bluuebunny/crossref_metadata_2025_split huggingface dataset:
Projetos de Prefácios de As Flores do Mal, de Charles Baudelaire
Authors: Baudelaire Charles , Paixão Grace Alves da 
Published: December 2013

RESUMO: O trabalho consiste na tradução dos quatro projetos de prefácios que Baudelaire escreveu para As Flores do Mal, cujos rascunhos foram publicados apenas postumamente. PALAVRAS-CHAVE: Charles Baudelaire, As Flores do Mal, Crítica literária, Poesia, Tradução.
Finda a língua, fim da linha
Authors: Souza Jr. Paulo Sérgio de 
Published: December 2013

A obra de Vladímir Maiakóvski, entremeada de grandezas e engrandecida ao longo das décadas por seu poder de comoção social, apresenta um ponto-cego que, acreditamos, não pode ser deixado de lado — embora tenha sido em grande parte ignorado, em prol da imagem de força e bravura que interessaram, sobretudo, ao Regime. Assim, palavras como ‘futuro’ e ‘quotidiano’ — que, em sua obra, têm a força de conceitos —, quando levadas a sério, permitem que depreendamos a forte e ambígua relação do poeta com a necessidade de rompimento com a tradição, da qual, para ele, dependiam tanto a política quanto o amor, além da própria poesia. Trabalhar com essa dimensão de sua obra é procurar, atrás do mito criado por um governo, a dimensão de uma escrita que se ateve à tentativa de fugir da mera repetição do passado, encontrando nessa busca os seus limites.
Helicobacter pylori and mucosa-associated lymphoid tissue: what's new
Authors: Kuo Sung-Hsin , Cheng Ann-Lii 
Published: December 2013

AbstractLow-grade mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach, gastric MALT lymphoma, is associated with Helicobacter pylori infection. The eradication of H pylori using antibiotics is successful in 60% to 80% of affected patients. In contrast to the previous paradigm, we and other investigators have shown that a certain proportion of patients with H pylori–positive early-stage diffuse large B-cell lymphoma (DLBCL) of the stomach with histological evidence of MALT lymphoma, including high-grade transformed gastric MALT lymphoma and gastric DLBCL(MALT), achieved long-term complete pathological remission (pCR) after first-line H pylori eradication therapy, indicating that the loss of H pylori dependence and high-grade transformation are separate events in the progression of gastric lymphoma. In addition, patients with H pylori–positive gastric DLBCL without histological evidence of MALT (gastric pure DLBCL) may also respond to H pylori eradication therapy. A long-term follow-up study showed that patients who achieved pCR remained lymphoma free. Gastric MALT lymphoma is indirectly influenced by H pylori infection through T-cell stimulation, and recent studies have shown that H pylori–triggering chemokines and their receptors, H pylori–associated epigenetic changes, H pylori–regulated miRNA expression, and tumor infiltration by CD4+CD25+ regulatory T cells contribute to lymphomagenesis of gastric MALT lymphoma. Recent studies have also demonstrated that the translocation of CagA into B lymphocytes inhibits apoptosis through p53 accumulation, BAD phosphorylation, and the up-regulation of Bcl-2 and Bcl-XL expression. In gastric MALT lymphoma, CagA may stimulate lymphomagenesis directly, through the regulation of signal transduction, and intracellular CagA is associated with H pylori dependence. These findings represent a substantial paradigm shift compared with the classical theory of H pylori–reactive T cells contributing indirectly to the development of MALT lymphoma. In conclusion, a wide range of H pylori–related gastric lymphomas have been identified. The use of antibiotics as the sole first-line therapy for early-stage gastric pure DLBCL requires validation in a prospective study. The clinical and biological significance of the CagA oncoprotein in the lymphomagenesis of gastric MALT lymphoma warrants further study.
Treatment of older patients with chronic lymphocytic leukemia: key questions and current answers
Authors: Shanafelt Tait 
Published: December 2013

