bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative conservation analysis of the human mitotic phosphoproteome
Authors: Malik Rainer , Nigg Erich A. , Körner Roman 
Published: April 2008

Abstract
Motivation: A key challenge in phosphoproteomic studies is to distinguish functionally relevant phosphorylation sites from potentially ‘silent’ phosphorylation. Considering that relevant phosphorylation sites are expected to be better conserved during evolution than overall Serine, Threonine and Tyrosine (S/ T/ Y) residues, we asked whether this can be directly demonstrated through statistic analysis, using a large experimental dataset.
Results: Analyzing phosphoproteomic data derived from the human mitotic spindle apparatus, we found that 95.2% of 1744 phosphorylation sites are conserved in at least one of six other vertebrate species. Using a new score, termed conservation Z-score (CZ-score), we demonstrate that phosphorylation sites are significantly better conserved than other S/T/Y sites, a conclusion validated from several kinase consensus motifs. Most importantly, phosphorylation sites with experimentally verified biological functions were significantly better conserved than other phosphorylation sites, indicating that analysis utilizing evolutionary conservation may constitute a powerful basis for the development of improved phosphorylation site predictors.
Contact: malik@biochem.mpg.de
Supplementary information: Supplementary data are available at Bioinformatics online.
Eukaryotic transcription factor binding sites—modeling and integrative search methods
Authors: Hannenhalli Sridhar 
Published: April 2008

Abstract
A comprehensive knowledge of transcription factor binding sites (TFBS) is important for a mechanistic understanding of transcriptional regulation as well as for inferring gene regulatory networks. Because the DNA motif recognized by a transcription factor is typically short and degenerate, computational approaches for identifying binding sites based only on the sequence motif inevitably suffer from high error rates. Current state-of-the-art techniques for improving computational identification of binding sites can be broadly categorized into two classes: (1) approaches that aim to improve binding motif models by extracting maximal sequence information from experimentally determined binding sites and (2) approaches that supplement binding motif models with additional genomic or other attributes (such as evolutionary conservation). In this review we will discuss recent attempts to improve computational identification of TFBS through these two types of approaches and conclude with thoughts on future development.
Contact: sridharh@pcbi.upenn.edu
Genetic assignment identifies farm of origin for Atlantic salmon Salmo salar escapees in a Norwegian fjord
Authors: Glover K. A. , Skilbrei O. T. , Skaala Ø. 
Published: April 2008

AbstractGlover, K. A., Skilbrei, O. T., and Skaala, Ø. 2008. Genetic assignment identifies farm of origin for Atlantic salmon Salmo salar escapees in a Norwegian fjord. – ICES Journal of Marine Science, 65: 912–920. This study represents the first example of genetic assignment being used to identify the farm of origin for escaped Atlantic salmon. Following reports by local fishers of escaped farmed salmon in Romsdalfjord, western Norway, baseline samples were collected from 16 cages located on seven operational farms. The baseline samples, in addition to 29 escapees, were screened for 15 microsatellite loci. Pairwise FST values between baseline samples varied from <0.001 to 0.154, indicating variable but significant genetic differences among them. Direct assignment of the escapees (data from 13 informative loci) demonstrated that the most likely origin of 21 of them was from a single baseline sample (5I) collected at one farm. At a probability of 0.01, between 25 and 29 of the escapees were rejected in 12 baseline samples, 19–21 escapees were rejected from another three baseline samples, and only seven of the escapees were rejected from baseline sample 5I. Consequently, these data demonstrate that most of the escapees most likely originated from a single farm, and importantly, that 15 of the 16 baseline samples could with high probability be excluded as donors for most of the escapees recaptured in the area.
Phase 1 trial of denosumab safety, pharmacokinetics, and pharmacodynamics in Japanese women with breast cancer–related bone metastases
Authors: Yonemori Kan , Fujiwara Yasuhiro , Minami Hironobu , Kitagawa Koichi , Fujii Hirofumi , Arai Tatsuhiro , Sohn Winnie , Ohkura Masayuki , Ohtsu Tomoko 
Published: April 2008

