bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Genome-Wide Screen Reveals Functional Gene Clusters in the Cancer Genome and Identifies EphA2 as a Mitogen in Glioblastoma
Authors: Liu Fenghua , Park Peter J. , Lai Weil , Maher Elizabeth , Chakravarti Arnab , Durso Laura , Jiang Xiuli , Yu Yi , Brosius Amanda , Thomas Meredith , Chin Lynda , Brennan Cameron , DePinho Ronald A. , Kohane Isaac , Carroll Rona S. , Black Peter M. , Johnson Mark D. 
Published: November 2006

AbstractA novel genome-wide screen that combines patient outcome analysis with array comparative genomic hybridization and mRNA expression profiling was developed to identify genes with copy number alterations, aberrant mRNA expression, and relevance to survival in glioblastoma. The method led to the discovery of physical gene clusters within the cancer genome with boundaries defined by physical proximity, correlated mRNA expression patterns, and survival relatedness. These boundaries delineate a novel genomic interval called the functional common region (FCR). Many FCRs contained genes of high biological relevance to cancer and were used to pinpoint functionally significant DNA alterations that were too small or infrequent to be reliably identified using standard algorithms. One such FCR contained the EphA2 receptor tyrosine kinase. Validation experiments showed that EphA2 mRNA overexpression correlated inversely with patient survival in a panel of 21 glioblastomas, and ligand-mediated EphA2 receptor activation increased glioblastoma proliferation and tumor growth via a mitogen-activated protein kinase–dependent pathway. This novel genome-wide approach greatly expanded the list of target genes in glioblastoma and represents a powerful new strategy to identify the upstream determinants of tumor phenotype in a range of human cancers. (Cancer Res 2006; 66(22): 10815-23)
Inhibition of Transforming Growth Factor-β1 Signaling Attenuates Ataxia Telangiectasia Mutated Activity in Response to Genotoxic Stress
Authors: Kirshner Julia , Jobling Michael F. , Pajares Maria Jose , Ravani Shraddha A. , Glick Adam B. , Lavin Martin J. , Koslov Sergei , Shiloh Yosef , Barcellos-Hoff Mary Helen 
Published: November 2006

Abstract
Ionizing radiation causes DNA damage that elicits a cellular program of damage control coordinated by the kinase activity of ataxia telangiectasia mutated protein (ATM). Transforming growth factor β (TGFβ)-1, which is activated by radiation, is a potent and pleiotropic mediator of physiologic and pathologic processes. Here we show that TGFβ inhibition impedes the canonical cellular DNA damage stress response. Irradiated Tgfβ1 null murine epithelial cells or human epithelial cells treated with a small-molecule inhibitor of TGFβ type I receptor kinase exhibit decreased phosphorylation of Chk2, Rad17, and p53; reduced γH2AX radiation-induced foci; and increased radiosensitivity compared with TGFβ competent cells. We determined that loss of TGFβ signaling in epithelial cells truncated ATM autophosphorylation and significantly reduced its kinase activity, without affecting protein abundance. Addition of TGFβ restored functional ATM and downstream DNA damage responses. These data reveal a heretofore undetected critical link between the microenvironment and ATM, which directs epithelial cell stress responses, cell fate, and tissue integrity. Thus, Tgfβ1, in addition to its role in homoeostatic growth control, plays a complex role in regulating responses to genotoxic stress, the failure of which would contribute to the development of cancer; conversely, inhibiting TGFβ may be used to advantage in cancer therapy. (Cancer Res 2006; 66(22): 10861-9)
CD34 cells from patients with trisomy 8 myelodysplastic syndrome (MDS) express early apoptotic markers but avoid programmed cell death by up-regulation of antiapoptotic proteins
Authors: Sloand Elaine M. , Pfannes Loretta , Chen Gubin , Shah Simant , Solomou Elena E. , Barrett John , Young Neal S. 
Published: November 2006

