bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of the octahedral cations on the dimensions of the palygorskite cell
Authors: Suárez M. , García-Romero E. , Sánchez Del Río M. , Martinetto P. , Dooryhée E.
Published: October 2007

High-resolution synchrotron X-ray diffraction recorded on a collection of palygorskites with different chemical compositions (obtained by analytical electron microscopy) permits unambiguous correlation of the crystallographic parametersa(orasin β if a monoclinic phase is considered) with the nature of the octahedral sheet, i.e. with both the number of octahedral positions that are occupied and the type of octahedral cation. No significant changes in the lattice parametersbandcare observed. The unit cell modification consists essentially of an expansion inaas the number of cations with larger ionic radii (Mg2+and Fe3+) predominates over smaller cations (Al3+). A linear dependency ofa(orasin β) on the chemical composition of the octahedral sheet was obtained that can be used for classifying palygorskite into compositional groups, using only conventional diffraction data, without the need for chemical analyses.
Synthesis of linear alkylbenzene sulphonate intercalated iron(II) iron(III) hydroxide sulphate (green rust) and adsorption of carbon tetrachloride
Authors: Ayala-Luis K. B. , Kaldor D. K. , Bender Koch C. , Strobel B. W. , Hansen H. C. B.
Published: October 2007

Green rusts, GRs, can act as both sorbents and reductants towards selected pollutants. Organo-GRs are expected to combine these properties with a high affinity for hydrophobic substances. A novel organo-GR, GRLAS, was synthesized by incorporating a mixture of linear alkylbenzenesulphonates (LAS) into the interlayer space of synthetic sulphate green rust, GRSO4 . Mössbauer analysis of GRLAS indicates that the structure of the organo-GR is very similar to that of the initial GRSO4 with regard to the FeII/FeIII ratio and local coordination of Fe atoms. X-ray diffraction demonstrates that the GRLAS formed was well ordered, although a mixture of surfactant was used for intercalation. The basal spacings of the GRLAS and the kinetics of the ion-exchange process were dependent on the initial surfactant loading; basal spacings of ~2.85 nm were obtained at LAS solution concentrations >10 mM. The ratio LASadsorbed/SO42–desorbed significantly exceeded the stoichiometric ratio of 2 during the initial part of the ion-exchange process (t = 5 h). However, this ratio was reached progressively with time. GRSO4 preferentially sorbed LAS homologues with long alkyl chains over short ones. Carbon tetrachloride was successfully adsorbed into GRLAS. The adsorption isotherm was linear with a distribution coefficient, Kd, of 505±19 litre kg–1.
RNAspa: a shortest path approach for comparative prediction of the secondary structure of ncRNA molecules
Authors: Horesh Yair , Doniger Tirza , Michaeli Shulamit , Unger Ron
Published: October 2007

Background

In recent years, RNA molecules that are not translated into proteins (ncRNAs) have drawn a great deal of attention, as they were shown to be involved in many cellular functions. One of the most important computational problems regarding ncRNA is to predict the secondary structure of a molecule from its sequence. In particular, we attempted to predict the secondary structure for a set of unaligned ncRNA molecules that are taken from the same family, and thus presumably have a similar structure.

Results

We developed the RNAspa program, which comparatively predicts the secondary structure for a set of ncRNA molecules in linear time in the number of molecules. We observed that in a list of several hundred suboptimal minimal free energy (MFE) predictions, as provided by the RNAsubopt program of the Vienna package, it is likely that at least one suggested structure would be similar to the true, correct one. The suboptimal solutions of each molecule are represented as a layer of vertices in a graph. The shortest path in this graph is the basis for structural predictions for the molecule. We also show that RNA secondary structures can be compared very rapidly by a simple string Edit-Distance algorithm with a minimal loss of accuracy. We show that this approach allows us to more deeply explore the suboptimal structure space.

Conclusion

The algorithm was tested on three datasets which include several ncRNA families taken from the Rfam database. These datasets allowed for comparison of the algorithm with other methods. In these tests, RNAspa performed better than four other programs.
Forelimb-hindlimb developmental timing changes across tetrapod phylogeny
Authors: Bininda-Emonds Olaf RP , Jeffery Jonathan E , Sánchez-Villagra Marcelo R , Hanken James , Colbert Matthew , Pieau Claude , Selwood Lynne , ten Cate Carel , Raynaud Albert , Osabutey Casmile K , Richardson Michael K
Published: October 2007

Background

Tetrapods exhibit great diversity in limb structures among species and also between forelimbs and hindlimbs within species, diversity which frequently correlates with locomotor modes and life history. We aim to examine the potential relation of changes in developmental timing (heterochrony) to the origin of limb morphological diversity in an explicit comparative and quantitative framework. In particular, we studied the relative time sequence of development of the forelimbs versus the hindlimbs in 138 embryos of 14 tetrapod species spanning a diverse taxonomic, ecomorphological and life-history breadth. Whole-mounts and histological sections were used to code the appearance of 10 developmental events comprising landmarks of development from the early bud stage to late chondrogenesis in the forelimb and the corresponding serial homologues in the hindlimb.

Results

An overall pattern of change across tetrapods can be discerned and appears to be relatively clade-specific. In the primitive condition, as seen in Chondrichthyes and Osteichthyes, the forelimb/pectoral fin develops earlier than the hindlimb/pelvic fin. This pattern is either retained or re-evolved in eulipotyphlan insectivores (= shrews, moles, hedgehogs, and solenodons) and taken to its extreme in marsupials. Although exceptions are known, the two anurans we examined reversed the pattern and displayed a significant advance in hindlimb development. All other species examined, including a bat with its greatly enlarged forelimbs modified as wings in the adult, showed near synchrony in the development of the fore and hindlimbs.