Denosumab, a fully human monoclonal antibody to receptor activator of nuclear factor–kappa B ligand (RANKL), suppresses bone resorption. This open‐label, multicenter, phase 1 study evaluated the safety, pharmacodynamics, and pharmacokinetics of denosumab in Japanese women with breast cancer–related bone metastases. Patients (n = 18; median age, 57 years) received a single subcutaneous injection of denosumab 60 mg or 180 mg or three doses of denosumab 180 mg on days 1, 29, and 57 (every 4 weeks) and were followed for ≥ 141 days. No major safety concerns related to denosumab were noted in any cohort. All patients experienced at least 1 adverse event (AE); most were mild (grade ≤ 2). One patient reported grade 4 myositis and grade 3 anemia, malaise, and dysphagia that the investigator deemed treatment‐related; other treatment‐related AE were grade ≤ 2. No antidenosumab antibodies or clinically significant changes in laboratory findings, vital signs, or electrocardiograms were observed. Pharmacokinetics were approximately dose‐linear. Denosumab caused rapid, substantial, and sustained suppression of urinary N‐telopeptide corrected for creatinine (uNTx/Cr) across all doses; at day 85, the median change from baseline uNTx/Cr ranged from –61.9% to –90.8%. No dose‐limiting toxicity was observed at any dosage. Coupled with pharmacokinetic and pharmacodynamic data, these results were consistent with those observed in non‐Japanese populations. (Cancer Sci 2008; 99: 1237–1242)
Risk of metachronous squamous cell carcinoma in the upper aerodigestive tract of Japanese alcoholic men with esophageal squamous cell carcinoma: a long‐term endoscopic follow‐up study
Authors: Yokoyama Akira , Omori Tai , Yokoyama Tetsuji , Sato Yasuo , Kawakubo Hirofumi , Maruyama Katsuya 
Published: April 2008

East Asian case–control studies have shown a strong relationship between alcohol consumption combined with inactive heterozygous aldehyde dehydrogenase‐2 (ALDH2*1/*2) and the development of squamous cell carcinoma (SCC), especially multiple SCC, of the upper aerodigestive tract (UADT). This study aimed to identify determinants of the development of metachronous SCC in the UADT in alcoholics with esophageal SCC. Follow‐up endoscopic examinations were carried out 4–160 months (median, 41 months) after initial diagnosis in 110 Japanese alcoholic men with esophageal SCC diagnosed by screening using endoscopy combined with oropharyngolaryngeal inspection and esophageal iodine staining. ALDH2*1/*2 was significantly associated with the presence of multiple primary intraesophageal SCC at the time of initial diagnosis. Metachronous primary SCC of the esophagus was diagnosed in 29 of the 81 patients whose initial esophageal SCC was treated by endoscopic mucosal resection alone, and metachronous primary SCC of the oropharyngolarynx was diagnosed in 23 of the 99 patients without synchronous primary SCC of the oropharyngolarynx at the time of initial diagnosis. The risks of metachronous esophageal SCC and oropharyngolaryngeal SCC were significantly higher in ALDH2*1/*2 heterozygotes than in ALDH2*1/*1 homozygotes (age‐adjusted and alcohol‐adjusted hazard ratio = 3.38 [95% confidence interval: 1.45–7.85] and 4.27 [1.42–12.89], respectively), and in patients with multiple intraesophageal SCC at the time of initial diagnosis than in patients with a solitary intraesophageal SCC (3.09 [1.41–6.78] and 3.25 [1.41–7.47], respectively). ALDH2*1/*2 and multiple synchronous intraesophageal SCC were found to be predictors of metachronous SCC in the UADT in this population. (Cancer Sci 2008; 99: 1164–1171)
Suicide gene/prodrug therapy using salmonella‐mediated delivery of Escherichia coli purine nucleoside phosphorylase gene and 6‐methoxypurine 2′‐deoxyriboside in murine mammary carcinoma 4T1 model
Authors: Fu Wei , Lan Hekui , Liang Shenghua , Gao Tong , Ren Daming 
Published: April 2008

