bluuebunny/crossref_metadata_2025_split huggingface dataset:
Kruppel-like factor 7 overexpression suppresses hematopoietic stem and progenitor cell function
Authors: Schuettpelz Laura G. , Gopalan Priya K. , Giuste Felipe O. , Romine Molly P. , van Os Ronald , Link Daniel C. 
Published: August 2012

AbstractIncreased expression of Kruppel-like factor 7 (KLF7) is an independent predictor of poor outcome in pediatric acute lymphoblastic leukemia. The contribution of KLF7 to hematopoiesis has not been previously described. Herein, we characterized the effect on murine hematopoiesis of the loss of KLF7 and enforced expression of KLF7. Long-term multilineage engraftment of Klf7−/− cells was comparable with control cells, and self-renewal, as assessed by serial transplantation, was not affected. Enforced expression of KLF7 results in a marked suppression of myeloid progenitor cell growth and a loss of short- and long-term repopulating activity. Interestingly, enforced expression of KLF7, although resulting in multilineage growth suppression that extended to hematopoietic stem cells and common lymphoid progenitors, spared T cells and enhanced the survival of early thymocytes. RNA expression profiling of KLF7-overexpressing hematopoietic progenitors identified several potential target genes mediating these effects. Notably, the known KLF7 target Cdkn1a (p21Cip1/Waf1) was not induced by KLF7, and loss of CDKN1A does not rescue the repopulating defect. These results suggest that KLF7 is not required for normal hematopoietic stem and progenitor function, but increased expression, as seen in a subset of lymphoid leukemia, inhibits myeloid cell proliferation and promotes early thymocyte survival.
Combined treatment with lenalidomide and epoetin alfa in lower-risk patients with myelodysplastic syndrome
Authors: Komrokji Rami S. , Lancet Jeffrey E. , Swern Arlene S. , Chen Nianhang , Paleveda Jennifer , Lush Richard , Saba Hussain I. , List Alan F. 
Published: August 2012

Abstract
The erythropoietic effects of lenalidomide are cytokine dependent, suggesting that the erythroid hematologic improvement (HI-E) rate may be augmented by combined treatment (CT) with recombinant human erythropoietin (rhu-EPO) in myelodysplastic syndrome (MDS). In the present study, we explored the benefits of CT and the relationship between lenalidomide pharmacokinetics and hematologic toxicity in transfusion-dependent patients with low- to intermediate-1–risk MDS who failed prior rhu-EPO. In stage I, patients received 10 or 15 mg/d of lenalidomide monotherapy. At week 16, erythroid nonresponders (NRs) were eligible for CT with rhu-EPO 40 000 U/wk. Among 39 patients, HI-E response rate to monotherapy was 86% (6 of 7) in del(5q) and 25% (8 of 32) in non-del(5q) patients (10 mg, 17.7%; 15 mg, 33.3%). Twenty-three patients proceeded to CT, with 6 (26.0%) achieving HI-E. In 19 non-del(5q) patients, 4 (21.1%) showed HI-E. Mean baseline serum EPO in non-del(5q) patients was lower in monotherapy and CT responders than in NR (not statistically significant). Thrombocytopenia was significantly correlated with lenalidomide area under the plasma concentration-time curve (P = .0015), but severity of myelosuppression did not. The benefits of lenalidomide plus rhu-EPO are currently under investigation in a phase 3 Eastern Cooperative Oncology Group (ECOG)–sponsored intergroup study. This study is registered at www.clinicaltrials.gov as NCT00910858.
HIF-1α is a negative regulator of plasmacytoid DC development in vitro and in vivo
Authors: Weigert Andreas , Weichand Benjamin , Sekar Divya , Sha Weixiao , Hahn Christina , Mora Javier , Ley Stephanie , Essler Silke , Dehne Nathalie , Brüne Bernhard 
Published: August 2012