Conclusion

Major heterochronic changes in early limb development and chondrogenesis were absent within major clades except Lissamphibia, and their presence across vertebrate phylogeny are not easily correlated with adaptive phenomena related to morphological differences in the adult fore- and hindlimbs. The apparently conservative nature of this trait means that changes in chondrogenetic patterns may serve as useful phylogenetic characters at higher taxonomic levels in tetrapods. Our results highlight the more important role generally played by allometric heterochrony in this instance to shape adult morphology.
Optimising the analysis of transcript data using high density oligonucleotide arrays and genomic DNA-based probe selection
Authors: Graham Neil S , Broadley Martin R , Hammond John P , White Philip J , May Sean T
Published: October 2007

Background

Affymetrix GeneChip arrays are widely used for transcriptomic studies in a diverse range of species. Each gene is represented on a GeneChip array by a probe-set, consisting of up to 16 probe-pairs. Signal intensities across probe-pairs within a probe-set vary in part due to different physical hybridisation characteristics of individual probes with their target labelled transcripts. We have previously developed a technique to study the transcriptomes of heterologous species based on hybridising genomic DNA (gDNA) to a GeneChip array designed for a different species, and subsequently using only those probes with good homology.

Results

Here we have investigated the effects of hybridising homologous species gDNA to study the transcriptomes of species for which the arrays have been designed. Genomic DNA from Arabidopsis thaliana and rice (Oryza sativa) were hybridised to the Affymetrix Arabidopsis ATH1 and Rice Genome GeneChip arrays respectively. Probe selection based on gDNA hybridisation intensity increased the number of genes identified as significantly differentially expressed in two published studies of Arabidopsis development, and optimised the analysis of technical replicates obtained from pooled samples of RNA from rice.

Conclusion

This mixed physical and bioinformatics approach can be used to optimise estimates of gene expression when using GeneChip arrays.
DNA copy number profiles of gastric cancer precursor lesions
Authors: Buffart Tineke E , Carvalho Beatriz , Mons Thomas , Reis Rui M , Moutinho Cátia , Silva Paula , van Grieken Nicole CT , Vieth Michael , Stolte Manfred , van de Velde Cornelis JH , Schrock Evelin , Matthaei Anja , Ylstra Bauke , Carneiro Fátima , Meijer Gerrit A
Published: October 2007

Background

Chromosomal instability (CIN) is the most prevalent type of genomic instability in gastric tumours, but its role in malignant transformation of the gastric mucosa is still obscure. In the present study, we set out to study whether two morphologically distinct categories of gastric cancer precursor lesions, i.e. intestinal-type and pyloric gland adenomas, would carry different patterns of DNA copy number changes, possibly reflecting distinct genetic pathways of gastric carcinogenesis in these two adenoma types.

Results

Using a 5K BAC array CGH platform, we showed that the most common aberrations shared by the 11 intestinal-type and 10 pyloric gland adenomas were gains of chromosomes 9 (29%), 11q (29%) and 20 (33%), and losses of chromosomes 13q (48%), 6(48%), 5(43%) and 10 (33%). The most frequent aberrations in intestinal-type gastric adenoma were gains on 11q, 9q and 8, and losses on chromosomes 5q, 6, 10 and 13, whereas in pyloric gland gastric adenomas these were gains on chromosome 20 and losses on 5q and 6. However, no significant differences were observed between the two adenoma types.

Conclusion

The results suggest that gains on chromosomes 8, 9q, 11q and 20, and losses on chromosomes 5q, 6, 10 and 13, likely represent early events in gastric carcinogenesis. The phenotypical entities, intestinal-type and pyloric gland adenomas, however, do not differ significantly (P = 0.8) at the level of DNA copy number changes.
Comparative genomic analysis of Tropheryma whipplei strains reveals that diversity among clinical isolates is mainly related to the WiSP proteins
Authors: La My-Van , Crapoulet Nicolas , Barbry Pascal , Raoult Didier , Renesto Patricia
Published: October 2007

Background

The aim of this study was to analyze the genomic diversity of severalTropheryma whippleistrains by microarray-based comparative genomic hybridization. Fifteen clinical isolates originating from biopsy samples recovered from different countries were compared with theT. whippleiTwist strain. For each isolate, the genes were defined as either present or absent/divergent using the GACK analysis software. Genomic changes were then further characterized by PCR and sequencing.

Results

The results revealed a limited genetic variation among theT. whippleiisolates, with at most 2.24% of the probes exhibiting differential hybridization against the Twist strain. The main variation was found in genes encoding the WiSP membrane protein family. This work also demonstrated a 19.2 kb-pair deletion within theT. whippleiDIG15 strain. This deletion occurs in the same region as the previously described large genomic rearrangement between Twist and TW08/27. Thus, this can be considered as a major hot-spot for intra-specificT. whippleidifferentiation. Analysis of this deleted region confirmed the role of WND domains in generatingT. whippleidiversity.

