bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nfe2l3 (Nrf3) deficiency predisposes mice to T-cell lymphoblastic lymphoma
Authors: Chevillard Grégory , Paquet Marilene , Blank Volker 
Published: December 2010

Abstract
We have previously generated mice deficient for Nfe213 (NF-E2 p45 related factor 3 or Nrf3), a member of the cap ‘n’ collar family of basic-leucine zipper transcription factors. To examine whether Nrf3 is involved in chemical-induced carcinogenesis, we exposed the mice to benzo[a]pyrene (B[a]P), a carcinogen found in cigarette smoke. Contrary to wild-type mice, Nrf3-null animals are highly susceptible to B[a]P, exhibiting significantly increased mortality. Pathology analysis of affected tissue sections revealed a high incidence of T-cell lymphoblastic lymphoma in B[a]P-treated Nrf3−/− mice. Lymphoblastic lymphoma occasionally metastasized into the lung as demonstrated by perivascular malignant lymphocytic infiltration. Together, our studies show that the absence of Nrf3 predisposes mice to lymphoma development, suggesting a protective role of this transcription factor in hematopoietic malignancies. Our data demonstrate the first in vivo function of Nrf3 and its link to tumor development. Nrf3-deficient mice may serve as a preclinical mouse model to study carcinogen-induced lymphomagenesis.
Clinical significance of CD56 expression in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline-based regimens
Authors: Montesinos Pau , Rayón Chelo , Vellenga Edo , Brunet Salut , González José , González Marcos , Holowiecka Aleksandra , Esteve Jordi , Bergua Juan , González José D. , Rivas Concha , Tormo Mar , Rubio Vicente , Bueno Javier , Manso Félix , Milone Gustavo , de la Serna Javier , Pérez Inmaculada , Pérez-Encinas Manuel , Krsnik Isabel , Ribera Josep M. , Escoda Lourdes , Lowenberg Bob , Sanz Miguel A. ,   on behalf of the PETHEMA and HOVON Groups
Published: December 2010

AbstractThe expression of CD56 antigen in acute promyelocytic leukemia (APL) blasts has been associated with short remission duration and extramedullary relapse. We investigated the clinical significance of CD56 expression in a large series of patients with APL treated with all-trans retinoic acid and anthracycline-based regimens. Between 1996 and 2009, 651 APL patients with available data on CD56 expression were included in 3 subsequent trials (PETHEMA LPA96 and LPA99 and PETHEMA/HOVON LPA2005). Seventy-two patients (11%) were CD56+ (expression of CD56 in ≥ 20% leukemic promyelocytes). CD56+ APL was significantly associated with high white blood cell counts; low albumin levels; BCR3 isoform; and the coexpression of CD2, CD34, CD7, HLA-DR, CD15, and CD117 antigens. For CD56+ APL, the 5-year relapse rate was 22%, compared with a 10% relapse rate for CD56− APL (P = .006). In the multivariate analysis, CD56 expression retained the statistical significance together with the relapse-risk score. CD56+ APL also showed a greater risk of extramedullary relapse (P < .001). In summary, CD56 expression is associated with the coexpression of immaturity-associated and T-cell antigens and is an independent adverse prognostic factor for relapse in patients with APL treated with all-trans-retinoic acid plus idarubicin–derived regimens. This marker may be considered for implementing risk-adapted therapeutic strategies in APL. The LPA2005 trial is registered at http://www.clinicaltrials.gov as NCT00408278.
Transcriptome analyses based on genetic screens for Pax3 myogenic targets in the mouse embryo
Authors: Lagha Mounia , Sato Takahiko , Regnault Béatrice , Cumano Ana , Zuniga Aimée , Licht Jonathan , Relaix Frédéric , Buckingham Margaret 
Published: December 2010

