bluuebunny/crossref_metadata_2025_split huggingface dataset:
Signaling of High Mobility Group Box 1 (HMGB1) through Toll-like Receptor 4 in Macrophages Requires CD14
Authors: Kim Sodam , Kim Sun Young , Pribis John P. , Lotze Michael , Mollen Kevin P. , Shapiro Richard , Loughran Patricia , Scott Melanie J. , Billiar Timothy R. 
Published: July 2013

AbstractHigh mobility group box 1 (HMGB1) is a DNA-binding protein that possesses cytokinelike, proinflammatory properties when released extracellularly in the C23–C45 disulfide form. HMGB1 also plays a key role as a mediator of acute and chronic inflammation in models of sterile injury. Although HMGB1 interacts with multiple pattern recognition receptors (PRRs), many of its effects in injury models occur through an interaction with toll-like receptor 4 (TLR4). HMGB1 interacts directly with the TLR4/myeloid differentiation protein 2 (MD2) complex, although the nature of this interaction remains unclear. We demonstrate that optimal HMGB1-dependent TLR4 activation in vitro requires the coreceptor CD14. TLR4 and MD2 are recruited into CD14-containing lipid rafts of RAW264.7 macrophages after stimulation with HMGB1, and TLR4 interacts closely with the lipid raft protein GM1. Furthermore, we show that HMGB1 stimulates tumor necrosis factor (TNF)-α release in WT but not in TLR4−/−, CD14−/−, TIR domain-containing adapter-inducing interferon-β (TRIF)−/− or myeloid differentiation primary response protein 88 (MyD88)−/− macrophages. HMGB1 induces the release of monocyte chemotactic protein 1 (MCP-1), interferon gamma-induced protein 10 (IP-10) and macrophage inflammatory protein 1α (MIP-1α) in a TLR4- and CD14-dependent manner. Thus, efficient recognition of HMGB1 by the TLR4/MD2 complex requires CD14.
Effect of Recombinant α1-Antitrypsin Fc-Fused (AAT-Fc) Protein on the Inhibition of Inflammatory Cytokine Production and Streptozotocin-Induced Diabetes
Authors: Lee Siyoung , Lee Youngmin , Hong Kwangwon , Hong Jaewoo , Bae Suyoung , Choi Jida , Jhun Hyunjhung , Kwak Areum , Kim Eunsom , Jo Seunghyun , Dinarello Charles A. , Kim Soohyun 
Published: July 2013

Abstractα1-Antitrypsin (AAT) is a member of the serine proteinase inhibitor family that impedes the enzymatic activity of serine proteinases, including human neutrophil elastase, cathepsin G and neutrophil proteinase 3. Here, we expressed recombinant AAT by fusing the intactAATgene to the constant region of IgG1 to generate soluble recombinant AAT-Fc protein. The recombinant AAT-Fc protein was produced in Chinese hamster ovary (CHO) cells and purified using mini-protein A affinity chromatography. Recombinant AAT-Fc protein was tested for antiinflammatory function and AAT-Fc sufficiently suppressed tumor necrosis factor (TNF)-α-induced interleukin (IL)-6 in human peripheral blood mononuclear cells (PBMCs) and inhibited cytokine-induced TNFα by different cytokines in mouse macrophage Raw 264.7 cells. However, AAT-Fc failed to suppress lipopolysaccharide-induced cytokine production in both PBMCs and macrophages. In addition, our data showed that AAT-Fc blocks the development of hyperglycemia in a streptozotocin-induced mouse model of diabetes. Interestingly, we also found that plasma-derived AAT specifically inhibited the enzymatic activity of elastase but that AAT-Fc had no inhibitory effect on elastase activity.
In Vivo Regulation of the μ Opioid Receptor: Role of the Endogenous Opioid Agents
Authors: Gonzalez-Nunez Veronica , González Ada Jimenez , Barreto-Valer Katherine , Rodríguez Raquel E. 
Published: July 2013