AbstractCD34 cells from patients with trisomy 8 myelodysplastic syndrome (MDS) are distinguished from other MDS cells and from normal hematopoietic cells by their pronounced expression of apoptotic markers. Paradoxically, trisomy 8 clones can persist in patients with bone marrow failure and expand following immunosuppression. We previously demonstrated up-regulation of c-myc and CD1 by microarray analysis. Here, we confirmed these findings by real-time polymerase chain reaction (PCR), demonstrated up-regulation of survivin, c-myc, and CD1 protein expression, and documented comparable colony formation by annexin+ trisomy 8− CD34+ and annexin− CD34 cells. There were low levels of DNA degradation in annexin+ trisomy 8 CD34 cells, which were comparable with annexin− CD34 cells. Trisomy 8 cells were resistant to apoptosis induced by gamma irradiation. Knock-down of survivin by siRNA resulted in preferential loss of trisomy 8 cells. These results suggest that trisomy 8 cells undergo incomplete apoptosis and are nonetheless capable of colony formation and growth.
The transcription factors Scl and Lmo2 act together during development of the hemangioblast in zebrafish
Authors: Patterson Lucy J. , Gering Martin , Eckfeldt Craig E. , Green Anthony R. , Verfaillie Catherine M. , Ekker Stephen C. , Patient Roger 
Published: November 2006

AbstractThe transcription factors Scl and Lmo2 are crucial for development of all blood. An important early requirement for Scl in endothelial development has also been revealed recently in zebrafish embryos, supporting previous findings in scl−/− embryoid bodies. Scl depletion culminates most notably in failure of dorsal aorta formation, potentially revealing a role in the formation of hemogenic endothelium. We now present evidence that the requirements for Lmo2 in zebrafish embryos are essentially the same as for Scl. The expression of important hematopoietic regulators is lost, reduced, or delayed, panendothelial gene expression is down-regulated, and aorta-specific marker expression is lost. The close similarity of the phenotypes for Scl and Lmo2 suggest that they perform these early functions in hemangioblast development within a multiprotein complex, as shown for erythropoiesis. Consistent with this, we find that scl morphants cannot be rescued by a non-Lmo2–binding form of Scl but can be rescued by non-DNA–binding forms, suggesting tethering to target genes through DNA-binding partners linked via Lmo2. Interestingly, unlike other hematopoietic regulators, the Scl/Lmo2 complex does not appear to autoregulate, as neither gene's expression is affected by depletion of the other. Thus, expression of these critical regulators is dependent on continued expression of upstream regulators, which may include cell-extrinsic signals.
K1 protein of human herpesvirus 8 suppresses lymphoma cell Fas-mediated apoptosis
Authors: Wang Suizhao , Wang Shu , Maeng Hoyoung , Young Daniel P. , Prakash Om , Fayad Luis E. , Younes Anas , Samaniego Felipe 
Published: November 2006

AbstractExpression of the K1 gene of human herpesvirus 8 activates nuclear factor-κB and induces lymph node hyperplasia and lymphomas in transgenic mice. To further delineate its role in cell survival, we determined whether K1 altered apoptosis of lymphoma cells. K1 protein is expressed in Kaposi sarcoma and primary effusion lymphoma. We retrovirally transfected BJAB lymphoma, THP-1, U937, and Kaposi sarcoma SLK cells to express K1 and a K1 mutant with the deleted immunoreceptor tyrosine-based activation motif (K1m). We challenged cells with an agonistic anti-Fas antibody, Fas ligand, irradiation, and tumor necrosis factor–related apoptosis-inducing ligand. K1 transfectants but not K1m transfectants exhibited reduced levels of apoptosis induced by the anti-Fas antibody but not apoptosis induced by the tumor necrosis factor–related apoptosis-inducing ligand or irradiation. K1 expression resulted in reduced apoptosis rates as shown in several assays. K1 induced a modest reduction in levels of Fas-associated death domain protein, and procaspase 8 recruited to the death-inducing signaling complex. Finally, K1 transfectants cleaved procaspase 8 at significantly lower rates than did K1m transfectants. K1-transfected mice, compared with vector-transfected mice, showed lower death rates after challenge with anti-Fas antibody. K1 may contribute to lymphoma development by stimulating cell survival by selectively blocking Fas-mediated apoptosis.
Safe and efficient transduction of the liver after peripheral vein infusion of self-complementary AAV vector results in stable therapeutic expression of human FIX in nonhuman primates
Authors: Nathwani Amit C. , Gray John T. , McIntosh Jenny , Ng Catherine Y. C. , Zhou Junfang , Spence Yunyu , Cochrane Melanie , Gray Elaine , Tuddenham Edward G. D. , Davidoff Andrew M. 
Published: November 2006

