bluuebunny/crossref_metadata_2025_split huggingface dataset:
In vivo imaging of the molecular distribution of the VEGF receptor during angiogenesis in a mouse model of ischemia
Authors: Hamada Yoh , Gonda Kohsuke , Takeda Motohiro , Sato Akira , Watanabe Mika , Yambe Tomoyuki , Satomi Susumu , Ohuchi Noriaki 
Published: August 2011

Abstract
Vascular endothelial growth factor (VEGF) plays a critical role in angiogenesis and has been applied to medical therapy. However, because vascular imaging at the molecular level is impossible, the detailed in vivo dynamics of VEGF and its receptor (VEGFR) remain unknown. In this study, to understand the molecular distribution of VEGF and the VEGFR, we prepared ischemic mice with a new surgical method and induced angiogenesis in the gastrocnemius muscle. Then, we made a VEGF-conjugated fluorescence nanoparticle and performed staining of VEGFR-expressing cells with the fluorescent probe, demonstrating the high affinity of the probe for VEGFR. To observe the physiologic molecular distribution of VEGFR, we performed in vivo single-particle imaging of gastrocnemius in the ischemic leg with the fluorescent probe. The results suggested that only a 3-fold difference of VEGFR distribution is involved in the formation of branched vasculature in angiogenesis, although previous ex vivo data showed a 13-fold difference in its distribution, indicating that a method inducing a several-fold local increase of VEGFR concentration may be effective in generating site-specific angiogenesis in ischemic disease. This new in vivo imaging of ischemic mice could make useful contributions to understanding the mechanisms of angiogenesis and to developing a VEGFR-related drug.
Bcr-abl signals to desensitize chronic myeloid leukemia cells to IFNα via accelerating the degradation of its receptor
Authors: Bhattacharya Sabyasachi , Zheng Hui , Tzimas Christos , Carroll Martin , Baker Darren P. , Fuchs Serge Y. 
Published: August 2011

Abstract
Constitutive activity of Bcr-abl fusion protein kinase causes chronic myeloid leukemia (CML). Inhibitors of Bcr-abl such as imatinib mesylate have replaced the cytokine IFNα as the primary treatment for the management of patients with this malignancy. We found that pretreatment of CML cells with imatinib mesylate augments the antigrowth effects of IFNα. Furthermore, introduction of Bcr-abl into non-CML cells inhibits the cellular responses to IFNα. This inhibition is mediated via a mechanism that involves activation of protein kinase D2. The latter promotes an accelerated phosphorylation-dependent degradation of the interferon-α/β receptor 1 chain of the type I interferon receptor, leading to attenuation of IFNα signaling. We discuss the relationship between Bcr-abl activity and IFNα signaling as a molecular basis of the combination of inhibitors of Bcr-abl and IFNα for CML treatment.
Occlusive thrombi arise in mammals but not birds in response to arterial injury: evolutionary insight into human cardiovascular disease
Authors: Schmaier Alec A. , Stalker Timothy J. , Runge Jeffrey J. , Lee Dooyoung , Nagaswami Chandrasekaran , Mericko Patricia , Chen Mei , Cliché Simon , Gariépy Claude , Brass Lawrence F. , Hammer Daniel A. , Weisel John W. , Rosenthal Karen , Kahn Mark L. 
Published: August 2011

Abstract
Mammalian platelets are small, anuclear circulating cells that form tightly adherent, shear-resistant thrombi to prevent blood loss after vessel injury. Platelet thrombi that form in coronary and carotid arteries also underlie common vascular diseases such as myocardial infarction and stroke and are the target of drugs used to treat these diseases. Birds have high-pressure cardiovascular systems like mammals but generate nucleated thrombocytes rather than platelets. Here, we show that avian thrombocytes respond to many of the same activating stimuli as mammalian platelets but are unable to form shear-resistant aggregates ex vivo. Avian thrombocytes are larger than mammalian platelets, spread less efficiently on collagen, and express much lower levels of the α2bβ3 integrin required for aggregate formation, features predicted to make thrombocyte aggregates less resistant than platelets are to the high fluid shear forces of the arterial vasculature. In vivo carotid vessel injury stimulates the formation of occlusive platelet thrombi in mice but not in the size- and flow-matched carotid artery of the Australian budgerigar. These studies indicate that unique physical and molecular features of mammalian platelets enable them to form shear-resistant arterial thrombi, an essential element in the pathogenesis of human cardiovascular diseases.
BeEAM (bendamustine, etoposide, cytarabine, melphalan) before autologous stem cell transplantation is safe and effective for resistant/relapsed lymphoma patients
Authors: Visani Giuseppe , Malerba Lara , Stefani Pietro Maria , Capria Saveria , Galieni Piero , Gaudio Francesco , Specchia Giorgina , Meloni Giovanna , Gherlinzoni Filippo , Giardini Claudio , Falcioni Sadia , Cuberli Francesca , Gobbi Marco , Sarina Barbara , Santoro Armando , Ferrara Felicetto , Rocchi Marco , Ocio Enrique M. , Caballero Maria Dolores , Isidori Alessandro 
Published: August 2011

