinsic regulators of proplatelet formation, and reveal a profound role for Wnt signaling in platelet production.
WT1-specific T-cell responses in high-risk multiple myeloma patients undergoing allogeneic T cell–depleted hematopoietic stem cell transplantation and donor lymphocyte infusions
Authors: Tyler Eleanor M. , Jungbluth Achim A. , O'Reilly Richard J. , Koehne Guenther 
Published: November 2012

Abstract
While the emergence of WT1-specific cytotoxic T lymphocytes (WT1-CTL) has been correlated with better relapse-free survival after allogeneic stem cell transplantation in patients with myeloid leukemias, little is known about the role of these cells in multiple myeloma (MM). We examined the significance of WT1-CTL responses in patients with relapsed MM and high-risk cytogenetics who were undergoing allogeneic T cell–depleted hematopoietic stem cell transplantation (alloTCD-HSCT) followed by donor lymphocyte infusions. Of 24 patients evaluated, all exhibited WT1-CTL responses before allogeneic transplantation. These T-cell frequencies were universally correlated with pretransplantation disease load. Ten patients received low-dose donor lymphocyte infusions beginning 5 months after transplantation. All patients subsequently developed increments of WT1-CTL frequencies that were associated with reduction in specific myeloma markers, in the absence of graft-versus-host disease. Immunohistochemical analyses of WT1 and CD138 in bone marrow specimens demonstrated consistent coexpression within malignant plasma cells. WT1 expression in the bone marrow correlated with disease outcome. Our results suggest an association between the emergence of WT1-CTL and graft-versus-myeloma effect in patients treated for relapsed MM after alloTCD-HSCT and donor lymphocyte infusions, supporting the development of adoptive immunotherapeutic approaches using WT1-CTL in the treatment of MM (registered at http://clinicaltrials.gov, ID: NCT01131169).
inv(16)/t(16;16) acute myeloid leukemia with non–type A CBFB-MYH11 fusions associate with distinct clinical and genetic features and lack KIT mutations
Authors: Schwind Sebastian , Edwards Colin G. , Nicolet Deedra , Mrózek Krzysztof , Maharry Kati , Wu Yue-Zhong , Paschka Peter , Eisfeld Ann-Kathrin , Hoellerbauer Pia , Becker Heiko , Metzeler Klaus H. , Curfman John , Kohlschmidt Jessica , Prior Thomas W. , Kolitz Jonathan E. , Blum William , Pettenati Mark J. , Dal Cin Paola , Carroll Andrew J. , Caligiuri Michael A. , Larson Richard A. , Volinia Stefano , Marcucci Guido , Bloomfield Clara D. 
Published: November 2012

Abstract
The inv(16)(p13q22)/t(16;16)(p13;q22) in acute myeloid leukemia results in multiple CBFB-MYH11 fusion transcripts, with type A being most frequent. The biologic and prognostic implications of different fusions are unclear. We analyzed CBFB-MYH11 fusion types in 208 inv(16)/t(16;16) patients with de novo disease, and compared clinical and cytogenetic features and the KIT mutation status between type A (n = 182; 87%) and non–type A (n = 26; 13%) patients. At diagnosis, non–type A patients had lower white blood counts (P = .007), and more often trisomies of chromosomes 8 (P = .01) and 21 (P < .001) and less often trisomy 22 (P = .02). No patient with non–type A fusion carried a KIT mutation, whereas 27% of type A patients did (P = .002). Among the latter, KIT mutations conferred adverse prognosis; clinical outcomes of non–type A and type A patients with wild-type KIT were similar. We also derived a fusion-type–associated global gene-expression profile. Gene Ontology analysis of the differentially expressed genes revealed—among others—an enrichment of up-regulated genes involved in activation of caspase activity, cell differentiation and cell cycle control in non–type A patients. We conclude that non–type A fusions associate with distinctclinical and genetic features, including lack of KIT mutations, and a unique gene-expression profile.
Biologic and clinical significance of somatic mutations of SF3B1 in myeloid and lymphoid neoplasms
Authors: Cazzola Mario , Rossi Marianna , Malcovati Luca 
Published: November 2012