Conclusion

This work provides the first comprehensive genomic comparison of severalT. whippleiisolates. It reveals that clinical isolates originating from various geographic and biological sources exhibit a high conservation rate, indicating thatT. whippleirarely interacts with exogenous DNA. Remarkably, frequent inter-strain variations were dicovered that affected members of the WiSP family.
RETRACTED ARTICLE: Agmatine protects retinal ganglion cells from hypoxia-induced apoptosis in transformed rat retinal ganglion cell line
Authors: Hong Samin , Lee Jong Eun , Kim Chan Yun , Seong Gong Je
Published: October 2007

Background

Agmatine is an endogenous polyamine formed by the decarboxylation of L-arginine. We investigated the protective effects of agmatine against hypoxia-induced apoptosis of immortalized rat retinal ganglion cells (RGC-5). RGC-5 cells were cultured in a closed hypoxic chamber (5% O2) with or without agmatine. Cell viability was determined by lactate dehydrogenase (LDH) assay and apoptosis was examined by annexin V and caspase-3 assays. Expression and phosphorylation of mitogen-activated protein kinases (MAPKs; JNK, ERK p44/42, and p38) and nuclear factor-kappa B (NF-κB) were investigated by Western immunoblot analysis. The effects of agmatine were compared to those of brain-derived neurotrophic factor (BDNF), a well-known protective neurotrophin for retinal ganglion cells.

Results

After 48 hours of hypoxic culture, the LDH assay showed 52.3% cell loss, which was reduced to 25.6% and 30.1% when agmatine and BDNF were administered, respectively. This observed cell loss was due to apoptotic cell death, as established by annexin V and caspase-3 assays. Although total expression of MAPKs and NF-κB was not influenced by hypoxic injury, phosphorylation of these two proteins was increased. Agmatine reduced phosphorylation of JNK and NF-κB, while BDNF suppressed phosphorylation of ERK and p38.

Conclusion

Our results show that agmatine has neuroprotective effects against hypoxia-induced retinal ganglion cell damage in RGC-5 cells and that its effects may act through the JNK and NF-κB signaling pathways. Our data suggest that agmatine may lead to a novel therapeutic strategy to reduce retinal ganglion cell injury related to hypoxia.
X-ray structures of two proteins belonging to Pfam DUF178 revealed unexpected structural similarity to the DUF191 Pfam family
Authors: Tyagi Rajiv , Burley Stephen K , Swaminathan Subramanyam
Published: October 2007

Background

Pfam is a comprehensive collection of protein domains and families, with a range of well-established information including genome annotation. Pfam has two large series of functionally uncharacterized families, known as Domains of Unknown Function (DUFs) and Uncharacterized Protein Families (UPFs).

Results

Crystal structures of two proteins from Deinococcus radiodurans and Streptomyces coelicolor belonging to Pfam protein family DUF178 (ID: PF02621) have been determined using Selenium-Single-wavelength Anomalous Dispersion (Se-SAD). Based on the structure, we have identified the putative function for this family of protein.

Conclusion

Unexpectedly, we found that DUF178 Pfam is remarkably similar to Pfam family DUF191 suggesting that the sequence-based classification alone may not be sufficient to classify proteins into Pfam families.
Metal ion-dependent, reversible, protein filament formation by designed beta-roll polypeptides
Authors: Scotter Andrew J , Guo Meng , Tomczak Melanie M , Daley Margaret E , Campbell Robert L , Oko Richard J , Bateman David A , Chakrabartty Avijit , Sykes Brian D , Davies Peter L
Published: October 2007

Background

A right-handed, calcium-dependent β-roll structure found in secreted proteases and repeat-in-toxin proteins was used as a template for the design of minimal, soluble, monomeric polypeptides that would fold in the presence of Ca2+. Two polypeptides were synthesised to contain two and four metal-binding sites, respectively, and exploit stacked tryptophan pairs to stabilise the fold and report on the conformational state of the polypeptide.

Results

Initial analysis of the two polypeptides in the presence of calcium suggested the polypeptides were disordered. The addition of lanthanum to these peptides caused aggregation. Upon further study by right angle light scattering and electron microscopy, the aggregates were identified as ordered protein filaments that required lanthanum to polymerize. These filaments could be disassembled by the addition of a chelating agent. A simple head-to-tail model is proposed for filament formation that explains the metal ion-dependency. The model is supported by the capping of one of the polypeptides with biotin, which disrupts filament formation and provides the ability to control the average length of the filaments.

Conclusion

Metal ion-dependent, reversible protein filament formation is demonstrated for two designed polypeptides. The polypeptides form filaments that are approximately 3 nm in diameter and several hundred nm in length. They are not amyloid-like in nature as demonstrated by their behaviour in the presence of congo red and thioflavin T. A capping strategy allows for the control of filament length and for potential applications including the "decoration" of a protein filament with various functional moieties.
Patterns of tumor response in canine and feline cancer patients treated with electrochemotherapy: preclinical data for the standardization of this treatment in pets and humans
Authors: Spugnini Enrico P , Baldi Feliciano , Mellone Pasquale , Feroce Florinda , D'Avino Alfredo , Bonetto Francesco , Vincenzi Bruno , Citro Gennaro , Baldi Alfonso
Published: October 2007

Electrochemotherapy (ECT) is a novel anticancer therapy that is currently being evaluated in human and pet cancer patients. ECT associates the administration of an anti-tumor agent to the delivery of trains of appropriate waveforms. The increased uptake of chemotherapy leads to apoptotic death of the neoplasm thus resulting in prolonged local control and extended survival. In this paper we describe the histological features of a broad array of spontaneous tumors of companion animals receiving pulse-mediated chemotherapy. Multivariate statistical analysis of the percentage of necrosis and apoptosis in the tumors before and after ECT treatment, shows that only a high percentage of necrosis and apoptosis after the ECT treatment were significantly correlated with longer survivals of the patients (p < 0.0001 and p = 0.004, respectively). Further studies on this topic are warranted in companion animals with spontaneous tumors to identify new molecular targets for electrochemotherapy and to the develop new therapeutical protocols to be translated to humans.
Dopaminergic regeneration by neurturin-overexpressing c17.2 neural stem cells in a rat model of Parkinson's disease
Authors: Liu Wei-Guo , Wang Xi-Jing , Lu Guo-Qiang , Li Biao , Wang Gang , Chen Sheng-Di
Published: October 2007

