bluuebunny/crossref_metadata_2025_split huggingface dataset:
A MAPK/HNRPK pathway controls BCR/ABL oncogenic potential by regulating MYC mRNA translation
Authors: Notari Mario , Neviani Paolo , Santhanam Ramasamy , Blaser Bradley W. , Chang Ji-Suk , Galietta Annamaria , Willis Anne E. , Roy Denis C. , Caligiuri Michael A. , Marcucci Guido , Perrotti Danilo 
Published: November 2005

AbstractAltered mRNA translation is one of the effects exerted by the BCR/ABL oncoprotein in the blast crisis phase of chronic myelogenous leukemia (CML). Here, we report that in BCR/ABL+ cell lines and in patient-derived CML blast crisis mononuclear and CD34+ cells, p210BCR/ABL increases expression and activity of the transcriptional-inducer and translational-regulator heterogeneous nuclear ribonucleoprotein K (hnRNP K or HNRPK) in a dose- and kinase-dependent manner through the activation of the MAPKERK1/2 pathway. Furthermore, HNRPK down-regulation and interference with HNRPK translation-but not transcription-regulatory activity impairs cytokine-independent proliferation, clonogenic potential, and in vivo leukemogenic activity of BCR/ABL-expressing myeloid 32Dcl3 and/or primary CD34+ CML-BC patient cells. Mechanistically, we demonstrate that decreased internal ribosome entry site (IRES)-dependent Myc mRNA translation accounts for the phenotypic changes induced by inhibition of the BCR/ABL-ERK-dependent HNRPK translation-regulatory function. Accordingly, MYC protein but not mRNA levels are increased in the CD34+ fraction of patients with CML in accelerated and blastic phase but not in chronic phase CML patients and in the CD34+ fraction of marrow cells from healthy donors. Thus, BCR/ABL-dependent enhancement of HNRPK translation-regulation is important for BCR/ABL leukemogenesis and, perhaps, it might contribute to blast crisis transformation. (Blood. 2006;107:2507-2516)
Siglec-H is an IPC-specific receptor that modulates type I IFN secretion through DAP12
Authors: Blasius Amanda L. , Cella Marina , Maldonado Jorge , Takai Toshiyuki , Colonna Marco 
Published: November 2005

Abstract
Natural interferon (IFN)-producing cells are the primary cell type responsible for production of type I IFN in response to viruses. Herein we report the identification of the first molecular marker of mouse natural interferon-producing cells (IPCs), a novel member of the sialic acid-binding immunoglobulin (Ig)-like lectin (Siglec) family termed Siglec-H. Siglec-H is expressed exclusively on IPCs and is unique among Siglec proteins in that it associates with the adaptor protein DAP12. Moreover, we show that DAP12 modulates the type I IFN response of IPCs to a Toll-like receptor 9 (TLR9) agonist. This observation explains our previous finding that stimulation of IPCs with 440c, a Siglec-H-specific antibody, reduces IPC secretion of type I IFN. Moreover, it supports a model in which engagement of DNAX-activation protein 12 (DAP12)-associated receptors with antibodies or low avidity endogenous ligands interferes with TLR-mediated cellular activation. (Blood. 2006;107:2474-2476)
A stepwise framework for the normalization of array CGH data
Authors: Khojasteh Mehrnoush , Lam Wan L , Ward Rabab K , MacAulay Calum 
Published: November 2005

Abstract
Background
In two-channel competitive genomic hybridization microarray experiments, the ratio of the two fluorescent signal intensities at each spot on the microarray is commonly used to infer the relative amounts of the test and reference sample DNA levels. This ratio may be influenced by systematic measurement effects from non-biological sources that can introduce biases in the estimated ratios. These biases should be removed before drawing conclusions about the relative levels of DNA. The performance of existing gene expression microarray normalization strategies has not been evaluated for removing systematic biases encountered in array-based comparative genomic hybridization (CGH), which aims to detect single copy gains and losses typically in samples with heterogeneous cell populations resulting in only slight shifts in signal ratios. The purpose of this work is to establish a framework for correcting the systematic sources of variation in high density CGH array images, while maintaining the true biological variations.

