bluuebunny/crossref_metadata_2025_split huggingface dataset:
Critical Role of Mast Cells and Peroxisome Proliferator–Activated Receptor γ in the Induction of Myeloid-Derived Suppressor Cells by Marijuana Cannabidiol In Vivo
Authors: Hegde Venkatesh L. , Singh Udai P. , Nagarkatti Prakash S. , Nagarkatti Mitzi 
Published: April 2015

Abstract
Cannabidiol (CBD) is a natural nonpsychotropic cannabinoid from marijuana (Cannabis sativa) with anti-epileptic and anti-inflammatory properties. Effect of CBD on naive immune system is not precisely understood. In this study, we observed that administering CBD into naive mice triggers robust induction of CD11b+Gr-1+ myeloid-derived suppressor cells (MDSC) in the peritoneum, which expressed functional arginase 1, and potently suppressed T cell proliferation ex vivo. Furthermore, CBD-MDSC suppressed LPS-induced acute inflammatory response upon adoptive transfer in vivo. CBD-induced suppressor cells were comprised of CD11b+Ly6-G+Ly6-C+ granulocytic and CD11b+Ly6-G−Ly6-C+ monocytic subtypes, with monocytic MDSC exhibiting higher T cell–suppressive function. Induction of MDSC by CBD was markedly attenuated in Kit-mutant (KitW/W-v) mast cell–deficient mice. MDSC response was reconstituted upon transfer of wild-type bone marrow–derived mast cells in KitW/W-v mice, suggesting the key role of cKit (CD117) as well as mast cells. Moreover, mast cell activator compound 48/80 induced significant levels of MDSC in vivo. CBD administration in mice induced G-CSF, CXCL1, and M-CSF, but not GM-CSF. G-CSF was found to play a key role in MDSC mobilization inasmuch as neutralizing G-CSF caused a significant decrease in MDSC. Lastly, CBD enhanced the transcriptional activity of peroxisome proliferator-activated receptor γ in luciferase reporter assay, and PPAR-γ selective antagonist completely inhibited MDSC induction in vivo, suggesting its critical role. Together, the results suggest that CBD may induce activation of PPAR-γ in mast cells leading to secretion of G-CSF and consequent MDSC mobilization. CBD being a major component of Cannabis, our study indicates that marijuana may modulate or dysregulate the immune system by mobilizing MDSC.
MicroRNA-125a Inhibits Autophagy Activation and Antimicrobial Responses during Mycobacterial Infection
Authors: Kim Jin Kyung , Yuk Jae-Min , Kim Soo Yeon , Kim Tae Sung , Jin Hyo Sun , Yang Chul-Su , Jo Eun-Kyeong 
Published: April 2015

Abstract
MicroRNAs (miRNAs) are small noncoding nucleotides that play critical roles in the regulation of diverse biological functions, including the response of host immune cells. Autophagy plays a key role in activating the antimicrobial host defense against Mycobacterium tuberculosis. Although the pathways associated with autophagy must be tightly regulated at a posttranscriptional level, the contribution of miRNAs and whether they specifically influence the activation of macrophage autophagy during M. tuberculosis infection are largely unknown. In this study, we demonstrate that M. tuberculosis infection of macrophages leads to increased expression of miRNA-125a-3p (miR-125a), which targets UV radiation resistance-associated gene (UVRAG), to inhibit autophagy activation and antimicrobial responses to M. tuberculosis. Forced expression of miR-125a significantly blocked M. tuberculosis–induced activation of autophagy and phagosomal maturation in macrophages, and inhibitors of miR-125a counteracted these effects. Both TLR2 and MyD88 were required for biogenesis of miR-125a during M. tuberculosis infection. Notably, activation of the AMP-activated protein kinase significantly inhibited the expression of miR-125a in M. tuberculosis–infected macrophages. Moreover, either overexpression of miR-125a or silencing of UVRAG significantly attenuated the antimicrobial effects of macrophages against M. tuberculosis. Taken together, these data indicate that miR-125a regulates the innate host defense by inhibiting the activation of autophagy and antimicrobial effects against M. tuberculosis through targeting UVRAG.
Mechanistic Assessment of PD-1H Coinhibitory Receptor–Induced T Cell Tolerance to Allogeneic Antigens
Authors: Flies Dallas B. , Higuchi Tomoe , Chen Lieping 
Published: April 2015

