bluuebunny/crossref_metadata_2025 huggingface dataset:
Gene Expression Profiling in Lungs of Chronic Asthmatic Mice Treated with Galectin-3: Downregulation of Inflammatory and Regulatory Genes
Authors: López Esther , Zafra M. Paz , Sastre Beatriz , Gámez Cristina , Lahoz Carlos , del Pozo Victoria
Published: March 2011

Background. Asthma is a disorder characterized by a predominance of Th2 cells and eosinophilic inflammation. Suppressors of cytokine signaling (SOCS) proteins act as negative regulators of cytokine signaling. In particular, SOCS1 and SOCS3 play an important role in immune response by controlling the balance between Th1 and Th2 cells. In a previous study, we demonstrated that treatment of chronic asthmatic mice with gene therapy using plasmid encoding galectin-3 (Gal-3) led to an improvement in Th2 allergic inflammation.Methods. Using a microarray approach, this study endeavored to evaluate the changes produced by therapeutic Gal-3 delivered by gene therapy in a well-characterized mouse model of chronic airway inflammation. Results were confirmed by real-time RT-PCR, Western blot and immunohistochemical analysis.Results. We identify a set of genes involved in different pathways whose expression is coordinately decreased/increased in mice treated with Gal-3 gene therapy. We report a correlation between Gal-3 treatment and inhibition of SOCS1 and SOCS3 expression in lungs.Conclusion. These results suggest that negative regulation of SOCS1 and 3 following Gal-3 treatment could be a valuable therapeutic approach in allergic disease.
Peculiarities of Shape Recovery in Polymer Composites with Compacting Filler
Authors: Beloshenko V. A. , Voznyak Yu. V.
Published: March 2011

Peculiarities of the shape memory effect development in composites based on the epoxy polymer and various fillers, such as thermoexpanded graphite, aerosils, metallized graphite, and basalt flakes, have been investigated. It has been determined that straining followed by the shape recovery of composites is accompanied by changes in their volume. Extent and character of the changes depend on the ability of fillers to compaction under pressure, deformation scheme, adsorption ability of the filler. It is shown that the combined deformation consisting of compression and stretching of specimens in different sequence gives structural states for which the longitudinal strain-transverse strain ratio can take zero, positive, or negative values.
Existence Result of Generalized Vector Quasiequilibrium Problems in Locally "Equation missing" -Convex Spaces
Authors: Plubtieng Somyot , Sitthithakerngkiet Kanokwan
Published: March 2011

This paper deals with the generalized strong vector quasiequilibrium problems without convexity in locally "Equation missing"-convex spaces. Using the Kakutani-Fan-Glicksberg fixed point theorem for upper semicontinuous set-valued mapping with nonempty closed acyclic values, the existence theorems for them are established. Moreover, we also discuss the closedness of strong solution set for the generalized strong vector quasiequilibrium problems.
Therapeutic Targeting of PELP1 Prevents Ovarian Cancer Growth and Metastasis
Authors: Chakravarty Dimple , Roy Sudipa Saha , Babu Challa Ram , Dandamudi Rajasekhar , Curiel Tyler J. , Vivas-Mejia Pablo , Lopez-Berestein Gabriel , Sood Anil K. , Vadlamudi Ratna K.
Published: March 2011

Purpose: Ovarian cancer remains a major threat to women's health, partly due to difficulty in early diagnosis and development of metastases. A critical need exists to identify novel targets that curb the progression and metastasis of ovarian cancer. In this study, we examined whether the nuclear receptor coregulator PELP1 (proline-, glutamic acid-, leucine-rich protein-1) contributes to progression and metastatic potential of ovarian cancer cells and determined whether blocking of the PELP1 signaling axis had a therapeutic effect.

