bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exon array analysis reveals neuroblastoma tumors have distinct alternative splicing patterns according to stage and MYCN amplification status
Authors: Guo Xiang , Chen Qing-Rong , Song Young K , Wei Jun S , Khan Javed 
Published: May 2011

Abstract

Background
Neuroblastoma (NB) tumors are well known for their pronounced clinical and molecular heterogeneity. The global gene expression and DNA copy number alterations have been shown to have profound differences in tumors of low or high stage and those with or without MYCN amplification. RNA splicing is an important regulatory mechanism of gene expression, and differential RNA splicing may be associated with the clinical behavior of a tumor.

Methods
In this study, we used exon array profiling to investigate global alternative splicing pattern of 47 neuroblastoma samples in stage 1 and stage 4 with normal or amplified MYCN copy number (stage 1-, 4- and 4+). The ratio of exon-level expression to gene-level expression was used to detect alternative splicing events, while the gene-level expression was applied to characterize whole gene expression change.

Results
Principal component analysis (PCA) demonstrated distinct splicing pattern in three groups of samples. Pairwise comparison identified genes with splicing changes and/or whole gene expression changes in high stage tumors. In stage 4- compared with stage 1- tumors, alternatively spliced candidate genes had little overlap with genes showing whole gene expression changes, and most of them were involved in different biological processes. In contrast, a larger number of genes exhibited either exon-level splicing, gene-level expression or both changes in stage 4+ versus stage 1- tumors. Those biological processes involved in stage 4- tumors were disrupted to a greater extent by both splicing and transcription regulations in stage 4+ tumors.

Conclusions
Our results demonstrated a significant role of alternative splicing in high stage neuroblastoma, and suggested a MYCN-associated splicing regulation pathway in stage 4+ tumors. The identification of differentially spliced genes and pathways in neuroblastoma tumors of different stages and molecular subtypes may be important to the understanding of cancer biology and the discovery of diagnostic markers or therapeutic targets in neuroblastoma.
Insecticide susceptibility of Aedes aegypti and Aedes albopictus in Central Africa
Authors: Kamgang Basile , Marcombe Sébastien , Chandre Fabrice , Nchoutpouen Elysée , Nwane Philippe , Etang Josiane , Corbel Vincent , Paupy Christophe 
Published: May 2011

AbstractBackgroundAedes aegypti(Linnaeus, 1762) andAedes albopictus(Skuse, 1894) are the main vectors of dengue (DENV) and chikungunya (CHIKV) viruses worldwide. As there is still no vaccine or specific treatment for DENV and CHIKV, vector control remains the cornerstone of prevention and outbreak control. Unfortunately, vector control programs are facing operational challenges with mosquitoes becoming resistant to commonly used insecticides in several areas through the world. Throughout Central Africa no recent data are available susceptible/resistant status of either vector species since the introduction/arrival ofAe. albopictusin this area. We therefore studied the level of resistance of these two major vectors to insecticides commonly used in Africa for mosquito control.ResultsAedes aegyptiandAe. albopictuswere sampled in six urban localities of Cameroon (Garoua, Bertoua, Yaoundé, Bafia, Buea) and Gabon (Libreville). Larval bioassays, carried out to determine the lethal concentrations (LC50and LC95) and resistance ratios (RR50and RR95) suggested that both vector species were susceptible toBti(Bacillus thuringiensis var israeliensis) and temephos. Bioassays were also performed on adults using WHO diagnostic test kits to assess phenotypic resistance to deltamethrin, DDT, fenitrothion and propoxur. These experiments showed that one population ofAe. aegypti(Libreville) and two populations ofAe. albopictus(Buea and Yaoundé) were resistant to DDT (mortality 36% to 71%). Resistance to deltamethrin was also suspected inAe. albopictusfrom Yaoundé (83% mortality). All other field mosquito populations were susceptible to deltamethrin, DDT, fenitrothion and propoxur. No increase in the knockdown times (Kdt50and Kdt95) was noted in the Yaoundé resistant population compared to otherAe. albopictuspopulations, suggesting the possible involvement of metabolic resistance to deltamethrin and DDT.ConclusionIn view of the recent increase in dengue and chikungunya outbreaks in Central Africa, these unique comparative data on the insecticide susceptibility ofAe. aegyptiandAe. albopictuscould help public health services to design more effective vector control measures.
Gene expression profiles in BCL11B-siRNA treated malignant T cells
Authors: Huang Xin , Shen Qi , Chen Si , Chen Shaohua , Yang Lijian , Weng Jianyu , Du Xin , Grabarczyk Piotr , Przybylski Grzegorz K , Schmidt Christian A , Li Yangqiu 
Published: May 2011

Abstract

Background
Downregulation of the B-cell chronic lymphocytic leukemia (CLL)/lymphoma11B (BCL11B) gene by small interfering RNA (siRNA) leads to growth inhibition and apoptosis of the human T-cell acute lymphoblastic leukemia (T-ALL) cell line Molt-4. To further characterize the molecular mechanism, a global gene expression profile of BCL11B-siRNA -treated Molt-4 cells was established. The expression profiles of several genes were further validated in the BCL11B-siRNA -treated Molt-4 cells and primary T-ALL cells.