AbstractDespite the advanced age at onset, chronic lymphocytic leukemia (CLL) shortens the life expectancy of the majority of newly diagnosed patients. The management of elderly patients with CLL is more complex than that of younger patients due to the greater frequency of comorbidities and functional impairment as well as reduced organ function. Many of the recent advances in the care of CLL patients (prognostication, more intense combination therapy regimens) are of unclear relevance for elderly patients. This review addresses 5 key questions in the management of elderly patients with CLL: (1) why is classifying the “fitness” of CLL patients necessary; (2) what criteria should be used to classify patient fitness; (3) when should elderly patients be treated; (4) how should therapy be selected for elderly patients; and (5) which therapy is best (for this patient)?
Alternative approaches to eradicating the malignant clone in chronic myeloid leukemia: tyrosine-kinase inhibitor combinations and beyond
Authors: Ahmed Wesam , Van Etten Richard A. 
Published: December 2013

AbstractIn patients with chronic myeloid leukemia (CML) in chronic phase who have achieved complete molecular remission on imatinib therapy, clinical trials from France and Australia have demonstrated that the majority experience prompt molecular relapse of their leukemia upon discontinuation of the drug, showing that long-term monotherapy with tyrosine kinase inhibitors is not curative in the majority of patients with CML. This has focused attention on strategies to eradicate residual disease in CML that is presumed to arise from malignant Ph+ stem cells, which should result in permanent cure and long-term leukemia-free survival. Here, we review the evidence that targeting CML stem cells will be of clinical benefit and discuss pharmacological and immunological approaches to accomplish this goal. Where possible, we link preclinical studies of CML stem cell biology to emerging results from clinical trials of agents that may target these cells.
von Willebrand disease: advances in pathogenetic understanding, diagnosis, and therapy
Authors: Lillicrap David 
Published: December 2013

Abstract
von Willebrand disease (VWD) is the most common autosomally inherited bleeding disorder. The disease represents a range of quantitative and qualitative pathologies of the adhesive glycoprotein von Willebrand factor (VWF). The pathogenic mechanisms responsible for the type 2 qualitative variants of VWF are now well characterized, with most mutations representing missense substitutions influencing VWF multimer structure and interactions with platelet GPIbα and collagen and with factor VIII. The molecular pathology of type 3 VWD has been similarly well characterized, with an array of different mutation types producing either a null phenotype or the production of VWF that is not secreted. In contrast, the pathogenetic mechanisms responsible for type 1 VWD remain only partially resolved. In the hemostasis laboratory, the measurement of VWF:Ag and VWF:RCo are key components in the diagnostic algorithm for VWD, although the introduction of direct GPIbα-binding assays may become the functional assay of choice. Molecular genetic testing can provide additional benefit, but its utility is currently limited to type 2 and 3 VWD. The treatment of bleeding in VWD involves the use of desmopressin and plasma-derived VWF concentrates and a variety of adjunctive agents. Finally, a new recombinant VWF concentrate has just completed clinical trial evaluation and has demonstrated excellent hemostatic efficacy and safety.
Molecular approaches for improved clotting factors for hemophilia
Authors: Kaufman Randal J. , Powell Jerry S. 
Published: December 2013

AbstractHemophilia is caused by a functional deficiency of one of the coagulation proteins. Therapy for no other group of genetic diseases has seen the progress that has been made for hemophilia over the past 40 years, from a life expectancy in 1970 of ∼ 20 years for a boy born with severe hemophilia to essentially a normal life expectancy in 2013 with current prophylaxis therapy. However, these therapies are expensive and require IV infusions 3 to 4 times each week. These are exciting times for hemophilia because several new technologies that promise extended half-lives for factor products, with potential for improvements in quality of life for persons with hemophilia, are in late-phase clinical development.
How should we treat newly diagnosed multiple myeloma patients?
Authors: Mateos María-Victoria , San Miguel Jesús F. 
Published: December 2013