AbstractWe designed a phase 1-2 study to evaluate the safety and the efficacy of increasing doses of bendamustine (160 mg/m2, 180 mg/m2, and 200 mg/m2 given on days −7 and −6) coupled with fixed doses of etoposide, cytarabine, and melphalan (BeEAM regimen) as the conditioning regimen to autologous stem cell transplantation for resistant/relapsed lymphoma patients. Forty-three patients (median age, 47 years) with non-Hodgkin (n = 28) or Hodgkin (n = 15) lymphoma were consecutively treated. Nine patients entered the phase 1 study; no patients experienced a dose-limiting toxicity. Thirty-four additional patients were then treated in the phase 2. A median number of 6 × 106 CD34+ cells/kg (range, 2.4-15.5) were reinfused. All patients engrafted, with a median time to absolute neutrophil count > 0.5 × 109/L of 10 days. The 100-day transplantation-related mortality was 0%. After a median follow-up of 18 months, 35 of 43 patients (81%) are in complete remission, whereas 6 of 43 relapsed and 2 of 43 did not respond. Disease type (non-Hodgkin lymphomas vs Hodgkin disease) and disease status at transplantation (chemosensitive vs chemoresistant) significantly influenced DFS (P = .01; P = .007). Remarkably, 4 of 43 (9%) patients achieved the first complete remission after receiving the high-dose therapy with autologous stem cell transplantation. In conclusion, the new BeEAM regimen is safe and effective for heavily pretreated lymphoma patients. The study was registered at European Medicines Agency (EudraCT number 2008-002736-15).
Interleukin-17A induces glucocorticoid insensitivity in human bronchial epithelial cells
Authors: Zijlstra G.J. , ten Hacken N.H.T. , Hoffmann R.F. , van Oosterhout A.J.M. , Heijink I.H. 
Published: August 2011

A subset of asthma patients suffer from glucocorticoid (GC) insensitivity. T-helper cell type 17 cells have an emerging role in GC insensitivity, although the mechanisms are still poorly understood.We investigated whether interleukin (IL)-17A induces GC insensitivity in airway epithelium by studying its effects on responsiveness of tumour necrosis factor (TNF)-α-induced IL-8 production to budesonide in human bronchial epithelial 16HBE cells. We unravelled the underlying mechanism by the use of specific pathway inhibitors, reporter and overexpression constructs and a histone deacetylase (HDAC) activity assay.We demonstrated that IL-17A-induced IL-8 production is normally sensitive to GCs, while IL-17A pre-treatment significantly reduced the sensitivity of TNF-α-induced IL-8 production to budesonide. IL-17A activated the p38, extracellular signal-related kinase (ERK) and phosphoinositide-3-kinase (PI3K) pathways, and the latter appeared to be involved in IL-17A-induced GC insensitivity. Furthermore, IL-17A reduced HDAC activity, and overexpression of HDAC2 reversed IL-17A-induced GC insensitivity. In contrast, IL-17A did not affect budesonide-induced transcriptional activity of the GC receptor, suggesting that IL-17A does not impair the actions of the ligated GC receptor.In conclusion, we have shown for the first time that IL-17A induces GC insensitivity in airway epithelium, which is probably mediated by PI3K activation and subsequent reduction of HDAC2 activity. Thus, blockade of IL-17A or downstream signalling molecule PI3K may offer new strategies for therapeutic intervention in GC-insensitive asthma.
Bosentan inhibits cigarette smoke-induced endothelin receptor expression in pulmonary arteries
Authors: Milara J. , Gabarda E. , Juan G. , Ortiz J.L. , Guijarro R. , Martorell M. , Morcillo E.J. , Cortijo J. 
Published: August 2011