Results
After an investigation of the systematic variations in the data from two array CGH platforms, SMRT (Sub Mega base Resolution Tiling) BAC arrays and cDNA arrays of Pollack et al., we have developed a stepwise normalization framework integrating novel and existing normalization methods in order to reduce intensity, spatial, plate and background biases. We used stringent measures to quantify the performance of this stepwise normalization using data derived from 5 sets of experiments representing self-self hybridizations, replicated experiments, detection of single copy changes, array CGH experiments which mimic cell population heterogeneity, and array CGH experiments simulating different levels of gene amplifications and deletions. Our results demonstrate that the three-step normalization procedure provides significant improvement in the sensitivity of detection of single copy changes compared to conventional single step normalization approaches in both SMRT BAC array and cDNA array platforms.

Conclusion
The proposed stepwise normalization framework preserves the minute copy number changes while removing the observed systematic biases.
An acquisition account of genomic islands based on genome signature comparisons
Authors: van Passel MWJ , Bart A , Thygesen HH , Luyf ACM , van Kampen AHC , van der Ende A 
Published: November 2005

Abstract

Background
Recent analyses of prokaryotic genome sequences have demonstrated the important force horizontal gene transfer constitutes in genome evolution. Horizontally acquired sequences are detectable by, among others, their dinucleotide composition (genome signature) dissimilarity with the host genome. Genomic islands (GIs) comprise important and interesting horizontally transferred sequences, but information about acquisition events or relatedness between GIs is scarce. In Vibrio vulnificus CMCP6, 10 and 11 GIs have previously been identified in the sequenced chromosomes I and II, respectively. We assessed the compositional similarity and putative acquisition account of these GIs using the genome signature. For this analysis we developed a new algorithm, available as a web application.

Results
Of 21 GIs, VvI-1 and VvI-10 of chromosome I have similar genome signatures, and while artificially divided due to a linear annotation, they are adjacent on the circular chromosome and therefore comprise one GI. Similarly, GIs VvI-3 and VvI-4 of chromosome I together with the region between these two islands are compositionally similar, suggesting that they form one GI (making a total of 19 GIs in chromosome I + chromosome II). Cluster analysis assigned the 19 GIs to 11 different branches above our conservative threshold. This suggests a limited number of compositionally similar donors or intragenomic dispersion of ancestral acquisitions. Furthermore, 2 GIs of chromosome II cluster with chromosome I, while none of the 19 GIs group with chromosome II, suggesting an unidirectional dispersal of large anomalous gene clusters from chromosome I to chromosome II.

Conclusion
From the results, we infer 10 compositionally dissimilar donors for 19 GIs in the V. vulnificus CMCP6 genome, including chromosome I donating to chromosome II. This suggests multiple transfer events from individual donor types or from donors with similar genome signatures. Applied to other prokaryotes, this approach may elucidate the acquisition account in their genome sequences, and facilitate donor identification of GIs.
Efficacy of sulfadoxine-pyrimethamine in Tanzania after two years as first-line drug for uncomplicated malaria: assessment protocol and implication for treatment policy strategies
Authors: Mugittu Kefas , Abdulla Salim , Falk Nicole , Masanja Honorati , Felger Ingrid , Mshinda Hassan , Beck Hans-Peter , Genton Blaise 
Published: November 2005

Abstract

Background
Systematic surveillance for resistant malaria shows high level of resistance of Plasmodium falciparum to sulfadoxine-pyrimethamine (SP) across eastern and southern parts of Africa. This study assessed in vivo SP efficacy after two years of use as an interim first-line drug in Tanzania, and determined the rates of treatment failures obtained after 14 and 28 days of follow-up.

Methods
The study was conducted in the Ipinda, Mlimba and Mkuranga health facilities in Tanzania. Children aged 6–59 months presenting with raised temperature associated exclusively with P. falciparum (1,000–100,000 parasites per μl) were treated with standard dose of SP. Treatment responses were classified according to the World Health Organization (WHO) definition as Adequate Clinical and Parasitological Response (ACPR), Early Treatment Failure (ETF), Late Clinical Failure (LCF) and Late Parasitological Failure (LPF) on day 14 and day 28.