Results
142 genes were found to be upregulated and 109 genes downregulated in the BCL11B-siRNA -treated Molt-4 cells by microarray analysis. Among apoptosis-related genes, three pro-apoptotic genes, TNFSF 10, BIK, BNIP 3, were upregulated and one anti-apoptotic gene, BCL2L 1 was downregulated. Moreover, the expression of SPP 1 and CREBBP genes involved in the transforming growth factor (TGF-β) pathway was down 16-fold. Expression levels of TNFSF 10, BCL2L 1, SPP 1, and CREBBP were also examined by real-time PCR. A similar expression pattern of TNFSF 10, BCL2L 1, and SPP 1 was identified. However, CREBBP was not downregulated in the BLC11B-siRNA -treated Molt-4 cells.

Conclusion

BCL11B-siRNA treatment altered expression profiles of TNFSF 10, BCL2L 1, and SPP 1 in both Molt-4 T cell line and primary T-ALL cells.
Antisense oligodeoxynucleotides targeting ATM strengthen apoptosis of laryngeal squamous cell carcinoma grown in nude mice
Authors: Feng Jun , Zou Jian , Li Li , Zhao Yongsheng , Liu Shixi 
Published: May 2011

Abstract

Background
To conserve laryngeal function and elevate living quality of laryngeal squamous cell carcinoma (LSCC) patients, we designed antisense oligodeoxynucleotides (AS-ODNs) to reduce expression of ATM and to enhance the apoptosis of hep-2 (Human epidermoid laryngeal carcinoma) cells to radiation in vitro and in vivo.

Methods
The expression of ATM mRNA and protein in hep-2 cells were examined by real-time quantitative PCR and western blotting respectively. Clonogenic survival assay was carried out to detect the survival ability of hep-2 cells after irradiation, and analyzed the cell apoptosis by flow cytometry. The volume of solid tumors was measured, while TUNEL assay and western blotting used to analyze cell apoptosis and protein expression after irradiation.

Results
The relative ATM mRNA and protein expression in hep-2 cells treated with ATM AS-ODNs were decreased to 11.03 ± 2.51% and 48.14 ± 5.53% of that in untreated cells respectively (P <0.05). After irradiation, the survival fraction (SF) of cells treated with ATM AS-ODNs was lower than that of other groups at the same dose of radiation (P < 0.05). The inhibition rate in hep-2 cells solid tumor exposed to X-ray alone was 5.95 ± 4.52%, while it was 34.28 ± 2.43% in the group which irradiated in combination with the treatment of ATM AS-ODNs (P < 0.05). The apoptotic index for the group irradiated in combination with ATM AS-ODNs injection was 17.12 ± 4.2%, which was significantly higher than that of others (P < 0.05).

Conclusion
AS-ODNs of ATM reduce ATM expression and enhance hep-2 cells apoptosis to radiation in vitro and in vivo.
Targeted Therapy With the T-Cell–Engaging Antibody Blinatumomab of Chemotherapy-Refractory Minimal Residual Disease in B-Lineage Acute Lymphoblastic Leukemia Patients Results in High Response Rate and Prolonged Leukemia-Free Survival
Authors: Topp Max S. , Kufer Peter , Gökbuget Nicola , Goebeler Mariele , Klinger Matthias , Neumann Svenja , Horst Heinz-A. , Raff Thorsten , Viardot Andreas , Schmid Mathias , Stelljes Matthias , Schaich Markus , Degenhard Evelyn , Köhne-Volland Rudolf , Brüggemann Monika , Ottmann Oliver , Pfeifer Heike , Burmeister Thomas , Nagorsen Dirk , Schmidt Margit , Lutterbuese Ralf , Reinhardt Carsten , Baeuerle Patrick A. , Kneba Michael , Einsele Hermann , Riethmüller Gert , Hoelzer Dieter , Zugmaier Gerhard , Bargou Ralf C. 
Published: May 2011