The endothelin (ET) system contributes to lung vascular tension and remodelling in smokers and chronic obstructive pulmonary disease (COPD) patients.This study examined the effect of cigarette smoke (CS) on ET receptor A (ETA) and B (ETB) expression in human pulmonary artery smooth muscle cells (HPASMCs) and human small intrapulmonary arteries, as well as their functional consequences.CS extract (CSE) increased ETAand ETBexpression in HPASMCs and small intrapulmonary arteries, which was attenuated by bosentan, the ETAantagonist BQ123 and the ETBantagonist BQ788, and by blocking ET-1 with a monoclonal antibody against ET-1, suggesting a feed-forward mechanism mediated by ET-1 release. ET receptor (ETR) antagonism attenuated the CSE-induced HPASMC proliferation. Furthermore, CSE exposure increased the acute ET-1-induced small intrapulmonary artery contraction, which was attenuated by bosentan, BQ123 and BQ788. Pulmonary arteries from smokers and COPD patients showed a higher expression of ETAand ETBthan those of nonsmoker patients.These results show a novel mechanism by which ETR blockade attenuates CS-induced ETR overexpression and, subsequently, small intrapulmonary artery tension. These data may be of potential value to explain therapeutic effects of bosentan in some forms of disproportionate pulmonary hypertension in COPD patients.
Surgical implications of the new IASLC/ATS/ERS adenocarcinoma classification
Authors: Van Schil P.E. , Asamura H. , Rusch V.W. , Mitsudomi T. , Tsuboi M. , Brambilla E. , Travis W.D. 
Published: August 2011

A new adenocarcinoma classification was recently introduced by a joint working group of the International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS) and European Respiratory Society (ERS). A distinction is made between pre-invasive lesions, and minimally invasive and invasive adenocarcinoma. The confusing term “bronchioloalveolar carcinoma” is not used any more and new subcategories include adenocarcinomain situand minimally invasive adenocarcinoma.Due to a renewed interest in screen-detected nodules and early-stage lung cancers of <2 cm, this classification also has profound implications for thoracic surgeons.In this article, surgical topics are discussed: the role of a minimally invasive approach, especially video-assisted thoracic surgery, limited resection for early-stage lung cancer, the extent of lymph node dissection, the accuracy of intraoperative frozen section analysis, management of multiple lung nodules and prognostic factors in operated patients. Specific key issues are presented based on the current evidence and areas of surgical uncertainty are defined providing a basis for further studies.Thoracic surgeons will play a major role in the application and global introduction of this new adenocarcinoma classification. The remaining controversies regarding the precise diagnosis and management of early-stage lesions will have to be resolved by multidisciplinary and international collaboration.
Resistin-like molecule-β is a human airway remodelling mediator
Authors: Fang C. , Meng Q. , Wu H. , Eid G. , Zhang G. , Zhang X. , Yang S. , Huang K. , Lee T.H. , Corrigan C.J. , Ying S. 
Published: August 2011

Though implicated in vascular remodelling, a role for the resistin-like molecule (RELM)-β in human airway remodelling remains unexplored. We hypothesised that RELM-β expression is increased in the airways of asthmatics and regulates airways epithelial cell function.Expression of RELM-β in the bronchial mucosa and its concentrations in bronchoalveolar lavage (BAL) fluid from asthmatics and controls were measured by immunohistochemistry and ELISA, respectively. Proliferation assays, Western blotting, ELISA and real-time PCR were employed to detect effects of RELM-β on airways epithelial cells.RELM-β expression was increased in the bronchial mucosa and BAL fluid of asthmatics compared with controls. In the asthmatics, the numbers of mucosal RELM-β+ cells correlated inversely with forced expiratory volume in 1 s (r=-0.531, p=0.016), while the numbers of epithelial RELM-β+ cells correlated positively with those of mucin (MUC)5AC+ cells.In vitro, interleukin-13 enhanced RELM-β expression by primary human airways epithelial cells, while RELM-β itself acted on these cells to induce proliferation, expression of MUC5AC, extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK)-phosphatidylinositol 3-kinase (PI3K)/Akt phosphorylation and elevated expression of transforming growth factor-β2, epidermal growth factor and vascular endothelial growth factor.RELM-β has the potential to contribute to airway remodelling in diseases such as asthma by acting on epithelial cells to increase proliferation, mucin and growth factor production, at least partlyviaERK/MAPK-PI3K/Akt signalling pathways.
Surfactant protein C G100S mutation causes familial pulmonary fibrosis in Japanese kindred
Authors: Ono S. , Tanaka T. , Ishida M. , Kinoshita A. , Fukuoka J. , Takaki M. , Sakamoto N. , Ishimatsu Y. , Kohno S. , Hayashi T. , Senba M. , Yasunami M. , Kubo Y. , Yoshida L.M. , Kubo H. , Ariyoshi K. , Yoshiura K. , Morimoto K. 
Published: August 2011