Abstract
PD-1H is a recently identified cell surface coinhibitory molecule of the B7/CD28 immune modulatory gene family. We showed previously that single injection of a PD-1H agonistic mAb protected mice from graft-versus-host disease (GVHD). In this study, we report two distinct mechanisms operate in PD-1H–induced T cell tolerance. First, signaling via PD-1H coinhibitory receptor potently arrests alloreactive donor T cells from activation and expansion in the initiation phase. Second, donor regulatory T cells are subsequently expanded to maintain long-term tolerance and GVHD suppression. Our study reveals the crucial function of PD-1H as a coinhibitory receptor on alloreactive T cells and its function in the regulation of T cell tolerance. Therefore, PD-1H may be a target for the modulation of alloreactive T cells in GVHD and transplantation.
The Processed Amino-Terminal Fragment of Human TLR7 Acts as a Chaperone To Direct Human TLR7 into Endosomes
Authors: Hipp Madeleine M. , Shepherd Dawn , Booth Sarah , Waithe Dominic , Reis e Sousa Caetano , Cerundolo Vincenzo 
Published: April 2015

Abstract
TLR7 mediates innate immune responses to viral RNA in endocytic compartments. Mouse and human (h)TLR7 undergo proteolytic cleavage, resulting in the generation of a C-terminal fragment that accumulates in endosomes and associates with the signaling adaptor MyD88 upon receptor triggering by TLR7 agonists. Although mouse TLR7 is cleaved in endosomes by acidic proteases, hTLR7 processing can occur at neutral pH throughout the secretory pathway through the activity of furin-like proprotein convertases. However, the mechanisms by which cleaved hTLR7 reaches the endosomal compartment remain unclear. In this study, we demonstrate that, after hTLR7 proteolytic processing, the liberated amino (N)-terminal fragment remains bound to the C terminus through disulfide bonds and provides key trafficking information that ensures correct delivery of the complex to endosomal compartments. In the absence of the N-terminal fragment, the C-terminal fragment is redirected to the cell surface, where it is functionally inactive. Our data reveal a novel role for the N terminus of hTLR7 as a molecular chaperone that provides processed hTLR7 with the correct targeting instructions to reach the endosomal compartment, hence ensuring its biological activity and preventing inadvertent cell surface responses to self-RNA.
Upregulation of the N-Formyl Peptide Receptors in Scleroderma Fibroblasts Fosters the Switch to Myofibroblasts
Authors: Rossi Francesca Wanda , Napolitano Filomena , Pesapane Ada , Mascolo Massimo , Staibano Stefania , Matucci-Cerinic Marco , Guiducci Serena , Ragno Pia , di Spigna Gaetano , Postiglione Loredana , Marone Gianni , Montuori Nunzia , de Paulis Amato 
Published: April 2015

Abstract
Systemic sclerosis (SSc) is characterized by chronic inflammation and fibrosis. N-Formyl peptide (fMLF) receptors (FPRs) are chemotactic receptors involved in inflammation. Three FPRs have been identified: FPR1, FPR2, and FPR3. We have examined, by RT-PCR, Western blot and immunohistochemistry, FPRs expression in skin fibroblasts from 10 normal subjects and 10 SSc patients, showing increased expression in SSc fibroblasts. Several functions of FPRs occur through the interaction with a region of the urokinase-type plasminogen activator receptor (uPAR88–92), able to interact with FPRs and to mediate urokinase (uPA) or fMLF-dependent cell migration. Soluble uPAR84–95 peptide can act as a direct ligand of FPRs. Furthermore, uPA or its aminoterminal fragment (ATF) can promote the exposure of the uPAR88–92 region. The WKYMVm peptide is a FPRs pan-agonist. We investigated the functional effects of these agonists on normal and SSc fibroblasts. ATF, uPAR84–95, and WKYMVm regulated adhesion, migration, and proliferation of normal fibroblasts. Despite FPR overexpression, the response of SSc fibroblasts to the same agonists was greatly reduced, except for the proliferative response to ATF. SSc fibroblasts showed increased α-smooth muscle actin expression and improved capability to induce wound closure. Indeed, they overexpressed a cleaved uPAR form, exposing the uPAR88–92 region, and vitronectin, both involved in fibrosis and in the fibroblast-to-myofibroblast transition. FPR stimulation promoted α-smooth muscle actin expression in normal fibroblasts as well as motility, matrix deposition, αvβ5 integrin expression, and radical oxygen species generation in normal and SSc fibroblasts. This study provides evidence that FPRs may play a role in fibrosis and in the fibroblast-to-myofibroblast transition.
Allogeneic Mature Human Dendritic Cells Generate Superior Alloreactive Regulatory T Cells in the Presence of IL-15
Authors: Litjens Nicolle H. R. , Boer Karin , Zuijderwijk Joke M. , Klepper Mariska , Peeters Annemiek M. A. , Prens Errol P. , Verschoor Wenda , Kraaijeveld Rens , Ozgur Zeliha , van den Hout-van Vroonhoven Mirjam C. , van IJcken Wilfred F. J. , Baan Carla C. , Betjes Michiel G. H. 
Published: April 2015