AbstractHypoxia-inducible factors (HIFs) regulate hematopoiesis in the embryo and maintain hematopoietic stem cell function in the adult. How hypoxia and HIFs contribute to hematopoietic lineage differentiation in the adult is ill defined. Here we provide evidence that HIF-1 limits differentiation of precursors into plasmacytoid dendritic cells (pDCs). Low oxygen up-regulated inhibitor of DNA binding 2 (ID2) and suppressed Flt3-L–induced differentiation of bone marrow cells to pDCs in wild-type but not HIF-1αfl/fl LysM-Cre bone marrow cells. Moreover, pDC differentiated normally in hypoxic ID2−/− bone marrow cultures. Finally, we observed elevated pDC frequencies in bone marrow, blood, and spleen of HIF-1αfl/fl LysM-Cre and ID2−/−, but not HIF-2αfl/fl LysM-Cre mice. Our data indicate that the low oxygen content in the bone marrow might limit pDC development. This might be an environmental mechanism to restrict the numbers of these potentially autoreactive cells.
Formation of a PKCζ/β-catenin complex in endothelial cells promotes angiopoietin-1–induced collective directional migration and angiogenic sprouting
Authors: Oubaha Malika , Lin Michelle I. , Margaron Yoran , Filion Dominic , Price Emily N. , Zon Leonard I. , Côté Jean-François , Gratton Jean-Philippe 
Published: August 2012

Abstract
Angiogenic sprouting requires that cell-cell contacts be maintained during migration of endothelial cells. Angiopoietin-1 (Ang-1) and vascular endothelial growth factor act oppositely on endothelial cell junctions. We found that Ang-1 promotes collective and directional migration and, in contrast to VEGF, induces the formation of a complex formed of atypical protein kinase C (PKC)-ζ and β-catenin at cell-cell junctions and at the leading edge of migrating endothelial cells. This complex brings Par3, Par6, and adherens junction proteins at the front of migrating cells to locally activate Rac1 in response to Ang-1. The colocalization of PKCζ and β-catenin at leading edge along with PKCζ-dependent stabilization of cell-cell contacts promotes directed and collective endothelial cell migration. Consistent with these results, down-regulation of PKCζ in endothelial cells alters Ang-1–induced sprouting in vitro and knockdown in developing zebrafish results in intersegmental vessel defects caused by a perturbed directionality of tip cells and by loss of cell contacts between tip and stalk cells. These results reveal that PKCζ and β-catenin function in a complex at adherens junctions and at the leading edge of migrating endothelial cells to modulate collective and directional migration during angiogenesis.
Transcriptome sequencing in Sézary syndrome identifies Sézary cell and mycosis fungoides-associated lncRNAs and novel transcripts
Authors: Lee Carolyn S. , Ungewickell Alexander , Bhaduri Aparna , Qu Kun , Webster Dan E. , Armstrong Randall , Weng Wen-Kai , Aros Cody J. , Mah Angela , Chen Richard O. , Lin Meihong , Sundram Uma , Chang Howard Y. , Kretz Markus , Kim Youn H. , Khavari Paul A. 
Published: August 2012

AbstractSézary syndrome (SS) is an aggressive cutaneous T-cell lymphoma (CTCL) of unknown etiology in which malignant cells circulate in the peripheral blood. To identify viral elements, gene fusions, and gene expression patterns associated with this lymphoma, flow cytometry was used to obtain matched pure populations of malignant Sézary cells (SCs) versus nonmalignant CD4+ T cells from 3 patients for whole transcriptome, paired-end sequencing with an average depth of 112 million reads per sample. Pathway analysis of differentially expressed genes identified mis-regulation of PI3K/Akt, TGFβ, and NF-κB pathways as well as T-cell receptor signaling. Bioinformatic analysis did not detect either nonhuman transcripts to support a viral etiology of SS or recurrently expressed gene fusions, but it did identify 21 SC-associated annotated long noncoding RNAs (lncRNAs). Transcriptome assembly by multiple algorithms identified 13 differentially expressed unannotated transcripts termed Sézary cell-associated transcripts (SeCATs) that include 12 predicted lncRNAs and a novel transcript with coding potential. High-throughput sequencing targeting the 3′ end of polyadenylated transcripts in archived tumors from 24 additional patients with tumor-stage CTCL confirmed the differential expression of SC-associated lncRNAs and SeCATs in CTCL. Our findings characterize the SS transcriptome and support recent reports that implicate lncRNA dysregulation in human malignancies.
Structural insights into inhibition of the bivalent menin-MLL interaction by small molecules in leukemia
Authors: Shi Aibin , Murai Marcelo J. , He Shihan , Lund George , Hartley Thomas , Purohit Trupta , Reddy Gireesh , Chruszcz Maksymilian , Grembecka Jolanta , Cierpicki Tomasz 
Published: August 2012