Experimental Design: Ovarian cancer cells stably expressing PELP1-shRNA (short hairpin RNA) were established. Fluorescent microscopy, Boyden chamber, invasion assays, wound healing, and zymography assays were performed to examine the role of PELP1 in metastasis. Expression analysis of the model cells was conducted using tumor metastasis microarray to identify PELP1 Target genes. Therapeutic potential of PELP1-siRNA in vivo was determined using a nanoliposomal formulation of PELP1-siRNA-DOPC (1,2-dioleoyl-sn-glycero-3-phosphatidylcholine) administered systemically in a xenograft model.

Results: PELP1 knockdown caused cytoskeletal defects and significantly affected the migratory potential of ovarian cancer cells. Microarray analysis revealed that PELP1 affected the expression of selective genes involved in metastasis including Myc, MTA1, MMP2, and MMP9. Zymography analysis confirmed that PELP1 knockdown caused a decrease in the activation of matrix metalloproteases (MMP) 2 and MMP9. Compared with control siRNA-DOPC–treated mice, animals injected with PELP1-siRNA-DOPC had 54% fewer metastatic tumor nodules, exhibited a 51% reduction in tumor growth and an 84% reduction in ascites volume.

Conclusion: The results suggest that PELP1 signaling axis is a potential druggable target and liposomal PELP1-siRNA-DOPC could be used as a novel drug to prevent or treat ovarian metastasis. Clin Cancer Res; 17(8); 2250–9. ©2011 AACR.
Brain-Derived Neurotrophic Factor Promotes Tumorigenesis via Induction of Neovascularization: Implication in Hepatocellular Carcinoma
Authors: Lam Chi-Tat , Yang Zhen-Fan , Lau Chi-Keung , Tam Ka-Ho , Fan Sheung-Tat , Poon Ronnie T.P.
Published: March 2011

Purpose: Brain-derived neurotrophic factor (BDNF) has emerged as a novel angiogenic factor, and yet its impact on tumorigenesis is unclear. This study aimed at investigating the roles of BDNF in angiogenesis and tumor development.

Experimental Design: BDNF was overexpressed in a mouse endothelial cell (EC) line by stable transfection, and angiogenic properties of the transfectants were assessed. Microarray analysis was employed to explore the molecular pathways. The impact of modulating BDNF levels in two mouse EC lines on tumorigenic potential of a transformed mouse liver cell line was evaluated by an in vivo cotransplantation model. BDNF and tropomyosin receptor kinase B (TrkB) protein levels were determined in 50 pairs of human hepatocellular carcinoma (HCC) tissues by Western blotting and immunohistochemistry. Survival analysis was carried out to determine their clinical significance.

Results: Overexpression of BDNF could promote EC proliferation, migration, invasion, and survival. Microarray and molecular studies showed that RhoA, caspase-9, caspase-3, growth arrest specific 6, and VEGF could mediate BDNF/TrkB-induced angiogenesis. The cotransplantation experiment showed that high BDNF-expressing ECs could facilitate tumor angiogenesis and growth, whereas knockdown of BDNF by short hairpin RNAs impaired such effects. Furthermore, examination on human HCC tissues revealed upregulation of BDNF and TrkB protein levels in 46.0% and 33.3% of the cases studied, respectively. Immunohistochemistry disclosed strong BDNF reactivity in both tumor and endothelial cells. High TrkB expression was associated with shorter overall survival.

Conclusions: BDNF/TrkB system was crucial for tumor angiogenesis and growth, which may represent a potential target for antiangiogenic therapy in HCC. Clin Cancer Res; 17(10); 3123–33. ©2011 AACR.
Vorinostat Increases Expression of Functional Norepinephrine Transporter in Neuroblastoma In Vitro and In Vivo Model Systems
Authors: More Swati S. , Itsara Melissa , Yang Xiaodong , Geier Ethan G. , Tadano Michelle K. , Seo Youngho , VanBrocklin Henry F. , Weiss William A. , Mueller Sabine , Haas-Kogan Daphne A. , DuBois Steven G. , Matthay Katherine K. , Giacomini Kathleen M.
Published: March 2011

Purpose: Histone deacetylase (HDAC) inhibition causes transcriptional activation or repression of several genes that in turn can influence the biodistribution of other chemotherapeutic agents. Here, we hypothesize that the combination of vorinostat, a HDAC inhibitor, with 131I-meta-iodobenzylguanidine (MIBG) would lead to preferential accumulation of the latter in neuroblastoma (NB) tumors via increased expression of the human norepinephrine transporter (NET).