Attenuated salmonella have been reported to be capable of both selectively growing in tumors and expressing exogenous genes for tumor‐targeted therapy. As 6‐methoxypurine 2′‐deoxyriboside (MoPdR) is similar to 6‐methylpurine 2′‐deoxyriboside in structure, we aimed to evaluate the antitumoral effect of the Escherichia coli purine nucleoside phosphorylase (ePNP) gene, using an attenuated salmonella‐mediated delivery system, in combination with MoPdR. A novel mutant serovar Typhimurium (SC36) was used to carry the pEGFP‐C1‐ePNP vector that contains an enhanced green fluorescent protein and an ePNP gene under the control of the cytomegalovirus promoter. The function of the ePNP expression vector was confirmed in vitro using the enzymic conversion of MoPdR into methoxypurine. We also observed a high bystander effect induced by the ePNP/MoPdR system with a very low proportion (1%) of ePNP‐positive cells and 5 µg/mL MoPdR, although the growth of parental cells was affected appreciably by MoPdR. The killing effect and increased apoptosis induced by SC36 carrying the ePNP expression vector (SC/ePNP) were detected by cytotoxicity assay and propidium iodide staining flow cytometry analysis, in combination with MoPdR. SC/ePNP was given orally to mice bearing mammary carcinomas, and its antitumor effect was evaluated. SC/ePNP plus MoPdR significantly inhibited tumor growth by approximately 86.6–88.7% and prolonged the survival of tumor‐hosting mice. Our data support the view that MoPdR combined with the ePNP gene could be used in gene‐directed enzyme prodrug therapy. Attenuated salmonella could be a promising strategy to improve ePNP/MoPdR bystander killing due to its preferential accumulation and anticancer activity in tumors. (Cancer Sci 2008; 99: 1172–1179)
Activity of a novel Aurora kinase inhibitor against the T315I mutant form of BCR‐ABL: In vitro and in vivo studies
Authors: Akahane Daigo , Tauchi Tetsuzo , Okabe Seiichi , Nunoda Kousuke , Ohyashiki Kazuma 
Published: April 2008

Despite promising results from clinical studies of ABL kinase inhibitors, a challenging problem that remains is the T315I mutation against which neither nilotinib nor dasatinib show significant activity. In the present study, we investigated the activity of a novel Aurora kinase inhibitor, VE‐465, against leukemia cells expressing wild‐type BCR‐ABL or the T315I mutant form of BCR‐ABL. We observed a dose‐dependent reduction in the level of BCR‐ABL autophosphorylation in VE‐465‐treated cells. Exposure to the combination of VE‐465 and imatinib exerted an enhanced apoptotic effect in K562 cells. Combined treatment with VE‐465 and imatinib caused more attenuation of the levels of phospho‐AKT and c‐Myc in K562 cells. Further, the isobologram indicated the synergistic effect of simultaneous exposure to VE‐465 and imatinib in K562 cells. To assess the in vivo efficacy of VE‐465, athymic nude mice were injected intravenously with BaF3 cells expressing wild‐type BCR‐ABL or the T315I mutant form. The vehicle‐treated mice died of a condition resembling acute leukemia by 28 days; however, nearly all mice treated with VE‐465 (75 mg/kg, twice daily; intraperitoneally for 14 days) survived for more than 56 days. Histopathological analysis of vehicle‐treated mice revealed infiltration of the spleen. In contrast, histopathological analysis of organs from VE‐465‐treated mice demonstrated normal tissue architecture. Taken together, the present study shows that VE‐465 exhibits a desirable therapeutic index that can reduce the in vivo growth of T315I mutant form and wild‐type BCR‐ABL‐expressing cells in an efficacious manner. (Cancer Sci 2008; 99: 1251–1257)
Soy consumption reduces the risk of non‐small‐cell lung cancers with epidermal growth factor receptor mutations among Japanese
Authors: Matsuo Keitaro , Hiraki Akio , Ito Hidemi , Kosaka Takayuki , Suzuki Takeshi , Hirose Kaoru , Wakai Kenji , Yatabe Yasushi , Mitsudomi Tetsuya , Tajima Kazuo 
Published: April 2008

Epidermal growth factor receptor (EGFR) mutations play substantial roles in genesis and proliferation of non‐small‐cell lung cancers (NSCLCs). We recently found that reproductive factors have a substantial impact on risk of development of NSCLCs featuring such EGFR mutations. Therefore, we explored the influence of dietary habits on NSCLC risk with reference to the EGFR mutational status. We conducted a case‐control study using 353 patients with NSCLCs (122 EGFR mutated and 231 EGFR wild‐type) and 1765 age‐sex matched non‐cancer control subjects. Dietary exposure was based on a semiquantitative food frequency questionnaire and impact of major food items, like meats, seafoods, vegetables and soybean products was assessed by multivariate logistic regression. Soybean products demonstrated a protective association with EGFR mutated, but not EGFR wild‐type NSCLCs, with multivariate‐adjusted odds ratios and 95% confidence intervals for the 2nd and 3rd tertile of soybean product consumption of 0.79 (0.50–1.27) and 0.56 (0.34–0.93) relative to those in the lowest tertile (trend P = 0.023). In conclusion, soy consumption may exert a protective association against the development of NSCLCs with EGFR mutations, providing possible insights into mechanisms of their genesis. (Cancer Sci 2008; 99: 1202–1208)
Do ridge–ridge–fault triple junctions exist on Earth? Evidence from the Aden–Owen–Carlsberg junction in the NW Indian Ocean
Authors: Fournier M. , Petit C. , Chamot‐Rooke N. , Fabbri O. , Huchon P. , Maillot B. , Lepvrier C. 
Published: April 2008