AbstractThe safety and efficacy of peripheral venous administration of a self-complementary adeno-associated viral vector encoding the human FIX gene (scAAV-LP1-hFIXco) was evaluated in nonhuman primates for gene therapy of hemophilia B. Peripheral vein infusion of 1 × 1012 vg/kg scAAV-LP1-hFIXco pseudotyped with serotype 8 capsid, in 3 macaques, resulted in stable therapeutic expression (more than 9 months) of human FIX (hFIX) at levels (1.1 ± 0.5 μg/mL, or 22% of normal) that were comparable to those achieved after direct delivery of the same vector dose into the portal circulation (1.3 ± 0.3 μg/mL, or 26% of normal). Importantly, the pattern of vector biodistribution after systemic and portal vein administration of scAAV-LP1-hFIXco was almost identical. Additionally, comparable levels of gene transfer were achieved in macaques with preexisting immunity to AAV8 following peripheral vein administration of 1 × 1012 vg/kg AAV5-pseudotyped scAAV-LP1-hFIXco. This confirms that alternative serotypes can circumvent preexisting naturally acquired immunity to AAV. Thus, peripheral venous administration of AAV5 and AAV8 vectors is safe and as effective at transducing the liver in nonhuman primates as direct vector administration into the portal circulation. These results should make vector administration to patients, especially those with a severe bleeding diathesis, significantly easier and safer.
In vitro and in vivo arterial differentiation of human multipotent adult progenitor cells
Authors: Aranguren Xabier L. , Luttun Aernout , Clavel Carlos , Moreno Cristina , Abizanda Gloria , Barajas Miguel A. , Pelacho Beatriz , Uriz Maialen , Araña Miriam , Echavarri Ana , Soriano Mario , Andreu Enrique J. , Merino Juana , Garcia-Verdugo Jose Manuel , Verfaillie Catherine M. , Prósper Felipe 
Published: November 2006

AbstractMany stem cell types have been shown to differentiate into endothelial cells (ECs); however, their specification to arterial or venous endothelium remains unexplored. We tested whether a specific arterial or venous EC fate could be induced in human multipotent adult progenitor cells (hMAPCs) and AC133+ cells (hAC133+). In vitro, in the presence of VEGF165, hAC133+ cells only adopted a venous and microvascular EC phenotype, while hMAPCs differentiated into both arterial and venous ECs, possibly because hMAPCs expressed significantly more sonic hedgehog (Shh) and its receptors as well as Notch 1 and 3 receptors and some of their ligands. Accordingly, blocking either of those pathways attenuated in vitro arterial EC differentiation from hMAPCs. Complementarily, stimulating these pathways by addition of Delta-like 4 (Dll-4), a Notch ligand, and Shh to VEGF165 further boosted arterial differentiation in hMAPCs both in vitro and in an in vivo Matrigel model. These results represent the first demonstration of adult stem cells with the potential to be differentiated into different types of ECs in vitro and in vivo and provide a useful human model to study arteriovenous specification.
Variations in glycosylation of von Willebrand factor with O-linked sialylated T antigen are associated with its plasma levels
Authors: van Schooten Carina J. M. , Denis Cécile V. , Lisman Ton , Eikenboom Jeroen C. J. , Leebeek Frank W. , Goudemand Jenny , Fressinaud Edith , van den Berg H. Marijke , de Groot Philip G. , Lenting Peter J. 
Published: November 2006

AbstractThe glycosylation profile of von Willebrand factor (VWF) is known to strongly influence its plasma levels. VWF contains several carbohydrate structures, including O-linked glycans that primarily consist of sialylated T antigen (NeuAc(α2-3)Gal-(β1-3)-[NeuAc(α2-6)]GalNAc). It is not yet known whether O-linked carbohydrates affect VWF levels. We developed an immunosorbent assay based on neuraminidase incubation allowing subsequent binding of peanut agglutinin (PNA) to desialylated O-linked T antigen on VWF. An inverse relation was found between PNA binding and VWF antigen levels in healthy individuals (n = 111; Pearson rank = −0.43; P < .001). A similar inverse association was observed in randomly selected plasma samples from our diagnostic laboratory: 252% ± 125% for VWF levels less than 0.5 U/mL (n = 15); 131% ± 36% for VWF levels between 0.5 and 1.5 U/mL (n = 32); and 92% ± 40% for VWF levels more than 1.5 U/mL (n = 19). Reduced or increased PNA binding was also observed in patients with increased (liver cirrhosis) or reduced (von Willebrand disease [VWD] type 1) VWF antigen levels, respectively. VWD type 1 patients further displayed increased ratios of propeptide over mature VWF antigen levels (0.38 ± 0.18 versus 0.17 ± 0.03 for patients and controls, respectively; P < .001), which is indicative of reduced VWF survival in these patients. Of interest, a linear relation between PNA binding and propeptide/VWF ratio was observed (Spearman rank = 0.47), suggesting a potential association between O-linked glycosylation and VWF survival. Finally, we detected a marked decrease in PNA binding in post-DDAVP (1-deamino-8-D-arginine vasopressin) samples from various patients, indicating that the O-linked glycosylation profile of VWF stored in endothelial storage organelles may differ from circulating VWF.
Adaptive secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) mediates imatinib and nilotinib resistance in BCR/ABL+ progenitors via JAK-2/STAT-5 pathway activation
Authors: Wang Ying , Cai Dali , Brendel Cornelia , Barett Christine , Erben Philipp , Manley Paul W. , Hochhaus Andreas , Neubauer Andreas , Burchert Andreas 
Published: November 2006