Abstract
Menin functions as a critical oncogenic cofactor of mixed lineage leukemia (MLL) fusion proteins in the development of acute leukemias, and inhibition of the menin interaction with MLL fusion proteins represents a very promising strategy to reverse their oncogenic activity. MLL interacts with menin in a bivalent mode involving 2 N-terminal fragments of MLL. In the present study, we reveal the first high-resolution crystal structure of human menin in complex with a small-molecule inhibitor of the menin-MLL interaction, MI-2. The structure shows that the compound binds to the MLL pocket in menin and mimics the key interactions of MLL with menin. Based on the menin–MI-2 structure, we developed MI-2-2, a compound that binds to menin with low nanomolar affinity (Kd = 22nM) and very effectively disrupts the bivalent protein-protein interaction between menin and MLL. MI-2-2 demonstrated specific and very pronounced activity in MLL leukemia cells, including inhibition of cell proliferation, down-regulation of Hoxa9 expression, and differentiation. Our results provide the rational and essential structural basis to design next generation of inhibitors for effective targeting of the menin-MLL interaction in leukemia and demonstrate a proof of concept that inhibition of complex multivalent protein-protein interactions can be achieved by a small-molecule inhibitor.
Kininogen deficiency protects from ischemic neurodegeneration in mice by reducing thrombosis, blood-brain barrier damage, and inflammation
Authors: Langhauser Friederike , Göb Eva , Kraft Peter , Geis Christian , Schmitt Joachim , Brede Marc , Göbel Kerstin , Helluy Xavier , Pham Mirko , Bendszus Martin , Jakob Peter , Stoll Guido , Meuth Sven G. , Nieswandt Bernhard , McCrae Keith R. , Kleinschnitz Christoph 
Published: August 2012

AbstractThrombosis and inflammation are hallmarks of ischemic stroke still unamenable to therapeutic interventions. High-molecular-weight kininogen (KNG) is a central constituent of the contact-kinin system which represents an interface between thrombotic and inflammatory circuits and is critically involved in stroke development. Kng−/− mice are protected from thrombosis after artificial vessel wall injury and lack the proinflammatory mediator bradykinin. We investigated the consequences of KNG deficiency in models of ischemic stroke. Kng−/− mice of either sex subjected to transient middle cerebral artery occlusion developed dramatically smaller brain infarctions and less severe neurologic deficits without an increase in infarct-associated hemorrhage. This protective effect was preserved at later stages of infarction as well as in elderly mice. Targeting KNG reduced thrombus formation in ischemic vessels and improved cerebral blood flow, and reconstitution of KNG-deficient mice with human KNG or bradykinin restored clot deposition and infarct susceptibility. Moreover, mice deficient in KNG showed less severe blood-brain barrier damage and edema formation, and the local inflammatory response was reduced compared with controls. Because KNG appears to be instrumental in pathologic thrombus formation and inflammation but dispensable for hemostasis, KNG inhibition may offer a selective and safe strategy for combating stroke and other thromboembolic diseases.
Aging and neoteny in the B lineage
Authors: Melamed Doron , Scott David W. 
Published: August 2012