Background

Genetically engineered neural stem cell (NSC) lines are promising vectors for the treatment of neurodegenerative diseases, particularly Parkinson's disease (PD). Neurturin (NTN), a member of the glial cell line-derived neurotrophic factor (GDNF) family, has been demonstrated to act specifically on mesencephalic dopaminergic neurons, suggesting its therapeutic potential for PD. In our previous work, we demonstrated that NTN-overexpressing c17.2 NSCs exerted dopaminergic neuroprotection in a rat model of PD. In this study, we transplanted NTN-c17.2 into the striatum of the 6-hydroxydopamine (6-OHDA) PD model to further determine the regenerative effect of NTN-c17.2 on the rat models of PD.

Results

After intrastriatal grafting, NTN-c17.2 cells differentiated and gradually downregulated nestin expression, while the grafts stably overexpressed NTN. Further, an observation of rotational behavior and the contents of neurotransmitters tested by high-performance liquid chromatography showed that the regenerative effect of the NTN-c17.2 group was significantly better than that of the Mock-c17.2 group, and the regenerative effect of the Mock-c17.2 group was better than that of the PBS group. Further research through reverse-transcriptase polymerase chain reaction assays and in vivo histology revealed that the regenerative effect of Mock-c17.2 and NTN-c17.2 cell grafts may be attributed to the ability of NSCs to produce neurotrophic factors and differentiate into tyrosine hydroxylase-positive cells.

Conclusion

The transplantation of NTN-c17.2 can exert neuroregenerative effects in the rat model of PD, and the delivery of NTN by NSCs may constitute a very useful strategy in the treatment of PD.
Comparison of different commercial kits for HER2 testing in breast cancer: looking for the accurate cutoff for amplification
Authors: Cayre Anne , Mishellany Florence , Lagarde Nicole , Penault-Llorca Frédérique
Published: October 2007

Introduction

Accurate determination of human epidermal growth factor receptor 2 (HER2) status is essential for optimal patient management with trastuzumab (Herceptin). However, standard guidelines do not specify a particular commercial kit, antibody or probe for testing, and discrepancies arise from variability between kits. The aim of this study was to compare the accuracy of four commercially available fluorescence/chromogenic in situ hybridisation (FISH/CISH) kits and validate one for the resolution of borderline immunohistochemistry (IHC) cases. The interpretation pitfalls, optimal threshold values, assay duration and complexity of each kit were also considered.

Methods

The Food and Drug Administration (FDA)-approved dual-probe FISH assay PathVysion was chosen as the 'gold standard' against which pharmDx (dual-probe) and INFORM (mono-probe) FDA-approved FISH kits and the SPoT-Light CISH kit were compared. Tumours were also evaluated by IHC with the FDA-approved HercepTest kit and a validated in-house IHC protocol. Fifty-five patients with invasive breast carcinoma were selected as a representative proportion of HER2 IHC 2+ cases.

Results

HER2 amplification was observed in 31% of tumours by PathVysion compared with 33% with pharmDx. The number of amplified tumours detected by INFORM and CISH varied with the threshold applied. Agreement was excellent between PathVysion and pharmDx (100%), good with SPoT-Light (89%; cutoff at least five signals per nucleus) and moderate with INFORM (76%; cutoff more than four signals per nucleus). Agreement with INFORM improved to 98% with a cutoff of at least six signals per nucleus.

Conclusion

With an appropriate cutoff, the INFORM kit was comparable to dual-probe FISH kits for evaluating HER2 status. We validate and recommend CISH as an appropriate assay for HER2 scoring that is easy to interpret and requires equipment readily found in, or that can be adapted to, all pathology laboratories. For borderline IHC cases, dual-probe FISH analysis remains the most useful protocol to apply.
Genetic Polymorphisms of Transforming Growth Factor β‐1 Promoter and Primary Biliary Cirrhosis in Japanese Patients
Authors: KIKUCHI KENTARO , TANAKA ATSUSHI , MATSUSHITA MASANAO , KITAZAWA ERIKO , HOSOYA NAOMI , KAWASHIMA YUMI , SELMI CARLO , GERSHWIN M. ERIC , MIYAKAWA HIROSHI
Published: October 2007

Abstract:  As suggested by concordance rates in twins, genetic factors are critical to the susceptibility and progression of primary biliary cirrhosis (PBC). Among cytokines, transforming growth factor beta‐1 (TGF‐β1) plays an important role in autoimmunity and liver fibrosis and a TGF‐β1 receptor knockout mouse has been recently proposed as a model for PBC. The promoter region of the TGF‐β1 gene has two single nucleotide polymorphisms (SNPs) at positions −800 and −509, which influence serum concentrations of latent and active TGF‐β1. We studied genomic DNA from 65 Japanese patients with PBC and 71 matched healthy controls for the association of TGF‐β1 SNPs analyzed by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) with susceptibility and disease progression of PBC. The −800 G to A SNP was not found in the Japanese population and no significant difference in the distribution of TGF‐β1 promoter gene −509 SNP was found between PBC cases and controls. Further, TGF‐β1 genotypes failed to correlate with clinical parameters, including histological stage and prognostic score. In conclusion, the TGF‐β1 promoter gene SNPs are not associated with disease susceptibility or progression in Japanese patients with PBC.
Genetic Background of Anticyclic Citrullinated Peptide Autoantibody Production in Hungarian Patients with Rheumatoid Arthritis
Authors: POÓR GYULA , NAGY ZSOLT B. , SCHMIDT ZSUZSANNA , BRÓZIK MÁRTA , MERÉTEY KATALIN , GERGELY PÉTER
Published: October 2007