Abstract
Expansion of Ag-specific naturally occurring regulatory T cells (nTregs) is required to obtain sufficient numbers of cells for cellular immunotherapy. In this study, different allogeneic stimuli were studied for their capacity to generate functional alloantigen-specific nTregs. A highly enriched nTreg fraction (CD4+CD25brightCD127− T cells) was alloantigen-specific expanded using HLA-mismatched immature, mature monocyte-derived dendritic cells (moDCs), or PBMCs. The allogeneic mature moDC-expanded nTregs were fully characterized by analysis of the demethylation status within the Treg-specific demethylation region of the FOXP3 gene and the expression of both protein and mRNA of FOXP3, HELIOS, CTLA4, and cytokines. In addition, the Ag-specific suppressive capacity of these expanded nTregs was tested. Allogeneic mature moDCs and skin-derived DCs were superior in inducing nTreg expansion compared with immature moDCs or PBMCs in an HLA-DR– and CD80/CD86-dependent way. Remarkably, the presence of exogenous IL-15 without IL-2 could facilitate optimal mature moDC-induced nTreg expansion. Allogeneic mature moDC-expanded nTregs were at low ratios (&lt;1:320), potent suppressors of alloantigen-induced proliferation without significant suppression of completely HLA-mismatched, Ag-induced proliferation. Mature moDC-expanded nTregs were highly demethylated at the Treg-specific demethylation region within the FOXP3 gene and highly expressed of FOXP3, HELIOS, and CTLA4. A minority of the expanded nTregs produced IL-10, IL-2, IFN-γ, and TNF-α, but few IL-17–producing nTregs were found. Next-generation sequencing of mRNA of moDC-expanded nTregs revealed a strong induction of Treg-associated mRNAs. Human allogeneic mature moDCs are highly efficient stimulator cells, in the presence of exogenous IL-15, for expansion of stable alloantigen-specific nTregs with superior suppressive function.
C-Reactive Protein Directly Suppresses Th1 Cell Differentiation and Alleviates Experimental Autoimmune Encephalomyelitis
Authors: Zhang Lin , Liu Shan-Hui , Wright Tyler T. , Shen Zhi-Yuan , Li Hai-Yun , Zhu Wei , Potempa Lawrence A. , Ji Shang-Rong , Szalai Alexander J. , Wu Yi 
Published: April 2015

Abstract
Human C-reactive protein (CRP) is a serum-soluble pattern recognition receptor that serves as a marker of inflammation and directly contributes to innate immunity. In this study, we show that human CRP also directly contributes to adaptive immunity, that is, native CRP binds specifically to human Jurkat T cells and to mouse naive CD4+ T cells and modulates their Th1 and Th2 responses. In vitro both exogenously added (purified) and endogenously expressed (via transfection) human CRP inhibited Th1 differentiation and augmented Th2 differentiation of naive CD4+ T cells. In vivo for human CRP transgenic compared with wild-type mice, a lesser proportion of the T cells recovered from the spleens of healthy animals were Th1 cells. Moreover, in both CRP transgenic mice and in wild-type mice treated with human CRP, during myelin oligodendrocyte glycoprotein peptide–induced experimental autoimmune encephalomyelitis both the Th1 cell response and disease severity were inhibited. These pattern recognition–independent actions of CRP directly on T cells highlights the potential for this soluble pattern recognition receptor to act as a tonic regulator of immunity, shaping global adaptive immune responses during both homeostasis and disease.
A New Approach for the Treatment of Arthritis in Mice with a Novel Conjugate of an Anti-C5aR1 Antibody and C5 Small Interfering RNA
Authors: Mehta Gaurav , Scheinman Robert I. , Holers V. Michael , Banda Nirmal K. 
Published: April 2015