AbstractBackgroundPax3 is a key upstream regulator of the onset of myogenesis, controlling progenitor cell survival and behaviour as well as entry into the myogenic programme. It functions in the dermomyotome of the somite from which skeletal muscle derives and in progenitor cell populations that migrate from the somite such as those of the limbs. Few Pax3 target genes have been identified. Identifying genes that lie genetically downstream ofPax3is therefore an important endeavour in elucidating the myogenic gene regulatory network.ResultsWe have undertaken a screen in the mouse embryo which employs aPax3GFPallele that permits isolation of Pax3 expressing cells by flow cytometry and aPax3PAX3-FKHRallele that encodes PAX3-FKHR in which the DNA binding domain of Pax3 is fused to the strong transcriptional activation domain of FKHR. This constitutes a gain of function allele that rescues thePax3mutant phenotype. Microarray comparisons were carried out betweenPax3GFP/+andPax3GFP/PAX3-FKHRpreparations from the hypaxial dermomyotome of somites at E9.5 and forelimb buds at E10.5. A further transcriptome comparison between Pax3-GFP positive and negative cells identified sequences specific to myogenic progenitors in the forelimb buds. Potential Pax3 targets, based on changes in transcript levels on the gain of function genetic background, were validated by analysis on loss or partial loss of functionPax3mutant backgrounds. Sequences that are up- or down-regulated in the presence of PAX3-FKHR are classified as somite only, somite and limb or limb only. The latter should not contain sequences from Pax3 positive neural crest cells which do not invade the limbs. Verification by whole mountin situhybridisation distinguishes myogenic markers. Presentation of potential Pax3 target genes focuses on signalling pathways and on transcriptional regulation.ConclusionsPax3 orchestrates many of the signalling pathways implicated in the activation or repression of myogenesis by regulating effectors and also, notably, inhibitors of these pathways. Important transcriptional regulators of myogenesis are candidate Pax3 targets. Myogenic determination genes, such asMyf5are controlled positively, whereas the effect ofPax3on genes encoding inhibitors of myogenesis provides a potential brake on differentiation. In the progenitor cell population,Pax7and alsoHdac5which is a potential repressor ofFoxc2, are subject to positive control byPax3.
Genomic organisation analysis of novel immunoglobulin-like transcripts in Atlantic salmon (Salmo salar) reveals a tightly clustered and multigene family
Authors: Østergaard Anders E , Lubieniecki Krzysztof P , Martin Samuel AM , Stet René JM , Davidson William S , Secombes Christopher J 
Published: December 2010

AbstractBackgroundSeveral novel immunoglobulin-like transcripts (NILTs) which have previously been identified in the salmonid species rainbow trout (Oncorhynchus mykiss) contain either one or two extracellular Ig domains of the V-type. NILTs also possess either an immunoreceptor tyrosine-based activating motif (ITAM) or immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in the cytoplasmic region resulting in different signalling abilities. Here we report for the first time the genomic organisation and structure of the multigene family of NILTs in Atlantic salmon (Salmo salar)using a BAC sequencing approach.ResultsWe have identified six novel Atlantic salmon NILT genes (Ssa-NILT1-6), two pseudogenes (Ssa-NILTp1andSsa-NILTp2) and seven genes encoding putative transposable elements in one BAC covering more than 200 kbp.Ssa-NILT1, 2, 4, 5 and 6 contain one Ig domain, all having a CX3C motif, whereasSsa-NILT3 contains two Ig domains, having a CX6C motif in Ig1 and a CX7C motif in Ig2. Atlantic salmon NILTs possess several ITIMs in the cytoplasmic region and the ITIM-bearing exons are in phase 0. A comparison of identity between the amino acid sequences of the CX3C Ig domains from NILTs varies from 77% to 96%.Ssa-NILT1,2,3and4were all confirmed to be expressed either by their presence in EST databases (Ssa-NILT1) or RT-PCR (Ssa-NILT2,3, and4) using cDNA as template. A survey of the repertoire of putative NILT genes in a single individual revealed three novel genes (Ssa-NILT7-9) represented by the Ig domain, which together with Ig domains fromSsa-NILT1-6could be divided into different groups based on specific motifs.ConclusionsThis report reveals a tightly clustered, multigene NILT family in Atlantic salmon. By screening a highly redundant Atlantic salmon BAC library we have identified and characterised the genomic organisation of six genes encoding NILT receptors. The genes show similar characteristics to NILTs previously identified in rainbow trout, having highly conserved cysteines in the Ig domain and several inhibitory signalling motifs in the cytoplasmic region. In a single individual three unique NILT Ig domain sequences were discovered at the genomic DNA level, which were divided into two different groups based on a four residue motif after the third cysteine. Our results from the BAC screening and analysis on the repertoire of NILT genes in a single individual indicates that many genes of this expanding Ig containing NILT family are still to be discovered in fish.
Natural diversity of potato (Solanum tuberosum) invertases
Authors: Draffehn Astrid M , Meller Sebastian , Li Li , Gebhardt Christiane 
Published: December 2010