AbstractIt is well known that genotypic differences can account for the subject-specific responses to opiate administration. In this regard, the basal activity of the endogenous system (either at the receptor or ligand level) can modulate the effects of exogenous agonists as morphine and vice versa. The µ opioid receptor from zebrafish, dre-oprm1, binds endogenous peptides and morphine with similar affinities. Morphine administration during development altered the expression of the endogenous opioid propeptides proenkephalins and proopiomelanocortin. Treatment with opioid peptides (Met-enkephalin (Met-ENK), Met-enkephalin-Gly-Tyr (MEGY) and β-endorphin (β-END)) modulated dre-oprm1 expression during development. Knocking down the dre-oprm1 gene significantly modified the mRNA expression of the penk and pomc genes, thus indicating that oprm1 is involved in shaping penk and pomc expression. In addition, the absence of a functional oprm1 clearly disrupted the embryonic development, since proliferation was disorganized in the central nervous system of oprm1-morphant embryos: mitotic cells were found widespread through the optic tectum and were not restricted to the proliferative areas of the mid- and hindbrain. Transferase-mediated dUTP nick-end labeling (TUNEL) staining revealed that the number of apoptotic cells in the central nervous system (CNS) of morphants was clearly increased at 24-h postfertilization. These findings clarify the role of the endogenous opioid system in CNS development. Our results will also help unravel the complex feedback loops that modulate opioid activity and that may be involved in establishing a coordinated expression of both receptors and endogenous ligands. Further knowledge of the complex interactions between the opioid system and analgesic drugs will provide insights that may be relevant for analgesic therapy.
Loss-of-Function Ferrochelatase and Gain-of-Function Erythroid-Specific 5-Aminolevulinate Synthase Mutations Causing Erythropoietic Protoporphyria and X-Linked Protoporphyria in North American Patients Reveal Novel Mutations and a High Prevalence of X-Linked Protoporphyria
Authors: Balwani Manisha , Doheny Dana , Bishop David F. , Nazarenko Irina , Yasuda Makiko , Dailey Harry A. , Anderson Karl E. , Bissell D. Montgomery , Bloomer Joseph , Bonkovsky Herbert L. , Phillips John D. , Liu Lawrence , Desnick Robert J. ,   The Porphyrias Consortium of the National Institutes of Health Rare Diseases Clinical Research Network
Published: July 2013

AbstractErythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are inborn errors of heme biosynthesis with the same phenotype but resulting from autosomal recessive loss-of-function mutations in the ferrochelatase (FECH) gene and gain-of-function mutations in the X-linked erythroid-specific 5-aminolevulinate synthase (ALAS2) gene, respectively. The EPP phenotype is characterized by acute, painful, cutaneous photosensitivity and elevated erythrocyte protoporphyrin levels. We report the FECH and ALAS2 mutations in 155 unrelated North American patients with the EPP phenotype. FECH sequencing and dosage analyses identified 140 patients with EPP: 134 with one loss-of-function allele and the common IVS3-48T>C low expression allele, three with two loss-of-function mutations and three with one loss-of-function mutation and two low expression alleles. There were 48 previously reported and 23 novel FECH mutations. The remaining 15 probands had ALAS2 gain-of-function mutations causing XLP: 13 with the previously reported deletion, c.1706_1709delAGTG, and two with novel mutations, c.1734delG and c.1642C>T(p.Q548X). Notably, XLP represented ~10% of EPP phenotype patients in North America, two to five times more than in Western Europe. XLP males had twofold higher erythrocyte protoporphyrin levels than EPP patients, predisposing to more severe photosensitivity and liver disease. Identification of XLP patients permits accurate diagnosis and counseling of at-risk relatives and asymptomatic heterozygotes.
XBP-1s Is Linked to Suppressed Gluconeogenesis in the Ebb Phase of Burn Injury
Authors: Brooks Natasha C. , Marshall Alexandra H. , Qa’aty Nour , Hiyama Yaeko , Boehning Darren , Jeschke Marc G. 
Published: July 2013

AbstractThe first 24 h following burn injury is known as the ebb phase and is characterized by a depressed metabolic rate. While the postburn ebb phase has been well described, the molecular mechanisms underlying this response are poorly understood. The endoplasmic reticulum (ER) regulates metabolic rate by maintaining glucose homeostasis through the hepatic ER stress response. We have shown that burn injury leads to ER stress in the liver during the first 24 h following thermal injury. However, whether ER stress is linked to the metabolic responses during the ebb phase of burn injury is poorly understood. Here, we show in an animal model that burn induces activation of activating transcription factor 6 (ATF6) and inositol requiring enzyme-1 (IRE-1) and this leads to increased expression of spliced X-box binding protein-1 (XBP-1s) messenger ribonucleic acid (mRNA) during the ebb phase. This is associated with increased expression of XBP-1target genes and downregulation of the key gluconeogenic enzyme glucose-6-phosphatase (G6Pase). We conclude that upregulation of the ER stress response after burn injury is linked to attenuated gluconeogenesis and sustained glucose tolerance in the postburn ebb phase.
Anti-CD38 Antibody Therapy: Windows of Opportunity Yielded by the Functional Characteristics of the Target Molecule
Authors: Chillemi Antonella , Zaccarello Gianluca , Quarona Valeria , Ferracin Manuela , Ghimenti Chiara , Massaia Massimo , Horenstein Alberto L. , Malavasi Fabio 
Published: July 2013