Abstract:  Polymorphisms of the peptidylarginine deiminase 4 (PADI4) gene encoding for the isoenzyme that converts arginyl into citrullyl residues have been shown to contribute to susceptibility to rheumatoid arthritis (RA), depending on the population studied. We aimed at determining whether PADI4 single nucleotide polymorphisms (SNPs) are associated with RA in a Hungarian population. The relationship between anticyclic citrullinated peptide (anti‐CCP) production and HLA‐DRB1 alleles encoding the shared epitope (SE) was also investigated. DNA samples were obtained from RA (n= 261) patients and from control donors (n= 120). HLA‐DRB1 genotyping was carried out by polymerase chain reaction (PCR) with sequence‐specific priming. PAD4_92 G/C and PAD4_104 T/C SNPs were genotyped using real‐time PCR allele discrimination. Autoantibodies against CCP were detected by ELISA. All healthy controls tested anti‐CCP negative, whereas 171 (66%) RA patients were anti‐CCP positive. No significant difference in allele or genotype frequencies were found between RA patients and controls for any of the PADI4 SNPs. Anti‐CCP seropositivity was unrelated to these two SNPs. No association was found between any of the PADI4 SNPs and HLA‐DRB1 subtypes. Presence of the HLA‐RB1 SE alleles was significantly associated with anti‐CCP seropositivity; HLA‐DRB1*0401 and HLA‐DRB1*1001 carriers showed the strongest association. In conclusion, our data suggest that polymorphisms of the PADI4 gene are not associated with rheumatoid arthritis and are unlikely to be responsible for the presence of anti‐CCP autoantibodies in a white Hungarian population. HLA‐DRB1 SE alleles, however, may significantly contribute to the genetic determination of anti‐CCP production in Hungarian patients with RA.
Role of the Interferon‐Inducible Gene IFI16 in the Etiopathogenesis of Systemic Autoimmune Disorders
Authors: MONDINI MICHELE , VIDALI MATTEO , AIRÒ PAOLO , DE ANDREA MARCO , RIBOLDI PIERSANDRO , MERONI PIER LUIGI , GARIGLIO MARISA , LANDOLFO SANTO
Published: October 2007

Abstract:  Interferons (IFNs) are now known to exert a multitude of immunological functions on both the innate and adaptive immunity. Given their pleiotropic effects on the immune system, it is conceivable that excess type I IFN or aberrant regulation of its signaling could contribute to autoimmunity. Several lines of evidence link IFNs to autoimmune disorders, in particular to systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). Expression of a spectrum of genes that constitutes an “IFN signature” is the most significant observation indicating that IFNs may be dominant among the pathogenic mediators involved in some autoimmune diseases. A family of IFN‐inducible genes, designated HIN‐200 in the human and IFI‐200 in the murine species, encodes evolutionary related human (IFI16, MNDA, AIM2, IFIX) and murine proteins (Ifi202 a, Ifi202b, Ifi203, Ifi204, Ifi205/D3). Physiological IFI16 expression was found in cells of the immune system, in endothelial cells, and in stratified squamous epithelia, such as skin. The presence of anti‐IFI16 antibodies was reported in SLE and primary/secondary Sjögren's syndrome. More recently, we reported that anti‐IFI16 autoantibodies differentiate limited cutaneous systemic sclerosis (lcSSc) from diffuse systemic sclerosis (dcSSc). Molecular studies performed in primary endothelial cells overexpressing IFI16 demonstrated that it may be involved in the early steps of inflammation by modulating endothelial cell function, such as expression of adhesion molecules and chemokine production, cell growth, and apoptosis. Moreover, here we report that IFI16 expression is induced by proinflammatory cytokines. In this article the role of the IFI16 protein and its corresponding autoantibodies in the etiopathogenesis of systemic autoimmune diseases, in which chronic inflammation is involved, are discussed.
Nitric Oxide Signaling Triggered by the Rheumatoid Arthritis–Shared Epitope
Authors: HOLOSHITZ JOSEPH , LING SONG
Published: October 2007

Abstract:  Many immune‐mediated diseases are associated with particular MHC class I or class II alleles. In rheumatoid arthritis (RA‐shared), the vast majority of patients possess HLA‐DRB1 alleles encoding a shared epitope, which is a five–amino acid sequence motif in positions 70–74 of the HLA‐DRβ chain. The mechanistic basis for this association is unknown. Here we discuss recent evidence suggesting that the shared epitope may act as an allele‐specific ligand that triggers increased nitric oxide (NO) production in opposite cells with resultant immune dysregulation. We propose that by doing that, the RA‐shared shared epitope may form an unintended bridge between the innate and adaptive immune systems, thereby allowing aberrant signaling events that could trigger disease.
X Monosomy in Female Systemic Lupus Erythematosus
Authors: INVERNIZZI PIETRO , MIOZZO MONICA , OERTELT‐PRIGIONE SABINE , MERONI PIER LUIGI , PERSANI LUCA , SELMI CARLO , BATTEZZATI PIER MARIA , ZUIN MASSIMO , LUCCHI SIMONA , MARASINI BIANCA , ZENI SILVANA , WATNIK MITCHELL , TABANO SILVIA , MAITZ SILVIA , PASINI SIMONE , GERSHWIN M. ERIC , PODDA MAURO
Published: October 2007