Several mutations in the surfactant protein C (SP-C) gene (SFTPC) have been reported as causing familial pulmonary fibrosis (FPF). However, the genetic background and clinical features of FPF are still not fully understood.We identified one Japanese kindred, in which at least six individuals over three generations were diagnosed with pulmonary fibrosis. We examined the patients radiologically and histopathologically and sequenced theirSFTPCandABCA3genes. We also established a cell line stably expressing the mutant gene.All the patients had similar radiological and histopathological characteristics. Their histopathological pattern was that of usual interstitial pneumonia, showing numerous fibroblastic foci even in areas without abnormal radiological findings on chest high-resolution computed tomography. No child had respiratory symptoms in the kindred. Sequencing ofSFTPCshowed a novel heterozygous mutation, c.298G>A (G100S), in the BRICHOS domain of proSP-C, which co-segregated with the disease. However, in theABCA3gene, no mutation was found.In vitroexpression of the mutant gene revealed that several endoplasmic reticulum stress-related proteins were strongly expressed.The mutation increases endoplasmic reticulum stress and induces apoptotic cell death compared with wild-type SP-C in alveolar type II cells, supporting the significance of this mutation in the pathogenesis of pulmonary fibrosis.
Primary lung adenocarcinoma: characteristics by smoking habit and sex
Authors: Nagy-Mignotte H. , Guillem P. , Vesin A. , Toffart A.C. , Colonna M. , Bonneterre V. , Brichon P.Y. , Brambilla C. , Brambilla E. , Lantuejoul S. , Timsit J.F. , Moro-Sibilot D. 
Published: August 2011

The incidence of adenocarcinoma is increasing, particularly among females. We sought to assess the role of tobacco consumption in clinical presentation according to sex.In this retrospective study, 848 patients diagnosed between 1997 and 2006 at Grenoble University Hospital (Grenoble, France) were stratified into four groups according to smoking habits.Differences between sexes and two contrasting female profiles emerged. Female current smokers were younger than female never-smokers (median 51versus69 yrs; p<0.001), more often had surgery (62.7%versus39%; p=0.01) and had a median (95% CI) estimated survival of 26.2 (18.1–49.2)versus15.1 (12.8–22.2) months (p=0.002). Both groups had similar survival when taking treatment into account. Among males, smoking did not influence presentation. Male current smokers were older than female current smokers (median 59 yrs; p<0.001) and fewer had surgery (48.8%; p=0.015), although the percentage of stage IIIb–IV disease was similar (53% and 46%; nonsignificant) and they had a poorer estimated survival of 14.3 (13.0–18.5) months (p=0.0024). Males smoked more than females (median 41versus30 pack-yrs; p<0.001). Quitting smoking delayed age at diagnosis by 11 yrs for females (p=0.0035) and 8 yrs for males (p<0.001).Our results support the hypothesis that carcinogenesis differs between males and females, and between female smokers and never-smokers.
Clara cells drive eosinophil accumulation in allergic asthma
Authors: Sonar S.S. , Ehmke M. , Marsh L.M. , Dietze J. , Dudda J.C. , Conrad M.L. , Renz H. , Nockher W.A. 
Published: August 2011