Experimental Design: In vitro and in vivo experiments examined the effect of vorinostat on the expression of NET, an uptake transporter for 131I-MIBG. Human NB cell lines (Kelly and SH-SY-5Y) and NB1691-luc mouse xenografts were employed. The upregulated NET protein was characterized for its effect on 123I-MIBG biodistribution.

Results: Preincubation of NB cell lines, Kelly, and SH-SY-5Y, with vorinostat caused dose-dependent increases in NET mRNA and protein levels. Accompanying this was a corresponding dose-dependent increase in MIBG uptake in NB cell lines. Four- and 2.5-fold increases were observed in Kelly and SH-SY-5Y cells, respectively, pretreated with vorinostat in comparison to untreated cells. Similarly, NB xenografts, created by intravenous tail vein injection of NB1691-luc, and harvested from nude mice livers treated with vorinostat (150 mg/kg i.p.) showed substantial increases in NET protein expression. Maximal effect of vorinostat pretreatment in NB xenografts on 123I-MIBG biodistribution was observed in tumors that exhibited enhanced uptake in vorinostat-treated [0.062 ± 0.011 μCi/(mg tissue-dose injected)] vs. -untreated mice [0.022 ± 0.003 μCi/(mg tissue-dose injected); P < 0.05].

Conclusions: The results of our study provide preclinical evidence that vorinostat treatment can enhance NB therapy with 131I-MIBG. Clin Cancer Res; 17(8); 2339–49. ©2011 AACR.
Aspirin and Low-Dose Nitric Oxide–Donating Aspirin Increase Life Span in a Lynch Syndrome Mouse Model
Authors: Mcilhatton Michael A. , Tyler Jessica , Kerepesi Laura A. , Bocker-Edmonston Tina , Kucherlapati Melanie H. , Edelmann Winfried , Kucherlapati Raju , Kopelovich Levy , Fishel Richard
Published: March 2011

Nonsteroidal anti–inflammatory drugs (NSAID) appear to be effective cancer chemopreventives. Previous cellular studies showed that aspirin (acetylsalicylic acid: ASA) and nitric oxide–donating ASA (NO-ASA) suppressed microsatellite instability (MSI) in mismatch repair (MMR)-deficient cells linked to the common cancer predisposition syndrome hereditary nonpolyposis colorectal cancer or Lynch syndrome (LS/HNPCC), at doses 300- to 3,000-fold less than ASA. Using a mouse model that develops MMR-deficient intestinal tumors that appear pathologically identical to LS/HNPCC, we show that ASA (400 mg/kg) and low-dose NO-ASA (72 mg/kg) increased life span by 18% to 21%. We also note a trend where ASA treatment resulted in intestinal tumors with reduced high MSI (H-MSI) and increased low MSI (L-MSI) as defined by the Bethesda Criteria. Low-dose NO-ASA had a minimal effect on MSI status. In contrast to previous studies, high-dose NO-ASA (720/1,500 mg/kg) treatments increased tumor burden, decreased life span, and exacerbated MSI uniquely in the LS/HNPCC mouse model. These results suggest that MMR-deficient tissues/mice may be specifically sensitive to intrinsic pharmacokinetic features of this drug. It is likely that long-term treatment with ASA may represent a chemopreventive option for LS/HNPCC patients. Moreover, as low-dose NO-ASA shows equivalent life span increase at 10-fold lower doses than ASA, it may have the potential to significantly reduce the gastropathy associated with long-term ASA treatment. Cancer Prev Res; 4(5); 684–93. ©2011 AACR.
Molecular Subtypes and Tumor Response to Neoadjuvant Chemotherapy in Patients with Locally Advanced Breast Cancer
Authors: Kim Seung Il , Sohn Joohyuk , Koo Ja Seung , Park Se Ho , Park Hyung Seok , Park Byeong Woo
Published: March 2011