AbstractPrecursor mRNA splicing is catalyzed by the spliceosome, a macromolecule composed of small nuclear RNAs associated with proteins. The SF3B1 gene encodes subunit 1 of the splicing factor 3b, which is important for anchoring the spliceosome to precursor mRNA. In 2011, whole-exome sequencing studies showed recurrent somatic mutations of SF3B1 and other genes of the RNA splicing machinery in patients with myelodysplastic syndrome or myelodysplastic/myeloproliferative neoplasm. SF3B1 mutations had a particularly high frequency among conditions characterized by ring sideroblasts, which is consistent with a causal relationship. SF3B1 mutants were also detected at a lower frequency in a variety of other tumor types. In chronic lymphocytic leukemia, SF3B1 was found to be the second most frequently mutated gene. In myelodysplastic syndromes, SF3B1 mutations appear to be founding genetic lesions and are associated with a low risk of leukemic evolution. In contrast, SF3B1 mutations have a lower incidence in early stages of chronic lymphocytic leukemia, are more common in advanced disease, and tend to be associated with poor prognosis, suggesting that they occur during clonal evolution of the disease. The assessment of SF3B1 mutation status may become innovative diagnostic and prognostic tools and the availability of spliceosome modulators opens novel therapeutic prospects.
Gene expression analysis of a murine model with pulmonary vascular remodeling compared to end-stage IPAH lungs
Authors: Shimodaira Kayoko , Okubo Yoichiro , Ochiai Eri , Nakayama Haruo , Katano Harutaka , Wakayama Megumi , Shinozaki Minoru , Ishiwatari Takao , Sasai Daisuke , Tochigi Naobumi , Nemoto Tetsuo , Saji Tsutomu , Kamei Katsuhiko , Shibuya Kazutoshi 
Published: November 2012

Abstract

Background
Idiopathic pulmonary arterial hypertension (IPAH) continues to be one of the most serious intractable diseases that might start with activation of several triggers representing the genetic susceptibility of a patient. To elucidate what essentially contributes to the onset and progression of IPAH, we investigated factors playing an important role in IPAH by searching discrepant or controversial expression patterns between our murine model and those previously published for human IPAH. We employed the mouse model, which induced muscularization of pulmonary artery leading to hypertension by repeated intratracheal injection of Stachybotrys chartarum, a member of nonpathogenic and ubiquitous fungus in our envelopment.

Methods
Microarray assays with ontology and pathway analyses were performed with the lungs of mice. A comparison was made of the expression patterns of biological pathways between our model and those published for IPAH.

Results
Some pathways in our model showed the same expression patterns in IPAH, which included bone morphogenetic protein (BMP) signaling with down-regulation of BMP receptor type 2, activin-like kinase type 1, and endoglin. On the other hand, both Wnt/planar cell polarity (PCP) signaling and its downstream Rho/ROCK signaling were found alone to be activated in IPAH and not in our model.

Conclusions
Activation of Wnt/PCP signaling, in upstream positions of the pathway, found alone in lungs from end stage IPAH may play essential roles in the pathogenesis of the disease.
Copy Number Variation detection from 1000 Genomes project exon capture sequencing data
Authors: Wu Jiantao , Grzeda Krzysztof R , Stewart Chip , Grubert Fabian , Urban Alexander E , Snyder Michael P , Marth Gabor T 
Published: November 2012

Abstract

Background
DNA capture technologies combined with high-throughput sequencing now enable cost-effective, deep-coverage, targeted sequencing of complete exomes. This is well suited for SNP discovery and genotyping. However there has been little attention devoted to Copy Number Variation (CNV) detection from exome capture datasets despite the potentially high impact of CNVs in exonic regions on protein function.

Results
As members of the 1000 Genomes Project analysis effort, we investigated 697 samples in which 931 genes were targeted and sampled with 454 or Illumina paired-end sequencing. We developed a rigorous Bayesian method to detect CNVs in the genes, based on read depth within target regions. Despite substantial variability in read coverage across samples and targeted exons, we were able to identify 107 heterozygous deletions in the dataset. The experimentally determined false discovery rate (FDR) of the cleanest dataset from the Wellcome Trust Sanger Institute is 12.5%. We were able to substantially improve the FDR in a subset of gene deletion candidates that were adjacent to another gene deletion call (17 calls). The estimated sensitivity of our call-set was 45%.

