bluuebunny/crossref_metadata_2025_split huggingface dataset:
FOXP3 Inhibits Activation-Induced NFAT2 Expression in T Cells Thereby Limiting Effector Cytokine Expression
Authors: Torgerson Troy R. , Genin Anna , Chen Chunxia , Zhang Mingce , Zhou Bin , Añover-Sombke Stephanie , Frank M. Barton , Dozmorov Igor , Ocheltree Elizabeth , Kulmala Petri , Centola Michael , Ochs Hans D. , Wells Andrew D. , Cron Randy Q. 
Published: June 2009

Abstract
The forkhead DNA-binding protein FOXP3 is critical for the development and suppressive function of CD4+CD25+ regulatory T cells (TREG), which play a key role in maintaining self-tolerance. Functionally, FOXP3 is capable of repressing transcription of cytokine genes regulated by NFAT. Various mechanisms have been proposed by which FOXP3 mediates these effects. Using novel cell lines that inducibly express either wild-type or mutant FOXP3, we have identified NFAT2 as an early target of FOXP3-mediated transcriptional repression. NFAT2 is typically expressed at low levels in resting T cells, but is up-regulated by NFAT1 upon cellular activation. We demonstrate that transcription from the NFAT2 promoter is significantly suppressed by FOXP3, and NFAT2 protein expression is markedly diminished in activated CD4+CD25+FOXP3+ TREG compared with CD4+CD25−FOXP3− T cells. Chromatin immunoprecipitation experiments indicate that FOXP3 competes with NFAT1 for binding to the endogenous NFAT2 promoter. This antagonism of NFAT2 activity by FOXP3 is important for the anergic phenotype of TREG, as ectopic expression of NFAT2 from a retroviral LTR partially restores expression of IL-2 in FOXP3+ TREG. These data suggest that FOXP3 functions not only to suppress the first wave of NFAT-mediated transcriptional responses, but may also affect sustained NFAT-mediated inflammatory gene expression through suppression of inducible NFAT2 transcription.
VAMP8 Is Essential in Anaphylatoxin-Induced Degranulation, TNF-α Secretion, Peritonitis, and Systemic Inflammation
Authors: Pushparaj Peter N. , Tay Hwee Kee , Wang Cheng-Chun , Hong Wanjin , Melendez Alirio J. 
Published: June 2009

Abstract
VAMP8, a member of the soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor (SNARE) family of fusion proteins, initially characterized in endosomal and endosomal-lysosomal fusion, may also function in regulated exocytosis. VAMP8 physiological function in inflammation has not been elucidated. In this paper, we show that deficiency of VAMP8 protects mice from anaphylatoxin (C5a)-induced neutropenia, peritonitis, and systemic inflammation. We show that, in vivo, VAMP8 deletion inhibits neutropenia and phagocyte recruitment. We also show that in macrophages, VAMP8 localizes on secretory granules and degranulation is inhibited in VAMP8-deficient macrophages. Moreover, VAMP8−/− mice show reduced systemic inflammation with inhibition of serum TNF-α levels, whereas IL-1β, IL-6, and MIP1α release are not affected. In wild-type macrophages, TNF-α colocalizes with VAMP8-positive vesicles, and in VAMP8-deficient macrophages, the TNF-α release is inhibited. Furthermore, VAMP8 regulates the release of TNF-α and β-hexosaminidase triggered by fMLP, and VAMP8−/− mice are protected from fMLP-induced peritonitis. These data demonstrate that the VAMP8 vesicle-associated-SNARE is required for the proper trafficking of secretory lysosomal granules for exocytosis in macrophages and for the release of the potent proinflammatory cytokine, TNF-α.
Ablation and Regeneration of Tolerance-Inducing Medullary Thymic Epithelial Cells after Cyclosporine, Cyclophosphamide, and Dexamethasone Treatment
Authors: Fletcher Anne L. , Lowen Tamara E. , Sakkal Samy , Reiseger Jessica J. , Hammett Maree V. , Seach Natalie , Scott Hamish S. , Boyd Richard L. , Chidgey Ann P. 
Published: June 2009