Purpose Blinatumomab, a bispecific single-chain antibody targeting the CD19 antigen, is a member of a novel class of antibodies that redirect T cells for selective lysis of tumor cells. In acute lymphoblastic leukemia (ALL), persistence or relapse of minimal residual disease (MRD) after chemotherapy indicates resistance to chemotherapy and results in hematologic relapse. A phase II clinical study was conducted to determine the efficacy of blinatumomab in MRD-positive B-lineage ALL. Patients and Methods Patients with MRD persistence or relapse after induction and consolidation therapy were included. MRD was assessed by quantitative reverse transcriptase polymerase chain reaction for either rearrangements of immunoglobulin or T-cell receptor genes, or specific genetic aberrations. Blinatumomab was administered as a 4-week continuous intravenous infusion at a dose of 15 μg/m2/24 hours. Results Twenty-one patients were treated, of whom 16 patients became MRD negative. One patient was not evaluable due to a grade 3 adverse event leading to treatment discontinuation. Among the 16 responders, 12 patients had been molecularly refractory to previous chemotherapy. Probability for relapse-free survival is 78% at a median follow-up of 405 days. The most frequent grade 3 and 4 adverse event was lymphopenia, which was completely reversible like most other adverse events. Conclusion Blinatumomab is an efficacious and well-tolerated treatment in patients with MRD-positive B-lineage ALL after intensive chemotherapy. T cells engaged by blinatumomab seem capable of eradicating chemotherapy-resistant tumor cells that otherwise cause clinical relapse.
Pazopanib Efficacy in Renal Cell Carcinoma: Evidence for Predictive Genetic Markers in Angiogenesis-Related and Exposure-Related Genes
Authors: Xu Chun-Fang , Bing Nan X. , Ball Howard A. , Rajagopalan Dilip , Sternberg Cora N. , Hutson Thomas E. , de Souza Paul , Xue Zhengyu G. , McCann Lauren , King Karen S. , Ragone Leigh J. , Whittaker John C. , Spraggs Colin F. , Cardon Lon R. , Mooser Vincent E. , Pandite Lini N. 
Published: May 2011

Purpose Pazopanib, an oral angiogenesis inhibitor, is approved for the treatment of advanced renal cell carcinoma (RCC). Response to pazopanib monotherapy varies between patients, and no validated biomarkers predictive of treatment outcome have been identified. We tested the hypothesis that this variability is partially dependent on germline genetic variants that may affect pazopanib exposure or angiogenesis pathways. Patients and Methods Twenty-seven functional polymorphisms within 13 genes were evaluated in 397 patients with RCC. Genetic association with progression-free survival (PFS) and objective response rate (RR) was analyzed using the Cox proportional hazards model and proportional odds model, respectively. Results Three polymorphisms in IL8 and HIF1A and five polymorphisms in HIF1A, NR1I2, and VEGFA showed nominally significant association (P ≤ .05) with PFS and RR, respectively. Compared with the wild-type AA genotype (median PFS, 48 weeks), the IL8 2767TT variant genotype showed inferior PFS (27 weeks, P = .009). The HIF1A 1790AG genotype was associated with inferior PFS and reduced RR, compared with the wild-type GG genotype (median PFS, 20 v 44 weeks; P = .03; RR, 30% v 43%, P = .02). Reductions in RR were detected for the NR1I2 −25385TT genotype, compared with the wild-type CC genotype (37% v 50%, P = .03), and for the VEGFA −1498CC genotype compared with the TT genotypes (33% v 51%). Conclusion Germline variants in angiogenesis- and exposure-related genes may predict treatment response to pazopanib monotherapy in patients with RCC. If validated, these markers may explain why certain patients fail antiangiogenesis therapy and they may support the use of alternative strategies to circumvent this issue.
Actual Status of Distribution and Prognostic Impact of Extramural Discontinuous Cancer Spread in Colorectal Cancer
Authors: Ueno Hideki , Mochizuki Hidetaka , Shirouzu Kazuo , Kusumi Takaya , Yamada Kazutaka , Ikegami Masahiro , Kawachi Hiroshi , Kameoka Shingo , Ohkura Yasuo , Masaki Tadahiko , Kushima Ryoji , Takahashi Keiichi , Ajioka Yoichi , Hase Kazuo , Ochiai Atsushi , Wada Ryo , Iwaya Keiichi , Nakamura Takahiro , Sugihara Kenichi 
Published: May 2011