ABSTRACTThe triple junctions predicted to be ridge–ridge–fault (RRF) types on the basis of large‐scale plate motions are the Azores triple junction between the Gloria Fault and the Mid‐Atlantic Ridge, the Juan Fernandez triple junction between the Chile Transform and the East Pacific Rise and the Aden–Owen–Carlsberg (AOC) triple junction between the Owen fracture zone (OFZ) and the Carlsberg and Sheba ridges. In the first two cases, the expected RRF triple junction does not exist because the transform fault arm of the triple junction has evolved into a divergent boundary before connecting to the ridges. Here, we report the results of a marine geophysical survey of the AOC triple junction, which took place in 2006 aboard theR/V Beautemps‐Beaupré. We show that a rift basin currently forms at the southern end of the OFZ, indicating that a divergent plate boundary between Arabia and India is developing at the triple junction. The connection of this boundary with the Carlsberg and Sheba ridges is not clearly delineated and the triple junction presently corresponds to a widespread zone of distributed deformation. The AOC triple junction appears to be in a transient stage between a former triple junction of the ridge–fault–fault type and a future triple junction of the ridge–ridge–ridge (RRR) type. Consequently, the known three examples of potential RRF triple junctions are actually of the RRR type, and RRF triple junctions do not presently exist on Earth.
The association of adiponectin allele 45T/G and −11377C/G polymorphisms with Type 2 diabetes and rosiglitazone response in Chinese patients
Authors: Sun Hong , Gong Zhi‐Cheng , Yin Ji‐Ye , Liu Hai‐Ling , Liu Ying‐Zi , Guo Zhi‐Wei , Zhou Hong‐Hao , Wu Jing , Liu Zhao‐Qian 
Published: April 2008

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Rosiglitazone is able to increase serum adiponectin levels significantly in Type 2 diabetic patients.• The role of genetic factors that determine the marked interindividual variability in glucose‐lowering efficacy of rosiglitazone in Chinese patients is not known.• The current study was designed to evaluate the impact of the adiponectin common allele 45T/G and −11377C/G polymorphisms on the response to rosiglitazone monotherapy in Chinese patients with Type 2 diabetes (T2D). WHAT THIS STUDY ADDS • The genetic polymorphisms of adiponectin alleles 45T/G and −11377C/G as well as their common diplotypes are significantly associated with an attenuated fasting plasma glucose, postprandial plasma glucose and homeostasis model assessment for insulin resistance as well as an enhanced adiponectin concentration in Chinese patients with T2D after rosiglitazone treatment.AIMS The aim of the present study was to evaluate the impact of adiponectin allele T45G and C‐11377G genetic polymorphisms on efficacy of rosiglitazone in Chinese patients with type 2 diabetes (T2D).METHODS Patients with T2D (n = 255) and 120 healthy volunteers were enrolled to identify 45T/G and –11377C/G genotypes by polymerase chain reaction‐restriction fragment length polymorphism assay. Forty‐two T2D patients with different 45T/G or –11377C/G genotypes received orally rosiglitazone as a single‐dose therapy (4 mg day‐1 p.o.) for 12 weeks. Serum triglyceride, fasting plasma glucose (FPG), postprandial plasma glucose (PPG), glycated hemoglobin, fasting serum insulin, postprandial serum insulin, total cholesterol, homeostasis model assessment for insulin resistance (HOMA‐IR), low‐density lipoprotein‐cholesterol, high‐density lipoprotein‐cholesterol (HDL‐c) and adiponectin concentration were determined before and after rosiglitazone treatment.RESULTS We showed an attenuated rosiglitazone effect in patients with –11377CG+GG heterozygote genotype on FPG, PPG, HOMA‐IR compared with –11377CC homozygote genotype. However, we found an enhanced rosiglitazone effect on serum adiponectin concentration in patients with –11377CC homozygote genotype compared with –11377CG+GG heterozygote genotype (P = 0.000) and in patients with 45TG + GG heterozygote genotype compared with 45TT homozygote genotype (P = 0.018). Finally, our results showed that there was an enhanced effect in patients with –11377/45 CGTT diplotype compared with other discovered diplotypes on FPG (P = 0.001) and PPG (P = 0.003) after rosiglitazone treatment.CONCLUSIONS These data suggest that the adiponectin allele 45T/G and –11377C/G polymorphisms are significantly associated with the therapeutic efficacy of multiple‐dose rosiglitazone in Chinese patients with T2D.
Use of erythropoiesis stimulating agents and intravenous iron for cancer and treatment‐related anaemia: the need for predictors and indicators of effectiveness has not abated
Authors: Katodritou Eirini , Zervas Konstantinos , Terpos Evangelos , Brugnara Carlo 
Published: April 2008