Abstract
Immunosuppressive drugs and cytotoxic chemotherapy agents are designed to kill or suppress autoreactive, alloaggressive, or hyperinflammatory T cells, or disseminated malignancies. However, they also cause severe immunological side effects ranging from interrupted thymopoiesis and general immunodeficiency to, paradoxically, autoimmunity. Consistent with the cross-talk between thymocytes and stromal cells, we now show that these common therapeutic agents have major effects on murine thymic epithelial cells (TEC), crucially required to rebuild immunity posttreatment. We show that the immunosuppressant cyclosporine A, which has been linked to a thymus-dependent autoimmune syndrome in some patients, causes extensive loss of autoimmune regulator (Aire+) tolerance-inducing MHC class IIhigh medullary TEC (mTEChigh). Post-cyclosporine A, Aire expression was restored within 7 days. Full recovery of the mTEChigh subset occurred within 10 days and was linked to a decrease in a relatively resistant MHC class IIlow mTEC subset (mTEClow), consistent with a previously described precursor-product relationship. Cyclophosphamide and dexamethasone caused more extensive ablation of thymocytes and stromal cells but again severely depleted tolerance-inducing mTEChigh. Together, these data show that Aire+ mTECs are highly sensitive to damage and that mTEC regeneration follows a conserved pattern regardless of the treatment regimen used.
Reduced Cytotoxic Function of Effector CD8+ T Cells Is Responsible for Indoleamine 2,3-Dioxygenase-Dependent Immune Suppression
Authors: Liu Hanzhong , Liu Li , Liu Kaifeng , Bizargity Peyman , Hancock Wayne W. , Visner Gary A. 
Published: June 2009

Abstract
Indoleamine 2,3-dioxygenase (IDO), a potent immunosuppressive enzyme, contributes to tumoral escape, immune tolerance, and protection against allograft injury. In this paper, we report that inhibition of CD8+ T cell-mediated cytotoxic function is an important mechanism behind IDO’s immune-modulating property. The experimental rat lung allograft proved attractive for evaluating effector CD8+ T cells. Enhanced IDO activity achieved by using a lung-tissue-targeted nonviral human IDO gene transfer approach reduced, but did not eliminate, infiltrating CD8+ T cells. Although CD8+ T cells existed in the IDO-high lung allografts, CD8+ T cells remained viable and could proliferate for an extended period. However, cells lost their ability to attack allogeneic donor lung cells in vivo and allogeneic target cells in vitro. The impaired cytotoxic function seen in the IDO-treated CD8+ T cells was accompanied by defects in production of granule cytotoxic proteins, including perforin and granzyme A and B. Furthermore, we discovered that IDO leads to an impaired bioenergetic condition in active CD8+ T cells via selective inhibition of complex I in the mitochondrial electron transfer chain. These intriguing findings provide a base for establishing a novel mode of IDO’s immune-suppressing action. Additionally, donor lung IDO delivery, a direct and/or leukocyte passenger effect, impaired CD8+ effector cell function.
MASP-1, a Promiscuous Complement Protease: Structure of Its Catalytic Region Reveals the Basis of Its Broad Specificity
Authors: Dobó József , Harmat Veronika , Beinrohr László , Sebestyén Edina , Závodszky Péter , Gál Péter 
Published: June 2009

Abstract
Mannose-binding lectin (MBL)-associated serine protease (MASP)-1 is an abundant component of the lectin pathway of complement. The related enzyme, MASP-2 is capable of activating the complement cascade alone. Though the concentration of MASP-1 far exceeds that of MASP-2, only a supporting role of MASP-1 has been identified regarding lectin pathway activation. Several non-complement substrates, like fibrinogen and factor XIII, have also been reported. MASP-1 belongs to the C1r/C1s/MASP family of modular serine proteases; however, its serine protease domain is evolutionary different. We have determined the crystal structure of the catalytic region of active MASP-1 and refined it to 2.55 Å resolution. Unusual features of the structure are an internal salt bridge (similar to one in factor D) between the S1 Asp189 and Arg224, and a very long 60-loop. The functional and evolutionary differences between MASP-1 and the other members of the C1r/C1s/MASP family are reflected in the crystal structure. Structural comparison of the protease domains revealed that the substrate binding groove of MASP-1 is wide and resembles that of trypsin rather than early complement proteases explaining its relaxed specificity. Also, MASP-1’s multifunctional behavior as both a complement and a coagulation enzyme is in accordance with our observation that antithrombin in the presence of heparin is a more potent inhibitor of MASP-1 than C1 inhibitor. Overall, MASP-1 behaves as a promiscuous protease. The structure shows that its substrate binding groove is accessible; however, its reactivity could be modulated by an unusually large 60-loop and an internal salt bridge involving the S1 Asp.
Extraosseous Osteosarcoma in Ibadan: Case Series over a 20-Year Period
Authors: Alonge Temitope O. , Obamuyide Henry A. , Ogun Gabriel Olabiyi 
Published: June 2009