AbstractAging and the physiologic decline of tissues and cells were once thought to be irreversible. However, recent studies suggest that various tissues, especially parts of the hematopoietic system, can be rejuvenated. Here we review potential mechanisms for this process and how they may be used to reverse age-related disorders and aging in general. We propose the novel hypothesis that altering the homeostatic process during cellular depletion can reverse aging in the hematopoietic system.
Smoking cessation strategies in patients with COPD
Authors: Warnier Miriam J. , van Riet Evelien E.S. , Rutten Frans H. , De Bruin Marie Louise , Sachs Alfred P.E. 
Published: August 2012

Smoking cessation is the cornerstone of treatment of chronic obstructive pulmonary disease (COPD) patients. This systematic review evaluates the effectiveness of behavioural and pharmacological smoking cessation strategies in COPD patients.MEDLINE was searched from January 2002 to October 2011. Randomised controlled trials evaluating the effect of smoking cessation interventions for COPD patients, published in English, were selected. The methodological quality of included trials was assessed using the Delphi list by two reviewers independently. The relative risks of smoking cessation due to the intervention, compared with controls, were calculated.Eight studies met the inclusion criteria. Heterogeneity was observed for study population, the intervention strategy, the follow-up period and the outcome. According to the Delphi list methodological quality scores, five studies were considered to be of acceptable quality. Pharmacological therapy combined with behavioural counselling was more effective than each strategy separately. In COPD patients, the intensity of counselling did not seem to influence the results, nor did the choice of drug therapy make a difference.This systematic review makes clear that in COPD patients, pharmacological therapy combined with behavioural counselling is more effective than each strategy separately. Neither the intensity of counselling nor the type of anti-smoking drug made a difference.
The lectin-like domain of thrombomodulin hampers host defence in pneumococcal pneumonia
Authors: Schouten Marcel , de Boer J. Daan , van ’t Veer Cornelis , Roelofs Joris J.T.H. , Meijers Joost C.M. , Levi Marcel , Conway Edward M. , van der Poll Tom 
Published: August 2012

The lectin-like domain of thrombomodulin (TM) plays an important regulatory role in sterile inflammatory conditions, but its role in severe Gram-positive infectious disease is unknown.Streptococcus pneumoniaeis the most common cause of community-acquired pneumonia. The aim of this study was to determine the role of the lectin-like domain of TM in murine pneumococcal pneumonia.Wild-type (WT) mice and mice lacking the lectin-like domain of TM (TMLeD/LeD) were infected intranasally with viableS. pneumoniaeand either observed in a survival study or euthanised 6, 24 or 48 h after infection.TMLeD/LeDmice had a markedly better survival in pneumococcal pneumonia when compared with WT mice. At 48 h post-infection withS. pneumoniae,TMLeD/LeDmice had lower bacterial loads in blood and liver, and exhibited less pulmonary inflammation, as shown by having less lung histopathology, less neutrophil influx and lower cytokine and chemokine levels. Plasma levels of pro-inflammatory cytokines were also reduced in TMLeD/LeDmice after exposure to the infection.Deletion of the lectin-like domain of TM improves the host defence in pneumococcal pneumonia. The lectin-like domain of TM may have a differential role in response to Gram-positive or Gram-negative bacteria.
A potential role for insulin resistance in experimental pulmonary hypertension
Authors: West James , Niswender Kevin D. , Johnson Jennifer A. , Pugh Meredith E. , Gleaves Linda , Fessel Joshua P. , Hemnes Anna R. 
Published: August 2012