Results
Overall 196 (85.2%) of 230 patients had ACPR on day 14 but only 116 (50.9%) on day 28 (57.7% after excluding new infections by parasite genotyping). Altogether 21 (9.1%) and 13 (5.7%) of the 230 patients assessed up to day 14 and 39 (17.1%) and 55 (24.1%) of the 228 followed up to day 28 had clinical and parasitological failure, respectively.

Conclusion
These findings indicate that SP has low therapeutic value in Tanzania. The recommendation of changing first line treatment to artemether + lumefantrine combination therapy from early next year is, therefore, highly justified. These findings further stress that, for long half-life drugs such as SP, establishment of cut-off points for policy change in high transmission areas should consider both clinical and parasitological responses beyond day 14.
Protein-protein interactions of the hyperthermophilic archaeon Pyrococcus horikoshiiOT3
Authors: Usui Kengo , Katayama Shintaro , Kanamori-Katayama Mutsumi , Ogawa Chihiro , Kai Chikatoshi , Okada Makiko , Kawai Jun , Arakawa Takahiro , Carninci Piero , Itoh Masayoshi , Takio Koji , Miyano Masashi , Kidoaki Satoru , Matsuda Takehisa , Hayashizaki Yoshihide , Suzuki Harukazu 
Published: November 2005

Abstract
Background
Although 2,061 proteins of Pyrococcus horikoshii OT3, a hyperthermophilic archaeon, have been predicted from the recently completed genome sequence, the majority of proteins show no similarity to those from other organisms and are thus hypothetical proteins of unknown function. Because most proteins operate as parts of complexes to regulate biological processes, we systematically analyzed protein-protein interactions in Pyrococcus using the mammalian two-hybrid system to determine the function of the hypothetical proteins.

Results
We examined 960 soluble proteins from Pyrococcus and selected 107 interactions based on luciferase reporter activity, which was then evaluated using a computational approach to assess the reliability of the interactions. We also analyzed the expression of the assay samples by western blot, and a few interactions by in vitro pull-down assays. We identified 11 hetero-interactions that we considered to be located at the same operon, as observed in Helicobacter pylori. We annotated and classified proteins in the selected interactions according to their orthologous proteins. Many enzyme proteins showed self-interactions, similar to those seen in other organisms.

Conclusion
We found 13 unannotated proteins that interacted with annotated proteins; this information is useful for predicting the functions of the hypothetical Pyrococcus proteins from the annotations of their interacting partners. Among the heterogeneous interactions, proteins were more likely to interact with proteins within the same ortholog class than with proteins of different classes. The analysis described here can provide global insights into the biological features of the protein-protein interactions in P. horikoshii.
Phase I/IIa Study of Cetuximab With Gemcitabine Plus Carboplatin in Patients With Chemotherapy-Naïve Advanced Non–Small-Cell Lung Cancer
Authors: Robert Francisco , Blumenschein George , Herbst Roy S. , Fossella Frank V. , Tseng Jennifer , Saleh Mansoor N. , Needle Michael 
Published: November 2005

PurposeThis multicenter, open-label, phase I/IIa study was undertaken to establish the safety/toxicity profile of cetuximab in combination with gemcitabine and carboplatin in patients with chemotherapy-naïve, epidermal growth factor receptor–positive, stage IV non–small-cell lung cancer. Secondary objectives were to gather preliminary evidence of efficacy including tumor response rate, time to progression, and overall survival.Patients and MethodsThirty-five patients received a total of 264 3-week cycles of treatment with cetuximab, carboplatin, and gemcitabine. An initial dose of cetuximab 400 mg/m2intravenously was administered the first week, followed by weekly doses of 250 mg/m2. Carboplatin (area under the curve = 5, day 1) and gemcitabine 1,000 mg/m2on days 1 and 8 were administered every 3 weeks. Patients were evaluated for tumor response after every two cycles of therapy.ResultsThe most frequently reported adverse events related to cetuximab included an acne-like rash (88.6%), dry skin (34.3%), asthenia and skin disorders (31.4%), mucositis/stomatitis (25.7%), fever/chills (20%), and nausea/vomiting (17.1%). The majority of these toxicities were mild to moderate. One patient withdrew from the study because of a grade 3 allergic reaction. Myelosuppression was the most frequently observed toxicity related to chemotherapy. Responses among 35 assessable patients included 10 partial responses (28.6%). Twenty-one patients had stable disease. The median time to progression was 165 days, and the median overall survival was 310 days.ConclusionThe combination of cetuximab, carboplatin, and gemcitabine was well tolerated with an acceptable toxicity profile. Most grade 3 adverse events were attributable to chemotherapy. The response rate and median survival are encouraging and warrant additional investigation.
Mammography, Breast Ultrasound, and Magnetic Resonance Imaging for Surveillance of Women at High Familial Risk for Breast Cancer
Authors: Kuhl Christiane K. , Schrading Simone , Leutner Claudia C. , Morakkabati-Spitz Nuschin , Wardelmann Eva , Fimmers Rolf , Kuhn Walther , Schild Hans H. 
Published: November 2005