Conclusions
This study demonstrates that exonic sequencing datasets, collected both in population based and medical sequencing projects, will be a useful substrate for detecting genic CNV events, particularly deletions. Based on the number of events we found and the sensitivity of the methods in the present dataset, we estimate on average 16 genic heterozygous deletions per individual genome. Our power analysis informs ongoing and future projects about sequencing depth and uniformity of read coverage required for efficient detection.
Genetic analysis of DNA methylation and gene expression levels in whole blood of healthy human subjects
Authors: van Eijk Kristel R , de Jong Simone , Boks Marco PM , Langeveld Terry , Colas Fabrice , Veldink Jan H , de Kovel Carolien GF , Janson Esther , Strengman Eric , Langfelder Peter , Kahn René S , van den Berg Leonard H , Horvath Steve , Ophoff Roel A 
Published: November 2012

Abstract

Background
The predominant model for regulation of gene expression through DNA methylation is an inverse association in which increased methylation results in decreased gene expression levels. However, recent studies suggest that the relationship between genetic variation, DNA methylation and expression is more complex.

Results
Systems genetic approaches for examining relationships between gene expression and methylation array data were used to find both negative and positive associations between these levels. A weighted correlation network analysis revealed that i) both transcriptome and methylome are organized in modules, ii) co-expression modules are generally not preserved in the methylation data and vice-versa, and iii) highly significant correlations exist between co-expression and co-methylation modules, suggesting the existence of factors that affect expression and methylation of different modules (i.e., trans effects at the level of modules). We observed that methylation probes associated with expression in cis were more likely to be located outside CpG islands, whereas specificity for CpG island shores was present when methylation, associated with expression, was under local genetic control. A structural equation model based analysis found strong support in particular for a traditional causal model in which gene expression is regulated by genetic variation via DNA methylation instead of gene expression affecting DNA methylation levels.

Conclusions
Our results provide new insights into the complex mechanisms between genetic markers, epigenetic mechanisms and gene expression. We find strong support for the classical model of genetic variants regulating methylation, which in turn regulates gene expression. Moreover we show that, although the methylation and expression modules differ, they are highly correlated.
Genomic insights into strategies used by Xanthomonas albilineans with its reduced artillery to spread within sugarcane xylem vessels
Authors: Pieretti Isabelle , Royer Monique , Barbe Valérie , Carrere Sébastien , Koebnik Ralf , Couloux Arnaud , Darrasse Armelle , Gouzy Jérôme , Jacques Marie-Agnès , Lauber Emmanuelle , Manceau Charles , Mangenot Sophie , Poussier Stéphane , Segurens Béatrice , Szurek Boris , Verdier Valérie , Arlat Matthieu , Gabriel Dean W , Rott Philippe , Cociancich Stéphane 
Published: November 2012