Abstract
Overcoming imatinib mesylate (IM) resistance and disease persistence in patients with chronic myeloid leukemia (CML) is of considerable importance to the issue of potential cure. Here we asked whether autocrine signaling contributes to survival of BCR/ABL+ cells in the presence of IM and nilotinib (NI; AMN107), a novel, more selective Abl inhibitor. Conditioned media (CM) of IM-resistant LAMA84 cell clones (R-CM) was found to substantially protect IM-naive LAMA cells and primary CML progenitors from IM- or NI-induced cell death. This was due to an increased secretion of the granulocyte-macrophage colony-stimulating factor (GM-CSF), which was identified as the causative factor mediating IM resistance in R-CM. GM-CSF elicited IM and NI drug resistance via a BCR/ABL-independent activation of the janus kinases 2 (JAK-2)/signal transducer and activator of transcription 5 (STAT-5) signaling pathway in GM-CSF receptor α receptor (CD116)–expressing cells, including primary CD34+/CD116+ GM progenitors (GMPs). Elevated mRNA and protein levels of GM-CSF were detected in IM-resistant patient samples, suggesting a contribution of GM-CSF secretion for IM and NI resistance in vivo. Importantly, inhibition of JAK-2 with AG490 abrogated GM-CSF–mediated STAT-5 phosphorylation and NI resistance in vitro. Together, adaptive autocrine secretion of GM-CSF mediates BCR/ABL-independent IM and NI resistance via activation of the antiapoptotic JAK-2/STAT-5 pathway. Inhibition of JAK-2 overcomes GM-CSF–induced IM and NI progenitor cell resistance, providing a rationale for the application of JAK-2 inhibitors to eradicate residual disease in CML.
Huntingtin gene evolution in Chordata and its peculiar features in the ascidian Ciona genus
Authors: Gissi Carmela , Pesole Graziano , Cattaneo Elena , Tartari Marzia 
Published: November 2006

Abstract

Background
To gain insight into the evolutionary features of the huntingtin (htt) gene in Chordata, we have sequenced and characterized the full-length htt mRNA in the ascidian Ciona intestinalis, a basal chordate emerging as new invertebrate model organism. Moreover, taking advantage of the availability of genomic and EST sequences, the htt gene structure of a number of chordate species, including the cogeneric ascidian Ciona savignyi, and the vertebrates Xenopus and Gallus was reconstructed.

Results
The C. intestinalis htt transcript exhibits some peculiar features, such as spliced leader trans-splicing in the 98 nt-long 5' untranslated region (UTR), an alternative splicing in the coding region, eight alternative polyadenylation sites, and no similarities of both 5' and 3'UTRs compared to homologs of the cogeneric C. savignyi. The predicted protein is 2946 amino acids long, shorter than its vertebrate homologs, and lacks the polyQ and the polyP stretches found in the the N-terminal regions of mammalian homologs. The exon-intron organization of the htt gene is almost identical among vertebrates, and significantly conserved between Ciona and vertebrates, allowing us to hypothesize an ancestral chordate gene consisting of at least 40 coding exons.