AbstractMultiple myeloma (MM) is the second most frequent hematological disease. Two-thirds of newly diagnosed MM patients are more than 65 years of age. Elsewhere in this issue, McCarthy et al discuss the treatment of transplantation candidates; this chapter focuses on the data available concerning therapy for non-transplantation-eligible MM patients. Treatment goals for these non-transplantation-eligible patients should be to prolong survival by achieving the best possible response while ensuring quality of life. Until recently, treatment options were limited to alkylators, but new up-front treatment combinations based on novel agents (proteasome inhibitors and immunomodulatory drugs) plus alkylating agents have significantly improved outcomes. Other nonalkylator induction regimens are also available and provide a novel backbone that may be combined with novel second- and third-generation drugs. Phase 3 data indicate that maintenance therapy or prolonged treatment in elderly patients also improves the quality and duration of clinical responses, extending time to progression and progression-free survival; however, the optimal scheme, appropriate doses, and duration of long-term therapy have not yet been fully determined. The potential for novel treatment regimens to improve the adverse prognosis associated with high-risk cytogenetic profiles also requires further research. In summary, although we have probably doubled the survival of elderly patients, this group requires close monitoring and individualized, dose-modified regimens to improve tolerability and treatment efficacy while maintaining their quality of life.
Prognostic models in myelodysplastic syndromes
Authors: Bejar Rafael 
Published: December 2013

Abstract
Establishing the prognosis for patients with myelodysplastic syndromes (MDS) is a key element of their care. It helps patients understand the severity of their disease and set expectations for their future. For physicians, an accurate estimate of prognosis drives decisions about the timing and choice of therapeutic options to consider. The International Prognostic Scoring System (IPSS) has been the standard tool for MDS risk stratification since it was released in 1997. It has been used to describe patients in pivotal clinical trials and is a key element of practice guidelines. Subsequent changes to the classification scheme for MDS and an underestimation of risk in some patients from the low and intermediate-1 categories have led to the development of several newer prognostic models. The most recent is the revised IPSS (IPSS-R), which addresses several of the perceived deficiencies of its predecessor. Despite their utility, none of the available prognostic systems incorporates disease-related molecular abnormalities such as somatic mutations. These lesions are present in the nearly all cases and many have been shown to improve upon existing prognostic models. However, the interpretation of somatic mutations can be challenging and it is not yet clear how best to combine them with clinical predictors of outcome. Here I review several prognostic scoring systems developed after the IPSS and describe the emerging use of molecular markers to refine risk stratification in the MDS patient population.
Who benefits from allogeneic transplantation for myelodysplastic syndromes?: new insights
Authors: Platzbecker Uwe 
Published: December 2013

Abstract
Recently, a refined cytogenetic and molecular classification fundamentally changed the prognostication of patients with myelodysplastic syndromes (MDS). The increasingly complex heterogeneity of this disease entity is mirrored by life expectancy rates ranging from almost a decade for very low-risk disease down to several months in higher-risk patients, even with conventional treatments. Intensive treatment approaches are hampered by the older age of most of the patients, potentially leading to an unacceptable adverse event rate. This is especially true for allogeneic hematopoietic stem cell transplantation (HCT), which, albeit of curative intent, can lead to considerable morbidity and mortality mostly as a result of organ toxicity, infectious complications, and GVHD. Furthermore, innovative drug developments, including hypomethylating agents, have broadened the therapeutic armamentarium and, although not curative, can lead to durable responses in subgroups of patients with higher-risk MDS. In fact, there is still no prospective randomized trial available that formally demonstrates the benefit of allogeneic HCT compared with standard treatments in MDS patients. In the absence of randomized data, when considering allogeneic HCT, emphasis should be put on patient selection and optimization of the pre- and posttransplantation treatment period. In these patients, a thorough comorbidity evaluation is mandatory and stratification according to age, cytogenetics, cytopenias, disease-related quality of life, and available alternative treatments should be performed in deciding whether, when, and how to perform allogeneic HCT.
Transplantation for mantle cell lymphoma: is it the right thing to do?
Authors: Williams Michael E. 
Published: December 2013