Objective: Pathologic complete response (pCR) is the most predictive factor for patients with neoadjuvant chemotherapy and we investigated the rate of pCR according to molecular subtypes defined by immunohistochemical staining. Methods: Our subjects comprised 257 breast cancer patients who received 3 cycles of anthracycline/taxane-based neoadjuvant chemotherapy. The patients were classified into 4 subtypes: luminal A, luminal B, HER2 and triple negative. We analyzed the pCR rate and treatment outcome according to these subtypes. Results: Of a total of 257 patients, the pCR rate of luminal A, luminal B, HER2 and triple negative was 3.9, 5.0, 10.5 and 21.1%, respectively (p = 0.001). The 5-year disease-free survival of the pCR group (88.4%) was higher than that of the non-pCR group (65.6%), but it was not significant (p = 0.228). Among patients who have residual disease, the 5-year disease-free survival of luminal A, luminal B, HER2 and triple negative was 64.0, 65.7, 75.2 and 66.5%, respectively (p = 0.243). Triple negative and HER2 subtypes are more sensitive to neoadjuvant chemotherapy. Conclusion: To increase the pCR rate, type-specific approaches according to subtypes, such as an addition of trastuzumab, increasing the number of cycles or a novel regimen, should be considered.
Partial Duplication of 18q Including a Distal Critical Region for Edwards Syndrome in a Patient with Normal Phenotype and Oligoasthenospermia: Case Report
Authors: Quiroga R. , Monfort S. , Oltra S. , Ferrer-Bolufer I. , Roselló M. , Mayo S. , Martinez F. , Orellana C.
Published: March 2011

Several authors have attempted to construct a phenotype map for duplications of different portions of chromosome 18 to identify a possible critical region (CR) for Edwards Syndrome. Partial duplications of 18q have been reported in the literature involving the distal CR in patients with some clinical features of Edwards Syndrome. Here, we describe a phenotypically normal male with a large duplication on chromosome 18 that involves the proposed distal CR. The lack of clinical features is remarkable, except for pathological semen analysis, which suggests that terminal 17.4 Mb of 18q do not contain the Edwards Syndrome CR. Alternatively, unknown modifier factors or undetected somatic mosaicism might cause incomplete penetrance of this duplication.
Cytogenetic Mapping of the Retroelements Rex1, Rex3 and Rex6 among Cichlid Fish: New Insights on the Chromosomal Distribution of Transposable Elements
Authors: Valente G.T. , Mazzuchelli J. , Ferreira I.A. , Poletto A.B. , Fantinatti B.E.A. , Martins C.
Published: March 2011

To enhance our understanding of the organization of the genome and chromosome evolution of cichlid fish species, we have isolated and physically mapped onto the chromosomes the transposable elements (TEs) Rex1, Rex3 and Rex6, which are conserved in teleost fish, in the chromosomes of African and South American cichlid species. The physical mapping of different Rex elements showed that they are primarily compartmentalized in the pericentromeric heterochromatic regions, although dispersed or clustered signals in euchromatic regions were also observed. The presence of TEs in heterochromatin can be correlated with their role in the structure and organization of heterochromatic areas (such as centromeres) or with the lower selective pressure that act on these gene-poor regions. The Rex elements were also concentrated in the largest chromosome pair of the Nile tilapia, Oreochromis niloticus. This chromosome pair is supposed to have originated by fusions, demonstrating the possible involvement of TEs with chromosome rearrangements. Besides general patterns of chromosomal distribution, comparative analysis suggests that Rex elements could differ in their chromosomal distribution among different fish groups or species and that intrinsic aspects of the genomes could influence the spread, accumulation or elimination of TEs.
Is Capecitabine Efficacious in Triple Negative Metastatic Breast Cancer?
Authors: Kotsori A.A. , Dolly S. , Sheri A. , Parton M. , Shaunak N. , Ashley S. , Walsh G. , Johnston S. , Smith I.E.
Published: March 2011