Purpose To compare the effectiveness of mammography, breast ultrasound, and magnetic resonance imaging (MRI) for surveillance of women at increased familial risk for breast cancer (lifetime risk of 20% or more). Patients and Methods We conducted a surveillance cohort study of 529 asymptomatic women who, based on their family history and/or mutational analysis, were suspected or proven to carry a breast cancer susceptibility gene (BRCA). A total of 1,542 annual surveillance rounds were completed with a mean follow-up of 5.3 years. Diagnostic accuracies of the three imaging modalities used alone or in different combinations were compared. Results Forty-three breast cancers were identified in the total cohort (34 invasive, nine ductal carcinoma-in-situ). Overall sensitivity of diagnostic imaging was 93% (40 of 43 breast cancers); overall node-positive rate was 16%, and one interval cancer occurred (one of 43 cancers, or 2%). In the analysis by modality, sensitivity was low for mammography (33%) and ultrasound (40%) or the combination of both (49%). MRI offered a significantly higher sensitivity (91%). The sensitivity of mammography in the higher risk groups was 25%, compared with 100% for MRI. Specificity of MRI (97.2%) was equivalent to that of mammography (96.8%). Conclusion Mammography alone, and also mammography combined with breast ultrasound, seems insufficient for early diagnosis of breast cancer in women who are at increased familial risk with or without documented BRCA mutation. If MRI is used for surveillance, diagnosis of intraductal and invasive familial or hereditary cancer is achieved with a significantly higher sensitivity and at a more favorable stage.
Phase II Study of Oxaliplatin for Treatment of Patients With Mucosa-Associated Lymphoid Tissue Lymphoma
Authors: Raderer Markus , Wöhrer Stefan , Bartsch Rupert , Prager Gerald , Drach Johannes , Hejna Michael , Gaiger Alexander , Turetschek Karl , Jaeger Ulrich , Streubel Berthold , Zielinski Christoph C. 
Published: November 2005

Purpose Various chemotherapeutic regimens have been applied for treatment of mucosa-associated lymphoid tissue (MALT) lymphoma, but no standard regimen has been identified to date. In view of the activity of oxaliplatin (L-OHP) in various types of lymphoma, we performed a phase II study to evaluate the activity of L-OHP for treatment of MALT lymphoma. The primary objective of this study was to determine the objective response rate according to WHO standard criteria. Patients and Methods A total of 16 patients with MALT lymphoma of various sites of origin (four of the ocular adnexa, five of the salivary glands, three of the stomach, two of the lung, and one of the colon and the breast) were administered L-OHP at a dose of 130 mg/m2 infused during 2 hours every 3 weeks. Restaging was performed every two cycles; treatment was continued until complete remission (CR) or for a maximum of six cycles in responders. Results Sixty-five cycles were administered (median, four; range, two to six); toxicity consisted of transient sensory neuropathy in eight patients and nausea/emesis WHO grade 2 in two patients, whereas hematologic adverse effects (thrombocytopenia and leukocytopenia grade 2) occurred in only one patient each. Fifteen patients responded to chemotherapy, with nine achieving CR (56%), six (37.5%) achieving partial response, and one achieving stable disease; the median time to response was 4 months (range; 2 to 4 months). Conclusion These data suggest L-OHP is a highly active agent for treatment of MALT lymphoma. However, a longer follow-up is needed to judge whether these remissions are durable.
Patterns of Treatment Failure in Pediatric and Young Adult Patients With Hodgkin's Disease: Local Disease Control With Combined-Modality Therapy
Authors: Krasin Matthew J. , Rai Shesh N. , Kun Larry E. , Merchant Thomas E. , Metzger Monika L. , Kaste Sue C. , Howard Scott C. , Hudson Melissa M. 
Published: November 2005