Development of allergic asthma is a complex process involving immune, neuronal and tissue cells. In the lung, Clara cells represent a major part of the “immunomodulatory barrier” of the airway epithelium.To understand the contribution of these cells to the inflammatory outcome of asthma, disease development was assessed using an adjuvant-free ovalbumin model. Mice were sensitised with subcutaneous injections of 10 μg endotoxin-free ovalbumin in conjunction with naphthalene-induced Clara cell depletion.Clara epithelial cell depletion in the lung strongly reduced eosinophil influx, which correlated with decreased eotaxin levels and, moreover, diminished the T-helper cell type 2 inflammatory response, including interleukin (IL)-4, IL-5 and IL-13. In contrast, airway hyperresponsiveness was increased. Further investigation revealed Clara cells as the principal source of eotaxin in the lung.These findings are the first to show that Clara airway epithelial cells substantially contribute to the infiltration of eotaxin-responsive CCR3+ immune cells and augment the allergic immune response in the lung. The present study identifies Clara cells as a potential therapeutic target in inflammatory lung diseases such as allergic asthma.
Cloning and expression profiling of the VLDLR gene associated with egg performance in duck (Anas platyrhynchos)
Authors: Wang Cui , Li Shi-jun , Yu Wen-hua , Xin Qing-wu , Li Chuang , Feng Yan-ping , Peng Xiu-li , Gong Yan-zhang 
Published: August 2011

Abstract

Background
The very low density lipoprotein receptor gene (VLDLR), a member of the low density lipoprotein receptor (LDLR) gene family, plays a crucial role in the synthesis of yolk protein precursors in oviparous species. Differential splicing of this gene has been reported in human, rabbit and rat. In chicken, studies showed that the VLDLR protein on the oocyte surface mediates the uptake of yolk protein precursors into growing oocytes. However, information on the VLDLR gene in duck is still scarce.

Methods
Full-length duck VLDLR cDNA was obtained by comparative cloning and rapid amplification of cDNA ends (RACE). Tissue expression patterns were analysed by semi-quantitative reverse-transcription polymerase chain reaction (RT-PCR). Association between the different genotypes and egg performance traits was investigated with the general linear model (GLM) procedure of the SAS® software package.

Results
In duck, two VLDLR transcripts were identified, one transcript (variant-a) containing an O-linked sugar domain and the other (variant-b) not containing this sugar domain. These transcripts share ~70 to 90% identity with their counterparts in other species. A phylogenetic tree based on amino acid sequences showed that duck VLDLR proteins were closely related with those of chicken and zebra finch. The two duck VLDLR transcripts are differentially expressed i.e. VLDLR-a is mainly expressed in muscle tissue and VLDLR-b in reproductive organs. We have localized the duck VLDLR gene on chromosome Z. An association analysis using two completely linked SNP sites (T/C at position 2025 bp of the ORF and G/A in intron 13) and records from two generations demonstrated that the duck VLDLR gene was significantly associated with egg production (P < 0.01), age of first egg (P < 0.01) and body weight of first egg (P < 0.05).

Conclusions
Duck and chicken VLDLR genes probably perform similar function in the development of growing oocytes and deposition of yolk lipoprotein. Therefore, VLDLR could be a candidate gene for duck egg performance and be used as a genetic marker to improve egg performance in ducks.
Insulin glycation by methylglyoxal results in native-like aggregation and inhibition of fibril formation
Authors: Oliveira Luis MA , Lages Ana , Gomes Ricardo A , Neves Henrique , Família Carlos , Coelho Ana V , Quintas Alexandre 
Published: August 2011

AbstractBackgroundInsulin is a hormone that regulates blood glucose homeostasis and is a central protein in a medical condition termed insulin injection amyloidosis. It is intimately associated with glycaemia and is vulnerable to glycation by glucose and other highly reactive carbonyls like methylglyoxal, especially in diabetic conditions. Protein glycation is involved in structure and stability changes that impair protein functionality, and is associated with several human diseases, such as diabetes and neurodegenerative diseases like Alzheimer's disease, Parkinson's disease and Familiar Amyloidotic Polyneuropathy. In the present work, methylglyoxal was investigated for their effects on the structure, stability and fibril formation of insulin.ResultsMethylglyoxal was found to induce the formation of insulin native-like aggregates and reduce protein fibrillation by blocking the formation of the seedingnuclei. Equilibrium-unfolding experiments using chaotropic agents showed that glycated insulin has a small conformational stability and a weaker dependence on denaturant concentration (smaller m-value). Our observations suggest that methylglyoxal modification of insulin leads to a less compact and less stable structure that may be associated to an increased protein dynamics.ConclusionsWe propose that higher dynamics in glycated insulin could prevent the formation of the rigid cross-β core structure found in amyloid fibrils, thereby contributing to the reduction in the ability to form fibrils and to the population of different aggregation pathways like the formation of native-like aggregates.