Purpose To clarify the prognostic impact of tumor nodules without residual lymph node (LN) structure (ND) in colorectal cancer and to determine optimal categorization of ND in tumor staging. Patients and Methods A multicenter, retrospective pathologic review was performed for 1,716 patients with stages I to III curatively resected colorectal cancer treated at 11 institutions between 1994 and 1998. An additional 2,242 patients from nine institutions were enrolled between 1999 and 2003 as a second cohort to validate the results. Results LN metastasis (LNM) and ND were observed in 33.7% and 16.0% (smooth-contour nodule [S-ND], 8.2%; irregular-contour nodule [I-ND], 10.7%) of patients in the first cohort. S-ND and I-ND were similarly distributed in the regional area. There was no considerable difference in the impact on survival between S-ND (hazard ratio [HR], 2.7; 95% CI, 1.9 to 3.8) and I-ND (HR, 4.3; 95% CI, 3.3 to 5.8) or between LNM (HR, 4.5; 95% CI, 3.4 to 6.0) and ND (HR, 4.0; 95% CI, 3.1 to 5.3). LNM and ND were similarly associated with the mode of recurrence. Tumor nodules ≥ 5 mm growing with venous/perineural invasion (ND [v/pni+]), judged with 0.61 κ value among 11 observers, had an independent prognostic value for 5-year survival of 42%; similar results were observed in the second cohort. Conclusion These results do not support the TNM system in which S-ND is treated differently from I-ND in tumor staging; LNM and ND should be considered together in the same category. The presence of ND (v/pni+) has a considerable adverse prognostic effect.
Success Story of Targeted Therapy in Chronic Myeloid Leukemia: A Population-Based Study of Patients Diagnosed in Sweden From 1973 to 2008
Authors: Björkholm Magnus , Ohm Lotta , Eloranta Sandra , Derolf Åsa , Hultcrantz Malin , Sjöberg Jan , Andersson Therese , Höglund Martin , Richter Johan , Landgren Ola , Kristinsson Sigurdur Y. , Dickman Paul W. 
Published: May 2011

Purpose Chronic myeloid leukemia (CML) management changed dramatically with the development of imatinib mesylate (IM), the first tyrosine kinase inhibitor targeting the BCR-ABL1 oncoprotein. In Sweden, the drug was approved in November 2001. We report relative survival (RS) of patients with CML diagnosed during a 36-year period. Patients and Methods Using data from the population-based Swedish Cancer Registry and population life tables, we estimated RS for all patients diagnosed with CML from 1973 to 2008 (n = 3,173; 1,796 males and 1,377 females; median age, 62 years). Patients were categorized into five age groups and five calendar periods, the last being 2001 to 2008. Information on use of upfront IM was collected from the Swedish CML registry. Results Relative survival improved with each calendar period, with the greatest improvement between 1994-2000 and 2001-2008. Five-year cumulative relative survival ratios (95% Cls) were 0.21 (0.17 to 0.24) for patients diagnosed 1973-1979, 0.54 (0.50 to 0.58) for 1994-2000, and 0.80 (0.75 to 0.83) for 2001-2008. This improvement was confined to patients younger than 79 years of age. Five-year RSRs for patients diagnosed from 2001 to 2008 were 0.91 (95% CI, 0.85 to 0.94) and 0.25 (95% CI, 0.10 to 0.47) for patients younger than 50 and older than 79 years, respectively. Men had inferior outcome. Upfront overall use of IM increased from 40% (2002) to 84% (2006). Only 18% of patients older than 80 years of age received IM as first-line therapy. Conclusion This large population-based study shows a major improvement in outcome of patients with CML up to 79 years of age diagnosed from 2001 to 2008, mainly caused by an increasing use of IM. The elderly still have poorer outcome, partly because of a limited use of IM.
Norms and Contracting
Authors: Kessler Judd B. , Leider Stephen 
Published: May 2011

We argue that contracts establish the norms of a relationship and that individuals incur disutility when deviating from these norms. In a laboratory experiment, we allow agents to make simple contracts before they play one of four games, and the most effective contract always includes an unenforceable “handshake” agreement to take the first-best action. In three games, a contract with only this handshake agreement is (at least weakly) optimal. The handshake is particularly effective in games with strategic complements. Our results highlight an explanation for contractual incompleteness: establishing a norm can effectively substitute for weak enforceable restrictions. This paper was accepted by Brad Barber, Teck Ho, and Terrance Odean, special issue editors.
The effects of zoledronic acid and hyperbaric oxygen on posterior lumbar fusion in a rabbit model
Authors: Yalçin N. , Öztürk A. , Özkan Y. , Çelimli N. , Özocak E. , Erdogan A. , Sahin N. , Ilgezdi S. 
Published: May 2011