Extraosseous osteosarcoma (EOO) is a rare form of sarcoma. There have been few reports of cases and outcome from an African population. Out of 112 cases of sarcomas seen at the UCH, Ibadan between 1986-2005, 5 were EOO. All presented late on account of initial excision without histology and outcomes were poor. EOO occurs in the black population of Sub-Saharan Africa. The outlook for these patients is still bleak.
Ferrocene Redox Controlled Reversible Immobilization of Ruthenium Carbene in Ionic Liquid: A Versatile Catalyst for Ring‐Closing Metathesis
Authors: Liu Guiyan , He Haiyan , Wang Jianhui 
Published: June 2009

AbstractA ferrocene‐tagged ruthenium carbene 15 that can be reversibly immobilized in an ionic liquid (IL) via the controlled oxidation and reduction of a ferrocene tag was prepared. This offers a new strategy which uses redox chemistry to control immobilization and to recycle both the catalyst and the IL. In this experiment, 11 recycles were performed for the ring‐closing metathesis (RCM) of a substrate using 16 as the catalyst in an ionic liquid (IL). More importantly, after the reaction was completed, the ruthenium catalyst was easily separated from the supporting IL by just adding decamethylferrocene (DMFc) to reduce the cationic ferrocene and then extracting it with benzene. Thus, this recycle system offers an easy way to recycle both the ruthenium catalyst and the IL.
Donor‐Stabilized Phosphenium Adducts as New Efficient and Immobilizing Ligands in Palladium‐Catalyzed Alkynylation and Platinum‐Catalyzed Hydrogenation in Ionic Liquids
Authors: Saleh Samer , Fayad Elie , Azouri Michèle , Hierso Jean‐Cyrille , Andrieu Jacques , Picquet Michel 
Published: June 2009

AbstractThe straightforward synthesis of a new donor‐stabilized phosphenium ligand 3d by addition of bromodifurylphosphine to 1,3‐dimethylimidazolium‐2‐carboxylate 1 is described. The obtained ligand exhibits a very strong π‐acceptor character, comparable to that of triphenyl phosphite [P(OPh)3] or of tris‐halogenophosphines, with a νCO(A1) at 2087 cm−1 for its nickel tricarbonyl complex. This ligand, as well as the related 3a which was obtained from chlorodiphenylphosphine, were tested in palladium‐catalyzed aryl alkynylation and in the platinum‐catalyzed selective hydrogenation of chloronitrobenzenes, both in an ionic liquid phase. In CC bond cross‐coupling we observed that the increase of the π‐acceptor character in ligand 3d, due to the introduction of an additional electron‐withdrawing group, provides a very efficient catalyst in the alkynylation reaction of aryl bromides with phenylacetylene, including the deactivated 4‐bromoanisole or the sterically hindered 2‐bromonaphthalene. The catalytic activity decreases with recycling due to the sensitiveness of ligands to protonation in the ionic phase. Conversely, a multiple recycling of the metal/ligand system in non‐acidic media was achieved from platinum‐catalyzed hydrogenation of m‐chloronitrobenzene. The catalytic results obtained by employing the complex of platinum(II) chloride with 3a [trans‐PtCl2(3a)2] in comparison with the non‐ionic related trans‐tris(triphenylphosphine)platinum dichloride [trans‐PtCl2(PPh3)2] complex clearly indicate that the simultaneous existence of a strong π‐acceptor character and a positive charge within the ligand 3a significantly increases the life‐time of the platinum catalyst. The selectivity of the reaction is also improved by decreasing the undesirable formation of dehalogenation products. This cationic platinum complex trans‐PtCl2(3a)2 is the first example of a highly selective catalyst for hydrogenation of chloronitroarenes immobilized in an ionic liquid phase. The system was recycled six times without noticeable metal leaching in the organic phase, and no loss of activity.
Particle shape manipulation and optimization in cooling crystallization involving multiple crystal morphological forms
Authors: Wan Jian , Wang Xue Z. , Ma Cai Y. 
Published: June 2009

AbstractA population balance model for predicting the dynamic evolution of crystal shape distribution is further developed to simulate crystallization processes in which multiple crystal morphological forms co‐exist and transitions between them can take place. The new model is applied to derive the optimal temperature and supersaturation profiles leading to the desired crystal shape distribution in cooling crystallization. Since tracking an optimum temperature or supersaturation trajectory can be easily implemented by manipulating the coolant flowrate in the reactor jacket, the proposed methodology provides a feasible closed‐loop mechanism for crystal shape tailoring and control. The methodology is demonstrated by applying it to a case study of seeded cooling crystallization of potash alum. © 2009 American Institute of Chemical Engineers AIChE J, 2009
Deferasirox removes cardiac iron and attenuates oxidative stress in the iron‐overloaded gerbil
Authors: Al‐Rousan Rabaa M. , Paturi Satyanarayana , Laurino Joseph P. , Kakarla Sunil K. , Gutta Anil K. , Walker Ernest M. , Blough Eric R. 
Published: June 2009