Purpose Refinement in managing pediatric Hodgkin's disease (HD) requires understanding of factors associated with local treatment failure. This study defines the cumulative incidence (CI) of local failure (LF) and prognostic factors for pediatric patients treated for HD with combined-modality therapy (CMT). Patients and Methods We enrolled 195 patients onto two prospective studies at St Jude Children's Research Hospital between 1990 and 2000. Patients received CMT with chemotherapy (vinblastine, doxorubicin, methotrexate, and prednisone [VAMP]; vinblastine, etoposide, prednisone, and doxorubicin; or VAMP/cyclophosphamide, vincristine, and procarbazine) and involved-field radiation therapy delivered to initial site(s) of disease on the basis of early response. Sites of disease involvement, treatment, and sites of failure were confirmed from the patients' medical record, imaging, and radiotherapy treatment records. We estimated the overall survival, event-free survival, and CI of LF. Results With a median follow-up of 7.6 years, the CI of LF was 10.9% and 11.6% at 5 and 10 years, respectively. Twenty-seven (14%) of 195 patients experienced recurrence of HD, and 22 (81%) of those experienced LF. Bulky mediastinal disease greater than one third transthoracic diameter predicted a higher incidence of LF, but did not predict failure in the mediastinum. Male sex, low initial hemoglobin, and bulky mediastinal disease were prognostic indicators of LF. Attenuation of radiation dose to 15 Gy based on response provides excellent infield control. Conclusion CMT provides excellent local disease control in children and young adults with HD. LF remains a primary site of disease recurrence, with male sex, low initial hemoglobin, and bulky mediastinal disease predicting for LF.
Prognostic Relevance of Response Evaluation Using [18F]-2-Fluoro-2-Deoxy-D-Glucose Positron Emission Tomography in Patients With Locally Advanced Non–Small-Cell Lung Cancer
Authors: Hoekstra Corneline J. , Stroobants Sigrid G. , Smit Egbert F. , Vansteenkiste Johan , van Tinteren Harm , Postmus Pieter E. , Golding Richard P. , Biesma Bonne , Schramel Frans J.H.M. , van Zandwijk Nico , Lammertsma Adriaan A. , Hoekstra Otto S. 
Published: November 2005

Purpose The objective of this study was to determine the accuracy of (early) response measurements using [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography (18FDG PET) with respect to survival of patients with stage IIIA-N2 non–small-cell lung cancer (NSCLC) undergoing induction chemotherapy (IC), with a comparative analysis of PET methods. Patients and Methods In a prospective multicenter study, PET was performed in patients before IC and after one and three cycles. Computed tomography (CT) was performed before and after IC. Glucose consumption (metabolic rate of glucose [MRglu]) was measured using Patlak graphical analysis and correlated with simplified methods. Mediastinal lymph node (MLN) status was assessed visually. Cox proportional hazards analysis was used to determine the prognostic relevance of CT and PET measures of response with respect to survival. Results Complete PET data sets were available in 47 patients. Median survival was 21 months. MLN status after IC by PET predicted survival (hazard ratio [HR], 2.33; 95% CI, 1.04 to 5.22; P = .04) in contrast with CT (HR, 1.87; 95% CI, 0.81 to 4.30; P = .14). Residual MRglu after IC proved to be the best prognostic factor (HR, 1.95; 95% CI, 1.28 to 2.97; P = .002). Multivariate stepwise analysis showed that PET identified prognostically different strata in patients considered responsive according to CT. Residual MRglu after one cycle selected patients with different outcomes (HR, 2.04; 95% CI, 1.18 to 3.52; P = .01). Simplified quantitative 18FDG PET methods were correlated with Patlak graphical analysis during and after therapy (r ≥ 0.90). Conclusion 18FDG PET has additional value over CT in monitoring response to IC in patients with stage IIIA-N2 NSCLC, and it seems feasible to predict survival early during IC. Simple semiquantitative and complex PET methods perform equally well.