Abstract:  Systemic lupus erythematosus (SLE) is a systemic autoimmune disease, predominantly occurring in women of childbearing age. SLE, like several other autoimmune diseases, is characterized by a striking female predominance and, although sex hormone influences have been suggested as an explanation for this phenomenon, definitive data are still unavailable. Our group recently reported an increased X monosomy in lymphocytes of women, affected with primary biliary cirrhosis (PBC), systemic sclerosis (SSc), and autoimmune thyroiditis (AITD) in comparison to healthy women, thus suggesting the involvement of this chromosome in female predominance and in the deregulation of the immune system that characterizes autoimmunity. We have now evaluated X monosomy rates in SLE using fluorescence in situ hybridization (FISH) on peripheral mononuclear white blood cells (PBMCs) from female patients compared to healthy age‐matched controls. In addition, because of a previous finding of microchimerism as a pathogenetic cause of a number of autoimmune diseases, we investigated the presence of cells carrying the Y chromosome. We did not identify an increased X monosomy in women with SLE compared to controls (P= 0.3960, SLE vs. HCs, Student's t‐test), thus suggesting that a different mechanism of immune deregulation might be predominant in the female population of patients with SLE.
Gene Vaccination for the Induction of Immune Tolerance
Authors: FERRERA FRANCESCA , CAVA ANTONIO LA , RIZZI MARTA , HAHN BEVRA H. , INDIVERI FRANCESCO , FILACI GILBERTO
Published: October 2007

Abstract:  DNA vaccination is a strategy of immunization based on the injection of a gene encoding for a target protein with the goal of eliciting a potentially protective immune response in the host. Compared to traditional immunization procedures, DNA vaccination offers several advantages: increased availability of antigenic peptides because of the endogenous and long‐term synthesis of the gene product, improved antigen processing and presentation, possibility of antigen structure modeling through molecular engineering, coexpression of immunologically relevant agents, and low cost of vaccine production. Although the choice of the most appropriate vector for gene transfer may still be controversial, the application of DNA vaccination to the treatment of autoimmune diseases in different experimental animal models has demonstrated the great potential of this procedure for therapeutic purposes. DNA vaccination has been successful in protecting mice from the development of organ‐specific autoimmunity (experimental allergic encephalomyelitis (EAE), autoimmune diabetes, experimental arthritis, experimental uveitis) as well as systemic autoimmune disease (systemic lupus erythematosus (SLE), antiphospholipid syndrome). The protection appears to be highly influenced by the capacity of DNA vaccination to modulate immune responses affecting the Th1, Th2 and, importantly, the T cell immunoregulatory arms. We review here the experimental evidence and most recent data supporting the use of DNA vaccination in the induction of immune tolerance.
A Genome‐Wide Study of Lupus
Authors: CERVINO ALESSANDRA C. L. , TSINOREMAS NICHOLAS F. , HOFFMAN ROBERT W.
Published: October 2007

Abstract:  Systemic lupus erythematosus (SLE) is a complex autoimmune disease in which genetics is one of the underlying risk factors. Complicating the analysis of SLE is the fact that the phenotype is heterogeneous, with variations in clinical features, and subgroups are associated with a variety of different autoantibodies. Many association studies of candidate genes as well as linkage studies have generated significant results, highlighting the multigenetic component of the disease. Those findings need to be replicated by independent laboratories and many other genes still remain to be identified. Here, we present our findings on the first genome‐wide association study performed in 105 Caucasian patients and controls using the Affymetrix NspI array. The SLE patients studied here were all characterized by the presence of autoantibodies against the U1–6 small nuclear ribonucleoprotein antigen spliceosomal complex. Testing each SNP individually for association with disease, we identified 7 markers with an uncorrected P‐value < 0.0001. Of those, three were in reported regions of linkage, namely 20p12, 2q37, and 4p15. To increase the power of our study, we included 60 controls corresponding to the parents from the publicly available CEPH families. The analysis of the 165 cases and controls leads to 28 SNPs being associated with an uncorrected P‐value < 0.0001.
T Cell Receptor Gene Therapy for Autoimmune Diseases
Authors: FUJIO KEISHI , OKAMURA TOMOHISA , OKAMOTO AKIKO , YAMAMOTO KAZUHIKO
Published: October 2007

Abstract:  The current quality of autoimmune disease treatments is not satisfactory in regard to efficacy and safety. Antigen‐specific immunotherapy is a future therapy that could achieve maximal efficacy with minimal adverse effects. T cells are essential components in antigen‐specific immunity. However, we do not have a sufficient strategy for manipulating antigen‐specific T cells. We propose that T cell receptor (TCR) gene transfer is a hopeful approach for antigen‐specific immunotherapy. We confirmed the efficacy of TCR gene therapy in animal models of systemic autoimmune disease and arthritis. In lupus‐prone NZB/W F1 mice, nucleosome‐specific TCR and CTLA4Ig transduced cells suppressed autoantibody production and nephritis development. In the therapeutic experiment of collagen‐induced arthritis (CIA), arthritis‐related TCRs were isolated from single T cells accumulating in the arthritis site. Arthritis‐related TCR and TNFRIg transduced cells or TCR and Foxp3 transduced cells suppressed arthritis progression and bone destruction. Therefore, engineered antigen‐specific cells manipulated to express appropriate functional genes could be applied to specific immunotherapy.
Interstitial Lung Disease Associated with Systemic Sclerosis
Authors: BÉREZNÉ ALICE , VALEYRE DOMINIQUE , RANQUE BRIGITTE , GUILLEVIN LOÏC , MOUTHON LUC
Published: October 2007