AbstractIn vivo use of monoclonal antibodies (mAbs) has become a mainstay of routine clinical practice in the treatment of various human diseases. A number of molecules can serve as targets, according to the condition being treated. Now entering human clinical trials, CD38 molecule is a particularly attractive target because of its peculiar pattern of expression and its twin role as receptor and ectoenzyme. This review provides a range of analytical perspectives on the current progress in and challenges to anti-CD38 mAb therapy. We present a synopsis of the evidence available on CD38, particularly in myeloma and chronic lymphocytic leukemia (CLL). Our aim is to make the data from basic science helpful and accessible to a diverse clinical audience and, at the same time, to improve its potential for in vivo use. The topics covered include tissue distribution and signal implementation by mAb ligation and the possibility of increasing cell density on target cells by exploiting information about the molecule’s regulation in combination with drugs approved for in vivo use. Also analyzed is the behavior of CD38 as an enzyme: CD38 is a component of a pathway leading to the production of adenosine in the tumor microenvironment, thus inducing local anergy. Consequently, not only might CD38 be a prime target for mAb-mediated therapy, but its functional block may contribute to general improvement in cancer immunotherapy and outcomes.
Preclinical Studies in the mdx Mouse Model of Duchenne Muscular Dystrophy with the Histone Deacetylase Inhibitor Givinostat
Authors: Consalvi Silvia , Mozzetta Chiara , Bettica Paolo , Germani Massimiliano , Fiorentini Francesco , Del Bene Francesca , Rocchetti Maurizio , Leoni Flavio , Monzani Valmen , Mascagni Paolo , Puri Pier Lorenzo , Saccone Valentina 
Published: July 2013

AbstractPrevious work has established the existence of dystrophin-nitric oxide (NO) signaling to histone deacetylases (HDACs) that is deregulated in dystrophic muscles. As such, pharmacological interventions that target HDACs (that is, HDAC inhibitors) are of potential therapeutic interest for the treatment of muscular dystrophies. In this study, we explored the effectiveness of long-term treatment with different doses of the HDAC inhibitor givinostat in mdx mice—the mouse model of Duchenne muscular dystrophy (DMD). This study identified an efficacy for recovering functional and histological parameters within a window between 5 and 10 mg/kg/d of givinostat, with evident reduction of the beneficial effects with 1 mg/kg/d dosage. The long-term (3.5 months) exposure of 1.5-month-old mdx mice to optimal concentrations of givinostat promoted the formation of muscles with increased cross-sectional area and reduced fibrotic scars and fatty infiltration, leading to an overall improvement of endurance performance in treadmill tests and increased membrane stability. Interestingly, a reduced inflammatory infiltrate was observed in muscles of mdx mice exposed to 5 and 10 mg/kg/d of givinostat. A parallel pharmacokinetic/pharmacodynamic analysis confirmed the relationship between the effective doses of givinostat and the drug distribution in muscles and blood of treated mice. These findings provide the preclinical basis for an immediate translation of givinostat into clinical studies with DMD patients.
Erythropoietin Receptor (EpoR) Agonism Is Used to Treat a Wide Range of Disease
Authors: Sanchis-Gomar Fabian , Perez-Quilis Carme , Lippi Giuseppe 
Published: July 2013

AbstractThe erythropoietin receptor (EpoR) was discovered and described in red blood cells (RBCs), stimulating its proliferation and survival. The target in humans for EpoR agonists drugs appears clear—to treat anemia. However, there is evidence of the pleitropic actions of erythropoietin (Epo). For that reason, rhEpo therapy was suggested as a reliable approach for treating a broad range of pathologies, including heart and cardiovascular diseases, neurodegenerative disorders (Parkinson’s and Alzheimer’s disease), spinal cord injury, stroke, diabetic retinopathy and rare diseases (Friedreich ataxia). Unfortunately, the side effects of rhEpo are also evident. A new generation of nonhematopoietic EpoR agonists drugs (asialoEpo, Cepo and ARA 290) have been investigated and further developed. These EpoR agonists, without the erythropoietic activity of Epo, while preserving its tissue-protective properties, will provide better outcomes in ongoing clinical trials. Nonhematopoietic EpoR agonists represent safer and more effective surrogates for the treatment of several diseases such as brain and peripheral nerve injury, diabetic complications, renal ischemia, rare diseases, myocardial infarction, chronic heart disease and others.
Utilization of Bipolar Membrane Electrodialysis for Salt Water Treatment
Authors: Venugopal Krishnaveni , Dharmalingam Sangeetha 
Published: July 2013