AbstractMantle cell lymphoma (MCL) is a unique subtype of non-Hodgkin lymphoma that is both biologically and clinically heterogeneous. A variety of biomarkers, the achievement of minimal residual disease negativity after initial therapy, and the MCL International Prognostic Index (MIPI) are associated with patient outcome, although none has as yet been used for routine treatment stratification. Given the lack of widely accepted and standardized treatment approaches, clinical trial enrollment should always be considered for the initial therapy of MCL. Outside of the trial setting, younger and transplantation-eligible patients with newly diagnosed MCL who require treatment should first be considered for a rituximab + a high-dose cytarabine–containing regimen, followed by autologous stem cell transplantation consolidation in first remission. Symptomatic elderly and nontransplantation-eligible individuals typically receive rituximab + bendamustine, or R-CHOP (rituximab + cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone/prednisolone) followed by maintenance rituximab, the latter a treatment plan that has demonstrated extended response duration and survival. Promising early results for consolidation approaches with proteasome inhibitors and immunomodulatory drugs are now being tested in randomized clinical trials. The availability of highly active BCR signaling pathway inhibitors and cell death pathway modulation via BH3 mimetics, among other novel agents, promise to rapidly expand treatment options, change existing treatment paradigms, and further improve outcomes for MCL patients.
Treatment strategies for aggressive lymphomas: what works?
Authors: Wilson Wyndham H. 
Published: December 2013

Abstract
Over the past 30 years, many treatment platforms have been developed for diffuse large B-cell lymphoma, but none proved better than CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone/prednisolone). In the immunochemotherapy era, however, there is convincing evidence for superior chemotherapy platforms. A randomized study from the Groupe d'Etude des Lymphomes de l'Adulte showed that R-ACVBP (rituximab plus doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone) was superior to rituximab plus CHOP (R-CHOP) in patients under 60 years of age, but toxicity limits its use to younger patients. Studies also suggest that DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab) is more effective in some subtypes of diffuse large B-cell lymphoma and a randomized comparison with R-CHOP is now nearing completion. The simplicity and safety of R-CHOP and the long history of failed contenders, however, has set a high bar for new approaches.
Sickle cell trait testing and athletic participation: a solution in search of a problem?
Authors: Thompson Alexis A. 
Published: December 2013

AbstractCarriers of a single sickle cell gene mutation generally enjoy normal lifespans without serious health consequences related to their sickle cell status, but under extreme conditions such as severe dehydration and high-intensity physical activity, complications such as exertional rhabdomyolysis, splenic infarction, and papillary necrosis can occur. Recently, the National Collegiate Athletic Association (NCAA) adopted a policy that requires sickle cell solubility testing for all incoming student athletes. However, the American Society of Hematology (ASH) and other physician organizations oppose this policy. What is the basis for this controversy and how have new findings moved the field forward? I discuss herein the epidemiology, genetics, and clinical studies of sickle cell trait; review the implications of current policies regarding sickle cell trait screening and interventions for the student athlete; and examine additional areas where more information is needed.
Allogeneic BM transplantation for the treatment of aplastic anemia: current results and expanding donor possibilities
Authors: Socié Gérard 
Published: December 2013

Abstract
Allogeneic BM transplantation from an HLA-identical sibling donor leads to long-term survival in the majority of patients (> 80%). Therefore, survival is no longer the sole concern and attention has to be paid to decreasing the incidence and severity of long-term complications. For patients without a sibling donor, transplantation from a well-matched unrelated donor can be considered after failure of a previous course of immunosuppressive therapy. After transplantation from an HLA-identical sibling donor or from an unrelated one, the use of peripheral blood stem cells must be strongly discouraged because they have been systematically associated with an increased incidence of chronic GVHD compared with the use of BM as a stem cell source, leading to an unacceptably higher risk of treatment-related mortality in this setting. For as yet unknown reasons, the age limit after which transplantation results are less satisfactory remains 40 years of age.
The mononuclear metal center of type-I dihydroorotase from aquifex aeolicus
Authors: Edwards Brian FP , Fernando Roshini , Martin Philip D , Grimley Edward , Cordes Melissa , Vaishnav Asmita , Brunzelle Joseph S , Evans Hedeel Guy , Evans David R 
Published: December 2013