AbstractBackgroundXanthomonas albilineanscauses leaf scald, a lethal disease of sugarcane.X. albilineansexhibits distinctive pathogenic mechanisms, ecology and taxonomy compared to other species ofXanthomonas. For example, this species produces a potent DNA gyrase inhibitor called albicidin that is largely responsible for inducing disease symptoms; its habitat is limited to xylem; and the species exhibits large variability. A first manuscript on the complete genome sequence of the highly pathogenicX. albilineansstrain GPE PC73 focused exclusively on distinctive genomic features shared withXylella fastidiosa—another xylem-limitedXanthomonadaceae. The present manuscript on the same genome sequence aims to describe all other pathogenicity-related genomic features ofX. albilineans, and to compare, using suppression subtractive hybridization (SSH), genomic features of two strains differing in pathogenicity.ResultsComparative genomic analyses showed that most of the known pathogenicity factors from otherXanthomonasspecies are conserved inX. albilineans, with the notable absence of two major determinants of the “artillery” of other plant pathogenic species ofXanthomonas: the xanthan gum biosynthesis gene cluster, and the type III secretion system Hrp (hypersensitive response and pathogenicity). Genomic features specific toX. albilineansthat may contribute to specific adaptation of this pathogen to sugarcane xylem vessels were also revealed. SSH experiments led to the identification of 20 genes common to three highly pathogenic strains but missing in a less pathogenic strain. These 20 genes, which include four ABC transporter genes, a methyl-accepting chemotaxis protein gene and an oxidoreductase gene, could play a key role in pathogenicity. With the exception of hypothetical proteins revealed by our comparative genomic analyses and SSH experiments, no genes potentially involved in any offensive or counter-defensive mechanism specific toX. albilineanswere identified, supposing thatX. albilineanshas a reduced artillery compared to other pathogenicXanthomonasspecies. Particular attention has therefore been given to genomic features specific toX. albilineansmaking it more capable of evading sugarcane surveillance systems or resisting sugarcane defense systems.ConclusionsThis study confirms thatX. albilineansis a highly distinctive species within the genusXanthomonas, and opens new perpectives towards a greater understanding of the pathogenicity of this destructive sugarcane pathogen.
Prospective memory tasks: a more sensitive method for screening cognitive impairment in ALS?
Authors: Ji Ying , Wei Ling , Chui Dehua , Wang Kai , Fan Dongsheng 
Published: November 2012

Abstract

Background
Cognitive change is prevalent in patients with amyotrophic lateral sclerosis (ALS), but still lack a widely accepted and sensitive screening method. In this study, we try to find a sensitive screening battery for detecting subtle cognitive deficits in patients with ALS.

Methods
Eighty consecutive ALS patients and 57 matched normal controls underwent the Mini-Mental Status Examination (MMSE), the verbal fluency test (VFT), the Stroop Color Word Interference Test (CWT), and the prospective memory (PM) tests, including event-based (EBPM) and time-based (TBPM).

Results
The patients did not differ from the controls in the MMSE, the VFT and the CWT. By contrast, statistically significant differences were found in the PM tests (EBPM: P=0.043; TBPM: P<0.001). More interestingly, TBPM was more sensitive than EBPM in the early-phase patients.

Conclusions
Prefrontal lobar dysfunction does exist among ALS patients and may spread from the medial to the lateral region. The PM tests seem more sensitive in ALS patients with frontotemporal dysfunction than are the classical cognitive measures.
The utilization of antenatal care among rural-to-urban migrant women in Shanghai:a hospital-based cross-sectional study
Authors: Zhao Qi , Huang Zhihuan Jennifer , Yang Sijia , Pan Jie , Smith Brian , Xu Biao 
Published: November 2012

Abstract

Background
Improving utilization of antenatal care is a critical strategy for achieving China’s Millennium Development Goal of decreasing the maternal mortality ratio (MMR). While overall utilization has increased recently in China, an urban vs. rural disparity in access remains. Here we aim to assess utilization of antenatal care in rural-to-urban migrant women and identify its risk and protective factors.

Methods
Migrant women who had been living in Shanghai for more than six months, delivered in one of the two study hospitals between August 2009 and February 2010, and provided written consent were interviewed using a structured questionnaire.

Results
Of 767 women, 90.1% (691) made at least one antenatal care visit, while 49.7% (381) had adequately utilized antenatal care (i.e., made five or more antenatal care visits). Only 19.7% of women visited an antenatal care center during the first trimester (12 weeks). Women between the ages of 25 and 30 and women older than 30 were more likely than younger women to have adequately utilized antenatal care (AOR=2.2 and 1.9, 95%CI=1.4-3.5 and 1.1-3.2, respectively). Women whose husbands held Shanghai residency status (AOR=4.9, 95%CI=2.2-10.9) or who had more than 10 years of education (AOR=1.8, 95%CI=1.2-2.9), previously experienced a miscarriage or abortion (AOR=2.2, 95%CI=1.3-3.8), had higher household income (AOR=1.6, 95%CI=1.0-2.5) were more likely to have adequately utilized antenatal care. Women from high-income households were also more likely to receive antenatal care during the first 12 weeks (AOR=3.5, 95%CI=1.7-5.5).