ABSTRACT: Bipolar ion‐exchange membranes, using polystyrene ethylene utylenes polystyrene (PSEBS) with polyvinyl alcohol as the intermediate, were fabricated and evaluated for their potential to remove secondary salts from lab‐prepared salt solutions. Experiments were carried out in batch re‐circulation mode. The mechanical properties and microscopic images of the membranes were analyzed before, during, and after the electrodialysis process. The performance of the membranes in the stack was evaluated in terms of energy consumption and current efficiency, and found to be 1.07 Wh/mol and 0.67, respectively. Commercially‐produced membranes were used as a comparison to the PSEBS‐based membranes. In the case of the commercial membrane, polystyrene divinylbenzene, the values for the above parameters were observed to be 2.59 Wh/mol and 0.63, respectively. In addition, other parameters, such as transport number of ions and acid – alkali production, were evaluated for both PSEBS‐based and commercially‐produced membranes. Results indicated that PSEBS‐based membranes exhibited better performance than the commercial membranes.
The Prediction of Type 1 Diabetes by Multiple Autoantibody Levels and Their Incorporation Into an Autoantibody Risk Score in Relatives of Type 1 Diabetic Patients
Authors: Sosenko Jay M. , Skyler Jay S. , Palmer Jerry P. , Krischer Jeffrey P. , Yu Liping , Mahon Jeffrey , Beam Craig A. , Boulware David C. , Rafkin Lisa , Schatz Desmond , Eisenbarth George ,   the Type 1 Diabetes TrialNet and the Diabetes Prevention Trial–Type 1 Study Groups
Published: July 2013

OBJECTIVEWe assessed whether a risk score that incorporates levels of multiple islet autoantibodies could enhance the prediction of type 1 diabetes (T1D).RESEARCH DESIGN AND METHODSTrialNet Natural History Study participants (n = 784) were tested for three autoantibodies (GADA, IA-2A, and mIAA) at their initial screening. Samples from those positive for at least one autoantibody were subsequently tested for ICA and ZnT8A. An autoantibody risk score (ABRS) was developed from a proportional hazards model that combined autoantibody levels from each autoantibody along with their designations of positivity and negativity.RESULTSThe ABRS was strongly predictive of T1D (hazard ratio [with 95% CI] 2.72 [2.23–3.31], P &lt; 0.001). Receiver operating characteristic curve areas (with 95% CI) for the ABRS revealed good predictability (0.84 [0.78–0.90] at 2 years, 0.81 [0.74–0.89] at 3 years, P &lt; 0.001 for both). The composite of levels from the five autoantibodies was predictive of T1D before and after an adjustment for the positivity or negativity of autoantibodies (P &lt; 0.001). The findings were almost identical when ICA was excluded from the risk score model. The combination of the ABRS and the previously validated Diabetes Prevention Trial–Type 1 Risk Score (DPTRS) predicted T1D more accurately (0.93 [0.88–0.98] at 2 years, 0.91 [0.83–0.99] at 3 years) than either the DPTRS or the ABRS alone (P ≤ 0.01 for all comparisons).CONCLUSIONSThese findings show the importance of considering autoantibody levels in assessing the risk of T1D. Moreover, levels of multiple autoantibodies can be incorporated into an ABRS that accurately predicts T1D.
High-Risk Human Papillomavirus (Hpv) Infection in Women Undergoing in Vitro Fertilization / Okužbe Z Visokorizičnimi Genotipi Humanih Papilomskih Virusov (Hpv) Pri Ženskah, Vključenih V Postopke Zunajtelesne Oploditve
Authors: Jančar Nina , Vrtačnik Bokal Eda , Poljak Mario , Oštrbenk Anja 
Published: July 2013