Abstract:  Interstitial lung disease (ILD) is a common manifestation of systemic sclerosis (SSc) that may be responsible for severe restrictive lung disease and represents one of the two main causes of disease‐related death in SSc patients. Since 1993, the beneficial effect of oral or intravenous cyclophosphamide (CYC) in the treatment of SSc‐related ILD has been reported in retrospective studies, one study showing improvement of pulmonary function test scores and/or chest computed tomography at 1 year and improvement of survival at 16 months. The results of two controlled trials were recently reported. The Scleroderma Lung Study, a prospective randomized placebo‐controlled trial, included 158 patients of whom 145 completed at least 6 months of treatment. The course of forced vital capacity (primary outcome) adjusted at 1 year was significantly better in the group treated with oral CYC (P < 0.03), although the effect of CYC was minor. The Fibrosing Alveolitis in Scleroderma Trial (FAST) included 45 patients with SSc‐related ILD who were randomized to receive prednisolone (20 mg per day) and 6 CYC infusions (600 mg/m monthly) or placebo. This trial did not demonstrate significant improvement of the primary or secondary endpoints in the active treatment group versus placebo. Since with the exception of the study of Silver et al. none of the patients included in retrospective or prospective studies were selected on the basis of progression of ILD. Since only a minority of SSc patients develops severe ILD, we propose that further studies evaluating CYC should focus on the subgroup of SSc patients with worsening ILD.
Treatment of Autoimmune Disease with Rabbit Anti‐T Lymphocyte Globulin
Authors: LYTTON SIMON D. , DENTON CHRISTOPHER P. , NUTZENBERGER ACHIM M.
Published: October 2007

Abstract:  The rabbit anti‐T lymphocyte globulins (rATGs) are immune‐suppressive anti‐T cell agents with beneficial effects in solid organ and hematological transplantation. The present review evaluates the potential mechanisms of rATGs and their impact on pilot and exploratory studies of diffuse cutaneous systemic sclerosis (scleroderma‐SSc), inclusion body myositis (IBM), vasculitis, and type 1 diabetes mellitus (T1DM). The rATGs are associated with improvements in well‐defined parameters of clinical autoimmunity: insulin usage, tissue inflammation, and systemic organ functions. Meta‐analysis of a retrospective database of SSc, N= 196 and two prospective randomized pilot studies; IBM, N= 11 and T1DM, N= 17 shows a two‐ to ninefold increase in the relative response to treatments with intravenous infusions of rATG. The rATGs deplete T cells and are associated with increases in the percentage of CD25+ T cell subsets. This may underlie the apparent long‐lasting immunomodulation associated with these agents. The future optimization of rATG adjunct therapy requires statistically powered‐controlled prospective trials of rATG dose‐finding and timing of administration. The potential mechanisms of rATGs:depletion of autoreactive T cells, generation CDCD25+Foxp3+ regulatory T cells (Tregs), and the acquisition of regulatory immune cell functions, need to be examined in patients prior to rATG infusion and at time intervals following rATG treatment to identify those mechanisms relevant to the improvement of their clinical outcome.
Acute ST Elevation Myocardial Infarction during Intravenous Immunoglobulin Infusion
Authors: BARSHESHET ALON , MARAI IBRAHIM , APPEL SHMULIK , ZIMLICHMAN EYAL
Published: October 2007

Abstract:  Intravenous immunoglobulin (IVIG) preparations are increasingly being used in the treatment of autoimmune disorders. This treatment is regarded as generally safe, and most of the adverse effects associated with IVIG administration are mild and transient. This paper reports a 72‐year‐old patient with known ischemic heart disease admitted for a Guillain–Barré syndrome variant, who developed acute ST elevation myocardial infarction (MI) during the first hours of IVIG infusion. The literature on acute MI during IVIG treatment is reviewed. Evaluation of each patient for cardiovascular risk prior to IVIG treatment is recommended as is the assessment of risk versus benefit. If IVIG is prescribed, we propose close monitoring and slow infusion rate.
Allogenic Mixed Chimerism Induced by Nonlymphoablative Regimen Including Donor BMT with Low‐Dose TBI and Anti‐CD40L Cured Proliferative Glomerulonephritis in Lupus Mice
Authors: TAKEUCHI EMIKO , TAKEUCHI YASUO
Published: October 2007

Abstract:  Allogeneic mixed chimerism achieved by low‐dose total body irradiation (TBI) and anti‐CD40L monoclonal antibody (mAb) with donor bone marrow transplantation (BMT) and host T cell depletion overcomes both allo‐ and autoimmunity. We investigated whether a similar regimen without T cell depletion cured diffuse proliferative glomerulonephritis. Male BXSB mice (H‐2b) were injected with 20 × 106 BALB/c (H‐2d) BM cells. When indicated, 3 Gy TBI on day –1 and anti‐CD40LmAb (2 mg) on day 0 of BMT was given. Skin grafting was performed 1 day after BMT. BXSB mice were divided into four groups—I: BMT with TBI and anti‐CD40LmAb; II: TBI; III: TBI and anti‐CD40LmAb; and IV: no treatment. Chimerism in peripheral blood was analyzed. The kidney was examined histologically. TBI with anti‐CD40LmAb and BMT allowed induction of multilineage mixed chimerism and donor‐specific tolerance to skin grafts without graft‐versus‐host disease (GVHD). There was significant decrease in glomerular PAS‐positive material deposition score, glomerular cell numbers, IgG, and C3 deposition in chimeric mice. All chimeric mice survived. Allogeneic mixed chimerism induced by a less toxic, nonlymphoablative regimen achieved allograft tolerance and cured glomerulonephritis in BXSB lupus mice.
Targeting Vascular Adhesion Protein‐1 to Treat Autoimmune and Inflammatory Diseases
Authors: SMITH DAVID J. , VAINIO PETRI J.
Published: October 2007