Abstract

Background
Invertases are ubiquitous enzymes that irreversibly cleave sucrose into fructose and glucose. Plant invertases play important roles in carbohydrate metabolism, plant development, and biotic and abiotic stress responses. In potato (Solanum tuberosum), invertases are involved in 'cold-induced sweetening' of tubers, an adaptive response to cold stress, which negatively affects the quality of potato chips and French fries. Linkage and association studies have identified quantitative trait loci (QTL) for tuber sugar content and chip quality that colocalize with three independent potato invertase loci, which together encode five invertase genes. The role of natural allelic variation of these genes in controlling the variation of tuber sugar content in different genotypes is unknown.

Results
For functional studies on natural variants of five potato invertase genes we cloned and sequenced 193 full-length cDNAs from six heterozygous individuals (three tetraploid and three diploid). Eleven, thirteen, ten, twelve and nine different cDNA alleles were obtained for the genes Pain-1, InvGE, InvGF, InvCD141 and InvCD111, respectively. Allelic cDNA sequences differed from each other by 4 to 9%, and most were genotype specific. Additional variation was identified by single nucleotide polymorphism (SNP) analysis in an association-mapping population of 219 tetraploid individuals. Haplotype modeling revealed two to three major haplotypes besides a larger number of minor frequency haplotypes. cDNA alleles associated with chip quality, tuber starch content and starch yield were identified.

Conclusions
Very high natural allelic variation was uncovered in a set of five potato invertase genes. This variability is a consequence of the cultivated potato's reproductive biology. Some of the structural variation found might underlie functional variation that influences important agronomic traits such as tuber sugar content. The associations found between specific invertase alleles and chip quality, tuber starch content and starch yield will facilitate the selection of superior potato genotypes in breeding programs.
Pituitary adenylyl cyclase activating polypeptide inhibits gli1 gene expression and proliferation in primary medulloblastoma derived tumorsphere cultures
Authors: Cohen Joseph R , Resnick Daniel Z , Niewiadomski Pawel , Dong Hongmei , Liau Linda M , Waschek James A 
Published: December 2010

AbstractBackgroundHedgehog (HH) signaling is critical for the expansion of granule neuron precursors (GNPs) within the external granular layer (EGL) during cerebellar development. Aberrant HH signaling within GNPs is thought to give rise to medulloblastoma (MB) - the most commonly-observed form of malignant pediatric brain tumor. Evidence in both invertebrates and vertebrates indicates that cyclic AMP-dependent protein kinase A (PKA) antagonizes HH signalling. Receptors specific for the neuropeptide pituitary adenylyl cyclase activating polypeptide (PACAP, gene name ADCYAP1) are expressed in GNPs. PACAP has been shown to protect GNPs from apoptosisin vitro, and to interact with HH signaling to regulate GNP proliferation. PACAP/ptch1double mutant mice exhibit an increased incidence of MB compared toptch1mice, indicating that PACAP may regulate HH pathway-mediated MB pathogenesis.MethodsPrimary MB tumorsphere cultures were prepared from thirteenptch1+/-/p53+/-double mutant mice and treated with the smoothened (SMO) agonist purmorphamine, the SMO antagonist SANT-1, the neuropeptide PACAP, the PKA activator forskolin, and the PKA inhibitor H89. Gene expression ofgli1and [3H]-thymidine incorporation were assessed to determine drug effects on HH pathway activity and proliferation, respectively. PKA activity was determined in cell extracts by Western blotting using a phospho-PKA substrate antibody.ResultsPrimary tumor cells cultured for 1-week under serum-free conditions grew as tumorspheres and were found to express PAC1 receptor transcripts.Gli1gene expression was significantly reduced by SANT-1, PACAP and forskolin, but was unaffected by purmorphamine. The attenuation ofgli1gene expression by PACAP was reversed by the PKA inhibitor H89, which also blocked PKA activation. Treatment of tumorsphere cultures with PACAP, forskolin, and SANT-1 for 24 or 48 hours reduced proliferation.ConclusionsPrimary tumorspheres derived fromptch1+/-/p53+/-mice exhibit constitutive HH pathway activity. PACAP antagonizes HH signalling in these cells in a manner blocked by the PKA antagonist H89. PACAP and pharmacological activation of PKA also inhibited proliferation. Our data suggests that regulation of HH signaling by PACAP/PKA signaling may provide an alternative to SMO inhibition for the treatment of MB.
Relationship between clinical signs and postmortem test status in cattle experimentally infected with the bovine spongiform encephalopathy agent
Authors: Konold Timm , Sayers A Robin , Sach Amanda , Bone Gemma E , van Winden Steven , Wells Gerald AH , Simmons Marion M , Stack Michael J , Wear Angus , Hawkins Steve AC 
Published: December 2010