Abstract
Objective: The aim of our study was to establish the prevalence of high-risk human papillomavirus (hr-HPV) infection in a population of women included in an in vitro fertilisation (IVF) program and to correlate the outcome of IVF cycles with HPV status.
Methods: A total of 195 women undergoing the IVF program were included in the study. A cervical smear for cytological analysis and hr-HPV determination was collected from every woman. RealTime High Risk HPV test (Abbott Molecular Inc., Des Plaines, IL) has been used for the detection of hr-HPV infection. All participants were invited to complete an anonymous questionnaire that included questions regarding medical and sexual history as well as risk factors for HPV infection. HPV 16 and HPV 18 positive women were invited for follow-up gynaecological examinations, including colposcopy 4 to 6 months after the inclusion.
Results: Mean age of included infertile women was 33.7 ± 4.36 years. A total of 16/195 women (8.2%) were hr-HPV positive. Hr-HPV infection was not associated with the percentage of mature oocytes, the percentage of fertilised oocytes, with embryo quality or with pregnancy rate in our study.
Conclusions: The prevalence of hr-HPV genotypes in Slovenian infertile women undergoing IVF is lower than the hr-HPV prevalence in the general population. We were unable to find an association between hr-HPV cervical infection and the outcome of IVF cycles.
Burden of Type 2 Diabetes from the Healthcare Payer Perspective in Slovenia / Breme Sladkorne Bolezni Tipa 2 S Stališča Plačnika Zdravstvenega Varstva V Sloveniji
Authors: Nerat Tomaž , Kos Mitja 
Published: July 2013

Abstract
Introduction: Diabetes prevalence and costs are rising on aglobal scale. Therefore, it is necessary to periodically conduct cost studies for assessing the healthcare burden impact. In Slovenia, the last type 2 diabetes cost assessment was conducted in 2006, not including all diabetes complication costs. The aim of this study was to revise, update and compare to previously published datadirect healthcare costs of type 2 diabetes in Slovenia with additional complications costs consideration.
Methods: The study was performed from the healthcare payer perspective using the bottom-up approach, was prevalence based and estimated direct medical costs.
Results: We estimated total yearly direct medical costs of type 2 diabetes in Slovenia to 99,120,419 euro with annual per capita costs of 834.70 euro. The highest cost shares were attributed to cardiovascular complication costs (21,683,919 euro), diabetes co-medication (20,977,269 euro) and diabetes treatment medication (18,505,015 euro). Highest yearly costs per complication (all cases, all occurrences) were estimated for dialysis I and III (9,162,635 euro), stroke first year costs (4,951,306 euro) and congestive heart failure first year costs (4,879,533 euro). Yearly per one patient, the complication costs were highest for kidney transplantation, followed by dialysis I and III (78,621.25 euro and 36,797.73 euro)
Conclusions: In comparison to the costs published in the literature before, our estimated total yearly direct medical costs were comparable, although annual per capita costs were assessed lower than elsewhere. Further, regarding the complication costs estimations, our assessed expenses were comparable to those published in other countries.
Attitudes Towards Genetically Modified Organisms in Slovenia: Between Knowledge and Myths / Stališča Do Genetsko Modificiranih Organizmov V Sloveniji: Poznavanje In Miti
Authors: Erjavec Karmen , Zajc Jožica , Poler Kovačič Melita , Šuštar Vozlič Jelka , Uhan Samo , Juvančič Luka 
Published: July 2013

Abstract
Objective: Because existing studies examining the impact of knowledge on people’s attitudes towards genetically modified organisms (GMOs) have had contradictory results, the goal of this study was to explore the attitudes that the population of Slovenia has towards GMOs and how knowledge affects their attitudes.
Methods: In January 2012, a telephone survey was conducted researching attitudes towards GMOs and knowledge about them on a representative sample of the population of Slovenia (N=446).
Results: The results revealed a predominantly negative attitude towards GMOs, regardless of their type, application and geographical distance; perceptions of the negative impact of GMOs on an individual’s health were particularly strong. The majority of respondents (59.5%) had moderate knowledge about GMOs, while a largeshare (30.4%) had poor knowledge of the topic. They had better objective knowledge about topics linked to formal education or legislation and a weaker understanding of mass media myths. Correlation analysis and one-way analysis of variance showed a statistically significant correlation between knowledge and attitudes towards GMOs. The respondents with better objective knowledge (who gave the correct answers to test questions) had a less firm and a more positive attitude towards GMOs and vice versa. The respondents who lacked objective knowledge but expressed subjective knowledge (they were convinced that their answers were correct) on average had a more negative attitude towards GMOs compared to those who lacked subjective knowledge.
Conclusions: This finding leads to the conclusion that knowledge, particularly relating to media myths about GMOs, has an important role in forming attitudes towards the impact of GMOs on an individual’s health.