Abstract:  The development of new, safe, and effective anti‐inflammatory drugs represents a major challenge for the pharmaceutical industry, as well as a significant opportunity. The increasing prevalence of chronic inflammatory and autoimmune diseases associated with an aging population has led to an intense effort to discover new anti‐inflammatory drug targets and drugs acting against them. This review highlights the recent progress made in developing therapies directed against an endothelial cell adhesion molecule called vascular adhesion protein (VAP)‐1 for the treatment of chronic inflammatory disease as well as highlighting other therapeutic opportunities offered by this vascular target.
Dual Inhibition of Dipeptidyl Peptidase IV and Aminopeptidase N Suppresses Inflammatory Immune Responses
Authors: REINHOLD DIRK , BITON ALIZA , GOIHL ALEXANDER , PIEPER STEFANIE , LENDECKEL UWE , FAUST JÜRGEN , NEUBERT KLAUS , BANK UTE , TÄGER MICHAEL , ANSORGE SIEGFRIED , BROCKE STEFAN
Published: October 2007

Abstract:  The ectopeptidases dipeptidyl peptidase IV (DP IV, CD26) and aminopeptidase N (APN, CD13) are known to regulate T cell activation. Since selective inhibitors of DP IV and APN suppress DNA synthesis and cytokine production of stimulated T cells in a TGF‐β1‐dependent manner, we tested whether combined application of DP IV and APN inhibitors enhances this immunomodulatory effect. The results show that simultaneous application of DP IV and APN inhibitors significantly suppressed DNA synthesis in mitogen‐ or anti‐CD3‐stimulated human T cells in vitro when compared to the use of a single DP IV or APN inhibitor. Moreover, the combined action of DP IV and APN inhibitors markedly increased TGF‐β1 production associated with the observed immunosuppressive effects. In vivo, targeting both DP IV and APN led to a potent treatment of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis (MS). This review summarizes the evidence for the role of both enzymes in T cell activation in vitro and in vivo and provides a rationale for using combined and dual peptidase inhibitors to treat autoimmune diseases like MS.
Therapeutic Challenges for Systemic Sclerosis
Authors: CERINIC MATUCCI M. , DEL ROSSO ANGELA , FEDERICO PERFETTO , LIVI RICCARDO , FIORI GINEVRA , BARTOLI FRANCESCA , BLAGOJEVIC JELENA , TEMPESTINI ALESSIO , PIGNONE ALBERTO
Published: October 2007

Abstract:  Pulmonary arterial hypertension (PAH) is an important cause of death in systemic sclerosis (SSc), despite the improvement of therapies. An early diagnosis and the use of drugs interfering with the main pathogenic pathways of PAH is pivotal for the improvement of prognosis in primary PAH and PAH secondary to autoimmune rheumatic diseases, mainly SSc. Lately, new specific therapies have been developed targeting prostacyclin, endothelin, and nitric oxide pathways, the major pathogenic pathways leading to endothelial dysfunction in PAH. Epoprostenol improved life expectancy of patients with primary and secondary PAH, but its continuous intravenous administration requires experienced centers. More stable analogues of prostacyclin, administrated by intravenous (iloprost, treprostinil), subcutaneous, inhalatory (treprostinil, iloprost), and oral route (Beraprost) have shown efficacy in PAH. Bosentan, the first oral endothelin receptor antagonist (with affinity for endothelin A and B receptors) improves exercise function and survival in PAH, both primary and secondary to autoimmune rheumatic diseases. This is confirmed also for Sitaxsentan and Ambrisentan, selective A receptor antagonists. Because of its short half‐life and systemic side effects, short‐term NO inhalation is used only in short‐term management of PAH in critically ill adults. Inhibitors of NO degradation, such as sildenafil, a phosphodiesterase (PDE) type 5 inhibitor, improved functional and hemodynamic parameters without significant side effects. Vardenafil and taladafil, longer‐acting PDE inhibitors, also have vascular pulmonary selectivity. All these drugs may be used in combination, to maximize their clinical benefit not only in patients unresponsive to single drugs, but also potentially as initial therapy of PAH.
Autologous Stem Cell Transplantation for Severe Autoimmune Diseases
Authors: GUALANDI F. , BRUNO B. , Van LINT M.T. , LUCHETTI S. , UCCELLI A. , CAPELLO E. , MANCARDI G.L. , BACIGALUPO A. , MARMONT A.
Published: October 2007

Abstract:  The first autologous hematopoietic stem cell transplantation in Europe for a patient with severe refractory systemic lupus erythematosus (SLE) was performed in Genoa in 1996. Since then, 32 patients with a wide spectrum of autoimmune diseases (ADs) received autologous transplants, 22 of them with multiple sclerosis (MS). There were no fatal adverse events. All patients had complete or very good partial remissions, but relapses were frequent, especially in SLE, though never as aggressive as pretransplant. The mechanism of action of this intervention remains not completely understood, as briefly discussed here.