We studied the effects of hyperbaric oxygen (HBO) and zoledronic acid (ZA) on posterior lumbar fusion using a validated animal model. A total of 40 New Zealand white rabbits underwent posterior lumbar fusion at L5–6 with autogenous iliac bone grafting. They were divided randomly into four groups as follows: group 1, control; group 2, HBO (2.4 atm for two hours daily); group 3, local ZA (20 μg of ZA mixed with bone graft); and group 4, combined HBO and local ZA. All the animals were killed six weeks after surgery and the fusion segments were subjected to radiological analysis, manual palpation, biomechanical testing and histological examination. Five rabbits died within two weeks of operation. Thus, 35 rabbits (eight in group 1 and nine in groups 2, 3 and 4) completed the study. The rates of fusion in groups 3 and 4 (p = 0.015) were higher than in group 1 (p < 0.001) in terms of radiological analysis and in group 4 was higher than in group 1 with regard to manual palpation (p = 0.015). We found a statistically significant difference in the biomechanical analysis between groups 1 and 4 (p = 0.024). Histological examination also showed a statistically significant difference between groups 1 and 4 (p = 0.036). Our results suggest that local ZA combined with HBO may improve the success rate in posterior lumbar spinal fusion.
Effect of vibration on the shear strength of impacted bone graft in revision hip surgery
Authors: Brennan S. A. , Brabazon D. , O’Byrne J. M. 
Published: May 2011

We developed a method of applying vibration to the impaction bone grafting process and assessed its effect on the mechanical properties of the impacted graft. Washed morsellised bovine femoral heads were impacted into shear test rings. A range of frequencies of vibration was tested, as measured using an accelerometer housed in a vibration chamber. Each shear test was repeated at four different normal loads to generate stress-strain curves. The Mohr-Coulomb failure envelope from which shear strength and interlocking values are derived was plotted for each test. The experiments were repeated with the addition of blood in order to replicate a saturated environment. Graft impacted with the addition of vibration at all frequencies showed improved shear strength when compared with impaction without vibration, with 60 Hz giving the largest effect. Under saturated conditions the addition of vibration was detrimental to the shear strength of the aggregate. The civil-engineering principles of particulate settlement and interlocking also apply to impaction bone grafting. Although previous studies have shown that vibration may be beneficial in impaction bone grafting on the femoral side, our study suggests that the same is not true in acetabular revision.
Intramedullary limb lengthening with the Intramedullary Skeletal Kinetic Distractor in the lower limb
Authors: Schiedel F. M. , Pip S. , Wacker S. , Pöpping J. , Tretow H. , Leidinger B. , Rödl R. 
Published: May 2011

We report the results of intramedullary leg lengthening conducted between 2002 and 2009 using the Intramedullary Skeletal Kinetic Distractor in 69 unilateral lengthenings involving 58 femora and 11 tibiae. We identified difficulties that occurred during the treatment and assessed whether they were specifically due to the implant or independent of it. Paley’s classification for evaluating problems, obstacles and complications with external fixators was adopted, and implant-specific difficulties were continuously noted. There were seven failures requiring premature removal of the device, in four due to nail breakage and three for other reasons, and five unsuccessful outcomes after completion of the lengthening. In all, 116 difficulties were noted in 45 patients, with only 24 having problem-free courses. In addition to the difficulties arising from the use of external fixators, there were almost the same number again of implant-specific difficulties. Nevertheless, successful femoral lengthening was achieved in 52 of the 58 patients (90%). However, successful tibial lengthening was only achieved in five of 11 patients (45%).
Distal tibial physeal arrest after meningococcal septicaemia
Authors: Monsell F. P. , Barnes J. R. , Kirubanandan R. , McBride A. M. B. 
Published: May 2011

Survivors of infantile meningococcal septicaemia often develop progressive skeletal deformity as a result of physeal damage at many sites, particularly in the lower limb. Distal tibial physeal arrest typically occurs with sparing of the distal fibular physis leading to a rapidly progressive varus deformity. There have been reports of isolated cases of this deformity, but to our knowledge there have been no papers which specifically describe the development of the deformity and the options for treatment. Surgery to correct this deformity is complex because of the patient’s age, previous scarring and the multiplanar nature of the deformity. The surgical goal is to restore leg-length equality and the mechanical axis at the end of growth. Surgery should be planned and staged throughout growth in order to achieve the best functional results. We report our experience in six patients (seven ankles) with this deformity, who were managed by corrective osteotomy using a programmable circular fixator.