Patients with pulmonary arterial hypertension have increased prevalence of insulin resistance. We aimed to determine whether metabolic defects are associated with bone morphogenic protein receptor type 2 (Bmpr2) mutations in mice, and whether these may contribute to pulmonary vascular disease development.Metabolic phenotyping was performed on transgenic mice with inducible expression of Bmpr2 mutation, R899X. Phenotypic penetrance in Bmpr2R899Xwas assessed in a high-fat diet model of insulin resistance. Alterations in glucocorticoid responses were assessed in murine pulmonary microvascular endothelial cells and Bmpr2R899Xmice treated with dexamethasone.Compared to controls, Bmpr2R899Xmice showed increased weight gain and demonstrated insulin resistance as assessed by the homeostatic model assessment insulin resistance (1.0±0.4versus2.2±1.8) and by fat accumulation in skeletal muscle and decreased oxygen consumption. Bmpr2R899Xmice fed a high-fat diet had strong increases in pulmonary hypertension penetrance (seven out of 11versusthree out of 11). In cell culture andin vivoexperiments, Bmpr2 mutation resulted in a combination of constitutive glucocorticoid receptor activation and insensitivity.Insulin resistance is present as an early feature of Bmpr2 mutation in mice. Exacerbated insulin resistance through high-fat diet worsened pulmonary phenotype, implying a possible causal role in disease. Impaired glucocorticoid responses may contribute to metabolic defects.
Genome-wide association analysis reveals 12q13.3–q14.1 as new risk locus for sarcoidosis
Authors: Hofmann Sylvia , Fischer Annegret , Nothnagel Michael , Jacobs Gunnar , Schmid Benjamin , Wittig Michael , Franke Andre , Gaede Karoline I. , Schürmann Manfred , Petrek Martin , Mrazek Frantisek , Pabst Stefan , Grohé Christian , Grunewald Johan , Ronninger Marcus , Eklund Anders , Rosenstiel Philip , Höhne Kerstin , Zissel Gernot , Müller-Quernheim Joachim , Schreiber Stefan 
Published: August 2012

Sarcoidosis is a systemic inflammatory disease of unknown aetiology, influenced by genetic and environmental factors. However, the loci so far identified for sarcoidosis explain only a part of its assumed heritability.To identify further susceptibility loci, we performed a genome-wide association analysis using the Affymetrix 6.0 Human GeneChip followed by validation and replication stages.After quality control, 637 cases, 1233 controls and 677 619 single-nucleotide polymorphisms (SNPs) were available for an initial screening. 99 SNPs were selected for validation in an independent study panel (1664 patients, 2932 controls). SNP rs1050045 was significantly associated with sarcoidosis (corrected p=0.0215) in the validation panel and yielded a p-value of 9.22×10−8(OR 1.24) in the meta-analysis of the screening and validation stage. A meta-analysis of three populations from Germany, the Czech Republic and Sweden confirmed this finding (p=0.024; OR 1.14). Fine-mapping and mRNA expression studies pointed toosteosarcoma amplified 9 (OS9) as the most likely candidate for the underlying risk factor.The OS9 protein plays an important role in endoplasmic reticulum-associated protein degradation and acts during Toll-like receptor induced activation of myeloid cells. Expression analyses ofOS9mRNA provide evidence for a functional mechanism underlying the detected association signal.
Major bleeding with vitamin K antagonist anticoagulants in pulmonary hypertension
Authors: Henkens Ivo R. , Hazenoot Thomas , Boonstra Anco , Huisman Menno V. , Vonk-Noordegraaf Anton 
Published: August 2012