Abstract

Background
Various clinical protocols have been developed to aid in the clinical diagnosis of classical bovine spongiform encephalopathy (BSE), which is confirmed by postmortem examinations based on vacuolation and accumulation of disease-associated prion protein (PrPd) in the brain. The present study investigated the occurrence and progression of sixty selected clinical signs and behaviour combinations in 513 experimentally exposed cattle subsequently categorised postmortem as confirmed or unconfirmed BSE cases. Appropriate undosed or saline inoculated controls were examined similarly and the data analysed to explore the possible occurrence of BSE-specific clinical expression in animals unconfirmed by postmortem examinations.

Results
Based on the display of selected behavioural, sensory and locomotor changes, 20 (67%) orally dosed and 17 (77%) intracerebrally inoculated pathologically confirmed BSE cases and 21 (13%) orally dosed and 18 (6%) intracerebrally inoculated but unconfirmed cases were considered clinical BSE suspects. None of 103 controls showed significant signs and were all negative on diagnostic postmortem examinations. Signs indicative of BSE suspects, particularly over-reactivity and ataxia, were more frequently displayed in confirmed cases with vacuolar changes in the brain. The display of several BSE-associated signs over time, including repeated startle responses and nervousness, was significantly more frequent in confirmed BSE cases compared to controls, but these two signs were also significantly more frequent in orally dosed cattle unconfirmed by postmortem examinations.

Conclusions
The findings confirm that in experimentally infected cattle clinical abnormalities indicative of BSE are accompanied by vacuolar changes and PrPd accumulation in the brainstem. The presence of more frequently expressed signs in cases with vacuolar changes is consistent with this pathology representing a more advanced stage of disease. That BSE-like signs or sign combinations occur in inoculated animals that were not confirmed as BSE cases by postmortem examinations requires further study to investigate the potential causal relationship with prion disease.
Endocrine Actions of Myostatin: Systemic Regulation of the IGF and IGF Binding Protein Axis
Authors: Williams Nolann G. , Interlichia Jillian P. , Jackson Melissa F. , Hwang David , Cohen Pinchas , Rodgers Buel D. 
Published: December 2010

Abstract
Myostatin’s inhibitory actions on striated muscle growth are believed to be directly mediated by locally produced myostatin and possibly by IGF binding proteins (IGFBPs). We therefore measured skeletal muscle, heart, and liver expression, in neonates and adults, and circulating levels of various IGF axis components (IGF-I, IGFBP-1 to IGFBP-3, and acid labile subunit) in wild-type and mstn−/− mice. Compared with wild type, differences in muscle expression were tissue specific, although IGF-I receptor expression was higher in all mstn−/− neonatal tissues and in adult gastrocnemius. Liver expression of several components also differed between genotype as IGF-I receptor, IGFBP-3 and IGFBP-5 expression was higher in mstn−/− neonates and IGF-I and IGFBP-3 in adults. Circulating IGF-I levels were also higher in mstn−/− adults, whereas IGFBP-1 and IGFBP-2 levels were lower. Comparing IGF-I:IGFBP molar ratios suggested that the relative IGF-binding capacity was potentially lower in mstn−/− mice, and thus, total and “free” IGF-I levels may be elevated. This in turn may increase negative feedback control on GH, because mstn−/− liver weights were lower. Bone growth was similar in both genotypes, suggesting that changes in circulating IGF-I may be more important to muscle, whose mass is enhanced in mstn−/− mice, than to bone. Myostatin receptors, but not myostatin itself, are expressed in the liver. Changes in hepatic production of circulating IGF axis components could therefore result from the loss of endocrine myostatin. Thus, myostatin may inhibit striated muscle growth directly at the cellular level and indirectly through systemic effects on the IGF axis.
Advanced Pubertal Growth Spurt in Subjects Born Preterm: The Helsinki Study of Very Low Birth Weight Adults
Authors: Wehkalampi Karoliina , Hovi Petteri , Dunkel Leo , Strang-Karlsson Sonja , Järvenpää Anna-Liisa , Eriksson Johan G. , Andersson Sture , Kajantie Eero 
Published: December 2010