AbstractIron‐induced cardiovascular disease is the leading cause of death in iron‐overloaded patients. Deferasirox is a novel, once daily oral iron chelator that was recently approved for the treatment of transfusional iron overload. Here, we investigate whether deferasirox is capable of removing cardiac iron and improving iron‐induced pathogenesis of the heart using the iron overload gerbil model. Animals were randomly divided into three groups: control, iron overload, and iron overload + deferasirox treatment. Iron‐dextran was given 100 mg/kg per 5 days i.p for 10 weeks. Deferasirox treatment was taken post iron loading and was given at 100 mg/kg/day p.o for 1 or 3 months. Cardiac iron concentration was determined by inductively coupled plasma atomic emission spectroscopy. Compared with the untreated group, deferasirox treatment for 1 and 3 months decreased cardiac iron concentration 17.1% (P = 0.159) and 23.5% (P < 0.05), respectively. These treatment‐associated reductions in cardiac iron were paralleled by decreases in tissue ferritin expression of 20% and 38% at 1 and 3 months, respectively (P < 0.05). Using oxyblot analysis and hydroethidine fluorescence, we showed that deferasirox significantly reduces cardiac protein oxidation and superoxide abundance by 36 and 47.1%, respectively (P < 0.05). Iron‐induced increase in oxidative stress was also associated with increased phosphorylation of ERK‐, p38‐, and JNK‐mitogen‐activated protein kinase (MAPK). Interestingly, deferasirox treatment significantly diminished the phosphorylation of all three MAPK subfamilies. These results suggest that deferasirox may confer a cardioprotective effect against iron induced injury. Am. J. Hematol. 2009. © 2009 Wiley‐Liss, Inc.
Predicting survival in adults with invasive aspergillosis during therapy for hematological malignancies or after hematopoietic stem cell transplantation: Single‐center analysis and validation of the Seattle, French, and Strasbourg prognostic indexes
Authors: Parody Rocio , Martino Rodrigo , Sánchez Ferran , Subirá Maricel , Hidalgo Alberto , Sierra Jorge 
Published: June 2009

AbstractIn this retrospective monocenter study, we analyzed the outcomes of 130 adult hematological patients who developed a proven (n = 23), probable (n = 71), and possible (n = 36) invasive aspergillosis (IA) in a 13‐year period. Forty‐nine patients (38%) were recipients of an allogeneic hematopoietic stem cell transplantation (AlloHSCT). The main goal of the study was the identification of prognostic factors for 4‐month aspergillosis free survival (AFS) and overall survival (OS). IA was identified as the main cause of death in 27/49 recipients of an AlloHSCT (55%) and 28/81 nontransplanted patients (35%). Diagnosis of IA at or before 2000 had a negative impact in both 4‐month AFS and 4‐month OS in the entire group. In multivariate analysis performed separately for nontransplanted and allo‐HSCT patients, five variables (excluding the year of diagnosis) decreased 4‐month AFS: (i) impairment of one organ function (OF), (ii) impairment of two or more OFs (two points), (iii) disseminated IA, (iv) neutropenia lasting more than 10 days (non‐AlloHSCT group only) or monocytopenia (<0.1 × 109/l) [AlloHSCT group only], and (v) high‐dose steroids (non‐AlloHSCT group only) or an alternative donor (AlloHSCT group only). According to the number of adverse risk factors, three prognostic subgroups were defined in non‐transplanted and alloHSCT patients with good (97% and 78% AFS), intermediate (73% and 32% AFS) and poor prognosis (20% and 11% AFS) of IA [P < 0.01]. In addition, we validated the French and Seattle prognostic indexes for allo‐HSCT recipients and the Strasbourg model for all hematological patients with IA. Am. J. Hematol., 2009. © 2009 Wiley‐Liss, Inc.
Declining health insurance access among US hispanic workers: Not all jobs are created equal
Authors: McCollister Kathryn E. , Arheart Kristopher L. , Lee David J. , Fleming Lora E. , Davila Evelyn P. , LeBlanc William G. , Christ Sharon L. , Caban‐Martinez Alberto J. , West Jonathan P. , Clark John E. , Erard Michael J. 
Published: June 2009