Conclusion
During chordate diversification, events of gain/loss, sliding, phase changes, and expansion of introns occurred in both vertebrate and ascidian lineages predominantly in the 5'-half of the htt gene, where there is also evidence of lineage-specific evolutionary dynamics in vertebrates. On the contrary, the 3'-half of the gene is highly conserved in all chordates at the level of both gene structure and protein sequence. Between the two Ciona species, a fast evolutionary rate and/or an early divergence time is suggested by the absence of significant similarity between UTRs, protein divergence comparable to that observed between mammals and fishes, and different distribution of repetitive elements.
Evaluation of guided imagery as treatment for recurrent abdominal pain in children: a randomized controlled trial
Authors: Weydert Joy A , Shapiro Daniel E , Acra Sari A , Monheim Cynthia J , Chambers Andrea S , Ball Thomas M 
Published: November 2006

AbstractBackgroundBecause of the paucity of effective evidence-based therapies for children with recurrent abdominal pain, we evaluated the therapeutic effect of guided imagery, a well-studied self-regulation technique.Methods22 children, aged 5 – 18 years, were randomized to learn either breathing exercises alone or guided imagery with progressive muscle relaxation. Both groups had 4-weekly sessions with a therapist. Children reported the numbers of days with pain, the pain intensity, and missed activities due to abdominal pain using a daily pain diary collected at baseline and during the intervention. Monthly phone calls to the children reported the number of days with pain and the number of days of missed activities experienced during the month of and month following the intervention. Children with ≤ 4 days of pain/month and no missed activities due to pain were defined as being healed. Depression, anxiety, and somatization were measured in both children and parents at baseline.ResultsAt baseline the children who received guided imagery had more days of pain during the preceding month (23 vs. 14 days, P = 0.04). There were no differences in the intensity of painful episodes or any baseline psychological factors between the two groups. Children who learned guided imagery with progressive muscle relaxation had significantly greater decrease in the number of days with pain than those learning breathing exercises alone after one (67% vs. 21%, P = 0.05), and two (82% vs. 45%, P < 0.01) months and significantly greater decrease in days with missed activities at one (85% vs. 15%, P = 0.02) and two (95% vs. 77%. P = 0.05) months. During the two months of follow-up, more children who had learned guided imagery met the threshold of ≤ 4 day of pain each month and no missed activities (RR = 7.3, 95%CI [1.1,48.6]) than children who learned only the breathing exercises.ConclusionThe therapeutic efficacy of guided imagery with progressive muscle relaxation found in this study is consistent with our present understanding of the pathophysiology of recurrent abdominal pain in children. Although unfamiliar to many pediatricians, guided imagery is a simple, noninvasive therapy with potential benefit for treating children with RAP.
PCR detection of Plasmodium falciparum in human urine and saliva samples
Authors: Mharakurwa Sungano , Simoloka Christopher , Thuma Philip E , Shiff Clive J , Sullivan David J 
Published: November 2006

Abstract

Background
Current detection or screening for malaria infection necessitates drawing blood by fingerprick or venipuncture, which poses risks and limitations for repeated measurement. This study presents PCR detection of Plasmodium falciparum in human urine and saliva samples, and illustrates this potential application in genotyping malaria infections.

Methods
Urine and saliva were obtained from 47 thick film positive and 4 negative individuals one day after collection of blood slides and filter paper blood spots. P. falciparum DNA was extracted from blood, urine and saliva, in separate groups, using the Chelex method or Qiagen DNEasy® kit (urine and saliva only). Blood, urine and saliva extracts were subjected to PCR in separate batches. Amplicons from the various sample types were examined for MSP2 polymorphisms and restriction fragment patterns on DHFR amino acid codon 59.

Results and discussion
Malaria infections exhibited primarily low-grade parasite densities, with a geometric mean of 775 asexual parasites/μl. Regularly matching polymorphic MSP2 genotypes were found between the corresponding urine, saliva and peripheral blood amplicons of each individual, with different inter-individual polymorphic genotypes. Amplicon yields were significantly dependent on DNA extraction method, parasite density and primer set (p < 0.001). A Qiagen® kit extraction had more than 2× higher amplicon yield than the Chelex method, for both urine and saliva. Amplicon yields were 1.6 fold higher from saliva than urine. For each unit increase in log parasite density, the probability of amplicon enhanced 1.8 fold. Highest amplicon yields were obtained from the primer set with the shortest PCR product.

Conclusion

P. falciparum infection is detectable by PCR on human urine and saliva samples. Subject to further refinement of extraction technique and amplicon yields, large-scale malaria parasite screening and epidemiological surveys could be possible without the need to collect blood and use of needles or sharps.