abstract

Context:
Among people born at term, low birth weight is associated with early puberty. Early maturation may be on the pathway linking low birth weight with cardiovascular disease and type 2 diabetes. Subjects born preterm with very low birth weight (VLBW; &lt;1500 g) have as adults increased risk factors for cardiovascular disease. Little is known about their pubertal timing.

Objective:
The objective of the investigation was to study the timing of pubertal growth in subjects born preterm with VLBW as compared with controls.

Design, Setting, and Participants:
A follow-up study of subjects born preterm including 188 VLBW and 190 term-born control subjects. Growth data were available for 128 VLBW and 147 control subjects, of whom we excluded 15 and 1, respectively, because of neurological impairment.

Main Outcome Measure:
Timing of pubertal growth spurt was estimated by assessing the ages, corrected for gestational age at birth, at acceleration (take-off) and peak height velocity of pubertal growth, and age at attaining adult height.

Results:
All components of pubertal growth occurred earlier in VLBW subjects than in controls. Age at take-off was 0.8 yr earlier [95% confidence interval (CI) 0.4–1.3] in VLBW subjects born appropriate and 0.9 yr earlier (95% CI 0.4–1.5) in those born small for gestational age. VLBW subjects were more likely to have a pubertal growth spurt that was at least 2 yr earlier than population average [odds ratio 3.8 (95% CI: 1.5–9.6)].

Conclusions:
Prematurity per se is associated with advanced pubertal growth. Advanced puberty may be among the factors mediating adult metabolic outcomes in subjects born preterm with VLBW.
Treatment of Unresectable and Metastatic Cutaneous Squamous Cell Carcinoma
Authors: Cranmer Lee D. , Engelhardt Candace , Morgan Sherif S. 
Published: December 2010

Abstract
Cutaneous squamous cell carcinoma (SCC) is an already common disorder with a rapidly increasing incidence. Treatment of early disease depends primarily on surgery or destructive techniques. In contrast to the frequency of early SCC, unresectable or metastatic SCC is relatively rare, but potentially life-threatening without clearly proven treatment options. Few rigorous studies of the treatment of advanced SCC have been undertaken. In the past, various agents have been explored in a limited fashion, including chemotherapy (cisplatin, fluoropyrimidines, bleomycin, doxorubicin), 13-cis-retinoic acid, and interferon-α2a. Clinical activity has been suggested by these trials, but their small sizes, heterogeneous patient populations, and lack of randomization have hindered the use of their results in defining treatment paradigms. Only one rigorous randomized trial has focused on cutaneous SCC. Enrolling 66 patients, that trial randomized patients at high recurrence risk to either observation or postoperative interferon-α2a and 13-cis-retinoic acid. This treatment did not improve time to recurrence or prevent secondary cutaneous SCC from developing. Though not in the metastatic setting, this study casts doubt on the ability of this regimen to control metastatic disease. Recently, agents targeting the human epidermal growth factor receptor (erlotinib, gefitinib, cetuximab) have displayed preliminary evidence of activity in phase II clinical trials and case series reports. Expression of this receptor is frequent in cutaneous SCC and appears to be prognostically adverse. Only the conduct of rigorous trials, with well-defined endpoints, adequate patient numbers, and preferably randomization, can prove the clinical efficacy of this promising treatment approach and define better therapy for this vexing clinical problem.