Conclusions
Many migrant women in Shanghai did not receive adequate antenatal care and initiated antenatal care later than the optimal first 12 weeks of pregnancy. Poor antenatal care utilization was associated with low socioeconomic status, education, and certain demographic factors. Tailored health education for both migrant women and their husbands should be strengthened to improve maternal health. Financing supports should be provided to improve the utilization of antenatal care.
Ovarian cancer ascites increase Mcl-1 expression in tumor cells through ERK1/2-Elk-1 signaling to attenuate TRAIL-induced apoptosis
Authors: Goncharenko-Khaider Nadzeya , Matte Isabelle , Lane Denis , Rancourt Claudine , Piché Alain 
Published: November 2012

AbstractBackgroundAscites may affect the progression of ovarian cancer (OC). In particular, soluble factors present in OC ascites can create a protective environment for tumor cells that promotede novoresistance to drug- and death receptor-induced apoptosis. However, the underlying molecular mechanisms responsible for ascites-induced drug resistance are not well characterized.MethodsUsing human OC cell lines and tissues microarrays of human OC biopsies, we assessed the mechanism by which OC ascites increase Mcl-1 expression using Western blots, chemical inhibitors of ERK and small-inhibitory RNA treatments.ResultsIn the present study, we found that both Mcl-1 mRNA and protein levels were upregulated within 2 h upon treatment of OC cells with ascites obtained from women with advanced OC. In contrast, the expression of other Bcl-2 family antiapoptotic members such as Bcl-2 and Bcl-XLwas not affected by ascites. An increase of Mcl-1 expression was consistently observed across different ascites from women with advanced serous OC. The knockdown of Mcl-1 significantly blocked ascites-induced Mcl-1 upregulation and ascites-mediated inhibition of TRAIL-induced apoptosis. Ascites induced a rapid phosphorylation of ERK1/2 and Elk-1 transcription factor. Furthermore, we found that ERK1/2 inhibition or Elk-1 knockdown was sufficient to block ascites-induced Mcl-1 expression. In high grade serous OC, we found a positive correlation between phosphorylated ERK1/2 and Mcl-1 expression.ConclusionsThese results indicate that ascites-induced ERK1/2/Elk-1 signaling is critical for Mcl-1 expression and for the ascites-mediated attenuation of TRAIL-induced apoptosis. The ERK1/2/Elk-1/Mcl-1 pathway represents a novel mechanism by which ascites inducede novoTRAIL resistance in OC cells.
An investigation of excess residual cytoplasm in human spermatozoa and its distinction from the cytoplasmic droplet
Authors: Rengan Anil K , Agarwal Ashok , van der Linde Michelle , du Plessis Stefan S 
Published: November 2012

AbstractRecent studies have shown cytoplasmic droplets to be normal morphological occurrences in human male spermatozoa. When the cytoplasm around the sperm midpiece is present in large amounts, however, pathological effects may transpire. The cytoplasmic droplet then becomes known as excess residual cytoplasm, which can impair overall sperm function and produce higher levels of reactive oxygen species, potentially leading to male infertility. Though the distinction between cytoplasmic droplets and excess residual cytoplasm has been made, some studies fail to recognize the difference and incorrectly label the latter as a cytoplasmic droplet. This review attempts to clarify excess residual cytoplasm’s effect on fertility, examine the enzymes responsible, and suggest tests and possible treatment options for those affected by this defect.
An emerging role for microRNAs in NF1 tumorigenesis
Authors: Sedani Ashni , Cooper David N , Upadhyaya Meena 
Published: November 2012

Abstract
MicroRNAs (miRNAs) are a class of non-coding RNA, which have recently been shown to have a wide variety of regulatory functions in relation to gene expression. Since their identification nearly 20 years ago, miRNAs have been found to play an important role in cancer, including in neurofibromatosis type 1 (NF1)-associated tumours. NF1 is the most commonly inherited tumour predisposition syndrome and can lead to malignancy via the development of malignant peripheral nerve sheath tumours (MPNSTs). Although the mechanisms by which benign neurofibromas develop into MPNSTs still remain to be elucidated, it is becoming increasingly clear that miRNAs play a key role in this process and have the potential to be used as both diagnostic and prognostic markers of tumorigenesis.