SummaryCancer and treatment‐related anaemia is a significant clinical problem. Erythropoiesis stimulating agents (ESA) improve anaemia and ultimately enhance patients’ quality of life. However, about one‐third of patients do not respond to ESA administration, mostly because of the impaired supply of iron to the erythroid marrow (functional iron deficiency). Concomitant administration of intravenous (IV) iron may improve responsiveness. The use of baseline predictors of response to ESA and of indicators of appropriateness of response and iron availability should allow targeted therapeutic interventions with both ESA and IV iron. Several biochemical and haematological indicators of response and of iron balance have been studied, but firm criteria for their use have not yet been rigorously established. The commonly used early predictive markers of response to ESA, such as baseline endogenous erythropoietin levels and an increase in haemoglobin, reticulocytes, and soluble transferrin receptor levels during ESA treatment, have not proved reliable due to their low sensitivity and specificity. Traditional markers of iron availability, such as serum ferritin and transferrin saturation display interpretation pitfalls. The need for predictors and indicators of responsiveness to ESA and IV iron is still current and clinically relevant.
Cardiac and cardiovascular consequences after haematopoietic stem cell transplantation
Authors: Tichelli André , Bhatia Smita , Socié Gérard 
Published: April 2008

SummaryHaematopoietic stem cell transplantation (HCT) is the treatment of choice for defined malignant and non‐malignant haematological disorders. The main drawbacks of HCT are early transplant‐related mortality and late complications, which interfere with patient outcome, health status and quality of life. In comparison with other post‐transplant complications, cardiac or cardiovascular consequences seem to occur at a much lower frequency. Early complications are usually associated with patient history before transplantation, primary diagnosis, age of the patient and associated comorbidities, and the type of transplantation and conditioning used. Late cardiac and cardiovascular events may occur years and even decades after HCT, and are related to cardiotoxic chemotherapy, mediastinal radiation therapy, gender, age at transplantation, cardiovascular risk factors and graft‐versus‐host disease in allogeneic HCT. As has been observed in long‐term survivors of Hodgkin lymphoma, where the incidence of cardiovascular complications emerged as a significant problem with increasing follow‐up, it is anticipated that the incidence of these complications after HCT will also increase significantly with increasing follow‐up of the survivors. This review presents the available data on early and late cardiac and cardiovascular consequences after HCT, and presents recommendations for cardiac assessment and management of these complications.
Response of native parasitoids to a range‐expanding host
Authors: CHRIS GRÖBLER B. , LEWIS OWEN T. 
Published: April 2008

Abstract1. As species shift their geographic distributions, new feeding interactions with natural enemies such as parasitoids, and resources such as host plants, may be established, and existing interactions may be severed.2. The leaf mining mothPhyllonorycter leucographella(Zeller, 1850) (Lep.: Gracillariidae) first colonised the southern United Kingdom in the mid 1980s associated with its ancestral host plantPyracantha coccineaM. Roem. (Rosaceae), which is widely cultivated in the U.K. The moth has since spread northwards to central Scotland and has been recorded feeding on a novel host plant,Crataegus monogynaL.3. The combined effects of latitude and time since colonisation on parasitoid community responses to the arrival of this novel host were investigated across its U.K. range. The response of parasitoids to colonisation ofC. monogynawas also investigated.4. Both the observed richness of parasitoid species associated withP. leucographella, and the proportion ofP. leucographellaparasitised declined with latitude and towards the current range margin. A combination of a latitudinal gradient in parasitoid and alternative host species richness is likely to lead to the trends in species richness and parasitism observed.5. Experimental host patches exposed to parasitism beyond the current range margin ofP. leucographellaexperienced low levels of parasitism consistent with range‐margin populations, indicating an instantaneous response by native parasitoids to availability of the novel host. Parasitism levels and numbers of associated species in the U.K. were similar to those observed in the species’ native range in Turkey.6. The host plant switch toC. monogynawas not associated with an altered parasitoid assemblage, but rates of parasitism were significantly higher on the novel host plant.7. Alterations in the incidence and frequency of victim‐enemy interactions as species shift their geographic ranges may be key in determining rates of range expansion and the impact invading species have on ecological communities.