Vitamin K antagonists are advised in pulmonary arterial hypertension patients despite a lack of safety data.We reviewed major bleeding in three classes of pulmonary hypertension patients, all receiving vitamin K antagonists.Bleeding event rates were 5.4 per 100 patient-years for patients with idiopathic pulmonary arterial hypertension, 19 per 100 patient-years for connective tissue disease related pulmonary arterial hypertension patients and 2.4 per 100 patient-years for chronic thromboembolic pulmonary hypertension patients. Life tables analysis showed that event-free survival was worse in patients with connective tissue disease related pulmonary hypertension than in patients with idiopathic pulmonary arterial hypertension (Wilcoxon=12.8; p<0.001), and patients with chronic thromboembolic pulmonary hypertension (Wilcoxon=23.2; p<0.001). Patients with idiopathic pulmonary arterial hypertension suffered more events than patients with chronic thromboembolic pulmonary hypertension (Wilcoxon=7.2; p<0.01). Major bleeding was independent of age, sex, target international normalised ratio (INR) range, documented INR, vitamin K antagonist type, or right atrial pressure, but was associated with use of prostacyclin analogues.Major bleeding risk during vitamin K antagonist therapy differs among groups of patients with pulmonary hypertension. Further research regarding optimal anticoagulant therapy is needed, as well as risk–benefit analyses for pulmonary hypertension patients with a higher bleeding propensity.
Inhaled therapies, azithromycin andMycobacterium abscessusin cystic fibrosis patients
Authors: Catherinot Emilie , Roux Anne-Laure , Vibet Marie-Anne , Bellis Gil , Lemonnier Lydie , Le Roux Evelyne , Bernède-Bauduin Claire , Le Bourgeois Muriel , Herrmann Jean-Louis , Guillemot Didier , Gaillard Jean-Louis ,   for the OMA group
Published: August 2012

Cystic fibrosis (CF) patients are at particularly high risk of developing lung disease caused byMycobacterium abscessuscomplex (MABSC). Over the last 10 years, changes in CF treatment, with increasing use of inhaled therapies and low-dose azithromycin, have been accompanied by an increase in the prevalence of MABSC infections in CF patients. There is therefore some concern about the role of new CF treatments in the emergence of MABSC infections.We addressed this issue by means of a case–control study including 30 MABSC-positive cases and 60 nontuberculous mycobacteria-negative CF controls matched for age, sex and centre. We also compared practices at the CF centres with the highest prevalence of MABSC with those at the other centres.No positive association was found between MABSC lung disease and the use of inhaled therapies or low-dose azithromycin in the 4 years preceding MABSC isolation. These treatments were not significantly more frequently used at the CF centres with the highest MABSC prevalence rates.In conclusion, there is no evidence for a link betweenM. abscessuscomplex lung disease and inhaled therapies or low-dose azithromycin in patients with CF.
Contact investigation for tuberculosis: a systematic review and meta-analysis
Authors: Fox Gregory J. , Barry Simone E. , Britton Warwick J. , Marks Guy B. 
Published: August 2012

Investigation of contacts of patients with tuberculosis (TB) is a priority for TB control in high-income countries, and is increasingly being considered in resource-limited settings. This review was commissioned for a World Health Organization Expert Panel to develop global contact investigation guidelines.We performed a systematic review and meta-analysis of all studies reporting the prevalence of TB and latent TB infection, and the annual incidence of TB among contacts of patients with TB.After screening 9,555 titles, we included 203 published studies. In 95 studies from low- and middle-income settings, the prevalence of active TB in all contacts was 3.1% (95% CI 2.2–4.4%, I2=99.4%), microbiologically proven TB was 1.2% (95% CI 0.9–1.8%, I2=95.9%), and latent TB infection was 51.5% (95% CI 47.1–55.8%, I2=98.9%). The prevalence of TB among household contacts was 3.1% (95% CI 2.1–4.5%, I2=98.8%) and among contacts of patients with multidrug-resistant or extensively drug-resistant TB was 3.4% (95% CI 0.8–12.6%, I2=95.7%). Incidence was greatest in the first year after exposure. In 108 studies from high-income settings, the prevalence of TB among contacts was 1.4% (95% CI 1.1–1.8%, I2=98.7%), and the prevalence of latent infection was 28.1% (95% CI 24.2–32.4%, I2=99.5%). There was substantial heterogeneity among published studies.Contacts of TB patients are a high-risk group for developing TB, particularly within the first year. Children <5 yrs of age and people living with HIV are particularly at risk. Policy recommendations must consider evidence of the cost-effectiveness of various contact tracing strategies, and also incorporate complementary strategies to enhance case finding.