Abstract
Rheumatoid arthritis (RA) is an inflammatory autoimmune joint disease in which the complement system plays an important role. Of the several components of complement, current evidence points to C5 as the most important inducer of inflammation. Several groups generated Abs or small interfering RNAs (siRNAs) or small molecule inhibitors against C5 and C5aR1 (CD88) that have showed some efficacy in RA in animal models. However, none of these candidate therapeutics has moved from bench to bedside. In this study, we test in collagen Ab-induced arthritis (CAIA) a new therapeutic strategy using a novel anti–C5ab-C5 siRNA conjugate. We first demonstrate that although C5aR2 or C5L2 (GPR77) plays no role in CAIA, C5aR1 contributes to pathogenesis. We demonstrate that injection of siRNAs blocking C5, C5aR1, or the combination decreased clinical disease activity in mice with CAIA by 45%, 51%, and 58%, respectively. Anti-C5 Ab (BB5.1) has only limited efficacy, but significantly reduced arthritis up to 66%. We then generated a novel anti-C5aR1 Ab–protamine–C5 siRNA conjugate. To our knowledge, we show for the first time that whereas unconjugated Ab plus siRNAs reduce arthritis by 19%, our anti-C5aR1 Ab–protamine–C5 siRNA conjugate was effective in reducing arthritis by 83% along with a parallel decrease in histopathology, C3 deposition, neutrophils, and macrophages in the joints of mice with CAIA. These data suggest that by targeting anti-C5 siRNAs to the receptor for its C5a activation fragment (C5aR1), a striking clinical effect can be realized.
Thyroid Cancer in Patients with Hyperthyroidism
Authors: Tastan Baki , Dogu Alper , Sevim Yusuf 
Published: April 2015

ABSTRACT

Background and objective
Malignant tumors of the thyroid gland are the most common of the endocrine malignancies. Although, patients with thyroid cancer have high 5 years survival rate, thyroid cancer is the most seen cause of mortality among cancers of the endocrine organs. The incidence of thyroid cancer in hyperthyroid patients varies from 0.1 to 21% in the literature. We aimed in this study to analyze the frequency of coexisting thyroid cancer and hyperthyroidism in our experience.

Results
Total 230 patients, who were operated for hyperthyroidism without the suspicion of thyroid malignancy between January 2005 and September 2010 were included in our study. Toxic multinodular goiter, toxic adenoma and Graves’ disease were diagnosed preoperatively in 187, 16 and 27 patients respectively. Histopathological thyroid malignancy was detected in 13 patients (5.7%).

Conclusion
Thyroid cancer with variable incidence up to 21% should be remembered in differential diagnosis of hyperthyroid patients.

How to cite this article
Tastan B, Dogu A, Sevim Y. Thyroid Cancer in Patients with Hyperthyroidism. World J Endoc Surg 2015;7(2):29-32.
Review on Antagonists
Authors: Sardana Divya 
Published: April 2015

ABSTRACTGonadotropin-releasing hormone (GnRH) antagonists have been a breakthrough in reproductive medicine. The third generation antagonists (cetrorelix and ganirelix) do not have histamine releasing capability in the used doses. The competitive blockade of GnRH receptors by GnRH antagonists leads to an immediate but reversible arrest of gonadotropin secretion. Antagonists can be used as single-dose or multiple dose protocol in a fixed or flexible approach during ovarian stimulation to prevent premature luteinizing hormone surge. The stimulation remains close to the normal cycle, and more convenient and friendly to the patient with lesser dose and duration of stimulation. Recent Cochrane analysis suggests that there is no significant difference in the live birth rate when antagonists are compared with agonists (OR 0.86) and there is a significant reduction in the incidence of ovarian hyperstimulation syndrome (OHSS) (OR 0.43) with the use of antagonists. Gonadotropin-releasing hormone antagonists are of special benefit for use in patients with polycystic ovaries where agonist trigger can be used and OHSS can be prevented completely. Gonadotropin-releasing hormone antagonists have particular advantage in poor responders with lesser pituitary suppression in the early part of cycle. Gonadotropinreleasing hormone antagonists can be used in modified natural cycle, intrauterine insemination cycles, and frozen embryo transfer cycles. Novel uses of antagonists include suppression of established OHSS, and in various gynecological conditions (endometriosis, fibroids, precocious puberty).How to cite this articleSardana D. Review on Antagonists. Int J Infertil Fetal Med 2015;6(1):1-10.
Combined Tamoxifen and L-Carnitine Therapies for the Treatment of Idiopathic Male Infertility Attending Intracytoplasmic Sperm Injection: A Randomized Controlled Trial
Authors: Haje Milat , Naoom Kameel 
Published: April 2015