Abstract

Background
Dihydroorotase (DHO) is a zinc metalloenzyme, although the number of active site zinc ions has been controversial. E. coli DHO was initially thought to have a mononuclear metal center, but the subsequent X-ray structure clearly showed two zinc ions, α and β, at the catalytic site. Aquifex aeolicus DHO, is a dodecamer comprised of six DHO and six aspartate transcarbamoylase (ATC) subunits. The isolated DHO monomer, which lacks catalytic activity, has an intact α-site and conserved β-site ligands, but the geometry of the second metal binding site is completely disrupted. However, the putative β-site is restored when the complex with ATC is formed and DHO activity is regained. Nevertheless, the X-ray structure of the complex revealed a single zinc ion at the active site. The structure of DHO from the pathogenic organism, S. aureus showed that it also has a single active site metal ion.

Results
Zinc analysis showed that the enzyme has one zinc/DHO subunit and the addition of excess metal ion did not stimulate catalytic activity, nor alter the kinetic parameters. The metal free apoenzyme was inactive, but the full activity was restored upon the addition of one equivalent of Zn2+ or Co2+. Moreover, deletion of the β-site by replacing the His180 and His232 with alanine had no effect on catalysis in the presence or absence of excess zinc. The 2.2 Å structure of the double mutant confirmed that the β-site was eliminated but that the active site remained otherwise intact.

Conclusions
Thus, kinetically competent A. aeolicus DHO has a mononuclear metal center. In contrast, elimination of the putative second metal binding site in amidohydrolyases with a binuclear metal center, resulted in the abolition of catalytic activity. The number of active site metal ions may be a consideration in the design of inhibitors that selectively target either the mononuclear or binuclear enzymes.
Automated workflow-based exploitation of pathway databases provides new insights into genetic associations of metabolite profiles
Authors: Dharuri Harish , Henneman Peter , Demirkan Ayse , van Klinken Jan Bert , Mook-Kanamori Dennis Owen , Wang-Sattler Rui , Gieger Christian , Adamski Jerzy , Hettne Kristina , Roos Marco , Suhre Karsten , Van Duijn Cornelia M ,   EUROSPAN consortia, van Dijk Ko Willems , 't Hoen Peter AC 
Published: December 2013

Abstract

Background
Genome-wide association studies (GWAS) have identified many common single nucleotide polymorphisms (SNPs) that associate with clinical phenotypes, but these SNPs usually explain just a small part of the heritability and have relatively modest effect sizes. In contrast, SNPs that associate with metabolite levels generally explain a higher percentage of the genetic variation and demonstrate larger effect sizes. Still, the discovery of SNPs associated with metabolite levels is challenging since testing all metabolites measured in typical metabolomics studies with all SNPs comes with a severe multiple testing penalty. We have developed an automated workflow approach that utilizes prior knowledge of biochemical pathways present in databases like KEGG and BioCyc to generate a smaller SNP set relevant to the metabolite. This paper explores the opportunities and challenges in the analysis of GWAS of metabolomic phenotypes and provides novel insights into the genetic basis of metabolic variation through the re-analysis of published GWAS datasets.

Results
Re-analysis of the published GWAS dataset from Illig et al. (Nature Genetics, 2010) using a pathway-based workflow (http://www.myexperiment.org/packs/319.html), confirmed previously identified hits and identified a new locus of human metabolic individuality, associating Aldehyde dehydrogenase family1 L1 (ALDH1L1) with serine/glycine ratios in blood. Replication in an independent GWAS dataset of phospholipids (Demirkan et al., PLoS Genetics, 2012) identified two novel loci supported by additional literature evidence: GPAM (Glycerol-3 phosphate acyltransferase) and CBS (Cystathionine beta-synthase). In addition, the workflow approach provided novel insight into the affected pathways and relevance of some of these gene-metabolite pairs in disease development and progression.

Conclusions
We demonstrate the utility of automated exploitation of background knowledge present in pathway databases for the analysis of GWAS datasets of metabolomic phenotypes. We report novel loci and potential biochemical mechanisms that contribute to our understanding of the genetic basis of metabolic variation and its relationship to disease development and progression.