AbstractIntroductionApproximately 18% of the U.S. population are uninsured, a proportion that may continue to rise, particularly among Hispanics, as the cost of medical care increases faster than the growth in wages.MethodsHealth insurance trends were analyzed by race–ethnic category, and among Hispanic workers by occupation type and industrial sector, using data on employed respondents ≥18 years from 1997 to 2007 National Health Interview Survey (NHIS) (mean annual n = 17,392, representing 123 million US workers on average over this 11 year period).ResultsFrom 1997 to 2007, the relative decline in health insurance coverage for US workers was greatest among Hispanics (7.0%). Hispanic workers in the Construction and Services industries had the greatest overall decline in coverage (24.9% and 14.7%), as well as Hispanic blue collar workers (14.0%).ConclusionHispanic workers in general, and those employed in blue collar, construction, and services sectors in particular, are at greater risk for poor access to health care due to a lack of health insurance coverage. Am. J. Ind. Med. 53:163–170 2010. © 2009 Wiley‐Liss, Inc.
Primary central nervous system lymphoma in a patient treated with natalizumab
Authors: Schweikert Andreas , Kremer Marcus , Ringel Florian , Liebig Thomas , Duyster Justus , Stüve Olaf , Hemmer Bernhard , Berthele Achim 
Published: June 2009

AbstractA 40‐year‐old man with relapsing‐remitting multiple sclerosis (MS) developed primary central nervous system lymphoma (PCNSL) after having received 21 doses of natalizumab monotherapy. PCNSL is a disease of the elderly, with the majority of patients being diagnosed in the 7th to 8th decade of life. Immunodeficiency, iatrogenic immunosuppression, and some autoimmune diseases are known as predisposing conditions, and in these patients PCNSL peaks in the 4th decade. Because there is no increased prevalence of PCNSL in MS, and the patient was otherwise not immunocompromised, an association between natalizumab therapy and PCNSL cannot be ruled out. Ann Neurol 2009;66:403–406
Imaging the future of stroke: I. Ischemia
Authors: Liebeskind David S. 
Published: June 2009

AbstractEnvisioning the future of stroke appears daunting considering the milestones already achieved in stroke imaging. A historical perspective on the developments in stroke care provides a striking narrative of how imaging has transformed diagnosis, therapy, and prognosis of cerebrovascular disorders. Multimodal imaging techniques such as CT and MRI, incorporating parenchymal depictions, illustration of the vasculature, and perfusion data, can provide a wealth of information regarding ischemic pathophysiology. Key elements of ischemic pathophysiology depicted with imaging include vascular occlusion, compensatory collateral flow, resultant hemodynamic conditions that reflect these sources of blood flow, and the neurovascular injury that ensues. The mantra of “time is brain” has been perpetuated, but this does not provide an entirely accurate reflection of ischemic pathophysiology and imaging insight shows far more than time alone. Maximizing the potential of perfusion imaging will continue to expand the nascent concept that cerebral ischemia may be completely reversible in certain scenarios. Novel modalities provide a fertile ground for discovery of therapeutic targets and the potential to assess effects of promising strategies. Beyond clinical trials, imaging has become a requisite component of the neurological examination enabling tailored stroke therapy with the use of detailed neuroimaging modalities. In this first article on ischemia, the focus is on the most recent imaging advances and exploring aspects of cerebral ischemia where imaging may yield additional therapeutic strategies. A subsequent article will review recent and anticipated imaging advances in hemorrhage. These thematic overviews underscore that imaging will undoubtedly continue to dramatically shape the future of stroke. Ann Neurol 2009;66:574–590
Molecularly targeted therapies for glioma
Authors: Yamanaka Ryuya , Saya Hideyuki 
Published: June 2009

AbstractOver the past decade, molecularly targeted therapies have been added to cytotoxic and antiendocrine drugs in the treatment of cancer, with the aim of targeting the molecular pathways that underlie the carcinogenic process and maintain the cancer phenotype. Success with some of these agents has suggested that identification and validation of drug targets is the starting point for the development of active, safe, and effective drugs. The main molecular targets used to develop anticancer drugs are cell surface receptors, signal transduction pathways, gene transcription targets, ubiquitin‐proteasome/heat shock proteins, and tumor microenvironment components. Here, we review the development of the main molecularly targeted noncytotoxic agents studied in glioma, highlighting lessons derived from the development of these novel drugs and proposing new horizons for the clinical development of molecularly targeted therapies. Ann Neurol 2009;66:717–729