ABSTRACTAimThe aim of the present study is to evaluate the fertility outcomes of intracytoplasmic sperm injection (ICSI) as well as sperm count, motility and morphology in couples with infertile male partners exhibiting idiopathic oligoasthenozoospermia (OA) and treated with tamoxifen citrate and/or L-carnitine.Materials and methodsIn this randomized controlled trail, couples with female cause of infertility were excluded. Only couples with male cause of infertility with idiopathic OA were admitted to this study and randomly assigned into four different groups of treatments as follow: Group A (n = 45) received an anti-estrogen compound (tamoxifen 20 mg/day), group B (n = 20) received L-carnitine (1000 mg/day), group C (n = 34) received tamoxifen 20 mg/day plus L-carnitine 1000 mg/day, whereas group D (n = 29) received placebo. Treatments were continued for 3 to 6 months.ResultsTreatment groups of A, B, and C showed an overall improvement in the tested parameters of sperm when compared to the control group that showed an overall reduction in those parameters after termination of the treatment. In this context, sperm count increased from 7.58 ± 2.93 × 106/ml before treatment to 10.81 ± 1.84 × 106/ml after treatment in group A (p = 0.016). Similarly, sperm count increased from 5.32 ± 2.09 × 106/ml to 8.92 ± 2.29 × 106/ml in group C (p = 0.01). Patients from group C did not only have an improved total motility of sperm from 8.03 ± 1.59% to 13.78 ± 3.85% (p = 0.045) but also an improved sperm normal morphology from 0.88 ± 0.45% to 1.99 ± 0.71% (p = 0.026). Patients from group A or C exhibited an improved ICSI outcomes when compared to those in patients from group B or D (48.9 or 48.3 vs 16.6 or 20, respectively, p = 0.46).ConclusionIt is concluded that administration of tamoxifen and L-carnitine can improve both sperm parameters of fertility and ICSI outcomes. Combined tamoxifen and L-carnitine treatments result in maximum therapeutic effect in men with idiopathic OA.How to cite this articleHaje M, Naoom K. Combined Tamoxifen and L-Carnitine Therapies for the Treatment of Idiopathic Male Infertility Attending Intracytoplasmic Sperm Injection: A Randomized Controlled Trial. Int J Infertil Fetal Med 2015;6(1):20-24.
THERMOREVERSIBLE COVALENT CROSS-LINKING OF MALEIC ANHYDRIDE GRAFTED BUTYL RUBBER WITH GLYCEROL
Authors: Li Lin , Zhao Shuai , Ma Zhenguo , Xin Zhenxiang 
Published: April 2015

ABSTRACT
The formation of thermoreversible hemi-ester cross-links of maleic anhydride grafted butyl rubber (MAn-g-IIR) using glycerol as a cross-linking agent in the absence of catalyst was studied in the present work. The effects of the molar ratios of glycerol to anhydride, the amount of the mixed solvent, the reaction temperature, and the reaction time on the percentage conversion of anhydride to ester were determined. The maximum percentage conversion calculated from the Fourier transform infrared spectroscopy spectra was 52.11. Reaction temperature played the most important role on the percentage conversion, followed by reaction time. Compared with the original MAn-g-IIR, tensile strength of the hemi-ester cross-linked MAn-g-IIR was significantly improved. These macromolecular regular clusters acted as strong and multiple cross-linking points that led to impressive mechanical properties. This confirmed the formation of hemi-ester cross-links. The covalently cross-linked MAn-g-IIR was reprocessable via compression molding at 179 °C and higher, indicating that the cross-links were indeed thermoreversible. The cross-linked materials could be repeatedly compression molded at 179 °C into homogeneous films for at least three cycles.
Application of the Welfare Quality®animal welfare assessment system in Finnish pig production, part II: Associations between animal-based and environmental measures of welfare
Authors: Munsterhjelm C , Heinonen M , Valros A 
Published: April 2015

AbstractThis study aimed to establish associations between the environment and animal-based measures of welfare collected on 158 Finnish farms according to the Welfare Quality® systems for pigs. The data consisted of 95 welfare assessments in fattening pigs and 103 in sows, including suckling piglets. Principal Component Analysis had previously been applied to animal-based welfare measures (ABWM) and to the 20 descriptors of QBA to identify distinct types of welfare problems (WPT) and mood (MT), respectively. Generalised linear modeling was used to investigate environmental (space allowance, group size, feeding arrangement, floor type and use of enrichment or bedding) effects on WPT and MT scores. Those ABWMs not contributing to the major WPTs, but occurring on more than 40% of the farms, were considered important and used as outcome variables as well. The most important environmental determinants of pig welfare were space allowance for fattening pigs, group size in gestation and in the use of bedding for both fattening pigs and gestating sows. Bedding decreased tail biting and signs of fighting when used as a fairly thick layer for fattening pigs. In sows, the benefits of bedding, including less frustration and bursitis, required a smaller amount of material than in fattening pigs. An increasing space allowance was advantageous for fattening pigs, although signs of fighting increased in very spacious bedded pens. The positive effects of space, including a decrease of tail lesions and a more positive mood continued at least up to 1.5 m2per fattening pig. Signs of resource shortage in sows increased with a growing group size according to a steepening curve.