Background: Recent data suggest that capecitabine may have little efficacy in women with metastatic triple negative breast cancer (TNT). We have therefore retrospectively analysed capecitabine outcome in the TN subgroup of patients with locally advanced or metastatic breast cancer treated in our unit. Patients and Methods: All TNT patients on our prospectively maintained database with locally advanced or metastatic breast cancer who were given capecitabine as 1st-, 2nd- or 3rd-line chemotherapy were assessed for response and outcome. Results: In total, 363 patients with locally advanced or metastatic breast cancer treated with capecitabine were identified. Eighty-nine (24.5%) patients had TNT and of these, 47 (53%) patients received capecitabine as 1st-line treatment and 42 (47%) as 2nd- or 3rd-line treatment. The overall response rate was 21% (95% CI: 13–31%), including 1 (1%) complete response (CR) and 18 (20%) partial responses (PR). Another 11 (12%) patients maintained stable disease (SD) for ≥6 months. An overall disease control (CR + PR + SD) was, therefore, achieved in 30 (33%) patients. The median time to disease progression was 11 weeks (95% CI: 9–13) and the median overall survival was 39 weeks (95% CI: 33–45). Median response duration was 22 weeks (95% CI: 18–25). No significant difference in efficacy was seen between 1st- and 2nd-/3rd-line treatment. Conclusion: Capecitabine is a treatment option for patients with TN tumours in advanced disease including 1st line and 2nd/3rd line.
Local Recurrence after Breast Cancer Affects Specific Survival Differently according to Patient Age
Authors: Courdi A. , Doyen J. , Gal J. , Chamorey E.
Published: March 2011

Purpose: Young age is known to be an independent factor for developing local recurrence (LR) in breast cancer patients. It has also been shown that the occurrence of LR negatively affects patient outcome, especially if LR occurs within 3 years after treatment of the primary tumour. The question whether the impact of LR on patient outcome differs according to the patient’s age has not been addressed before. The purpose of the present study is to investigate cancer-specific survival (CSS) as well as overall survival after LR in young patients (<50 years old) and to compare it to older patients. The age cut-off level was taken as 50 to avoid strong imbalance in patient numbers between the 2 groups. Patients and Methods: Between 1974 and 2003, 2,130 breast cancer patients were treated with conservative surgery and axillary dissection. All of them received post-operative radiotherapy. Adjuvant chemo- and/or hormonal therapy was given according to the prognostic factors and the treatment policy at the time of diagnosis. Only biopsy-confirmed ipsilateral LRs were taken into account. Early LRs were those observed within 36 months after surgery, and late LRs were those which occurred thereafter. The median follow-up was 100 months. Survival analysis was conducted with the Kaplan-Meier method. Results: The median age was 59 years. There were 472 patients aged <50 years versus 1,658 older patients. Pathological tumour size, hormone receptor status and lymph node involvement were evenly distributed in the 2 groups. The 5- and 10-year CSS was 92.3 and 83.9% in young patients, and 94.4 and 87.6% in older patients (p = 0.061), respectively. Overall, 200 LRs were observed; 52 of them (26%) were early LRs. The rate of LR was significantly higher in young patients: at 5 years, it was 10.5 versus 3.7% in patients ≧50 years; the respective rates at 10 years were 17.8 and 8.8% (p < 0.0001). The 5- and 10-year CSS in patients who developed LR was 86.8 and 76.0%, versus 94.7 and 88.2% in patients who did not develop LR (p < 0.0001). The 5-year CSS after LR in young and older patients was 77.6 and 65.7%, respectively (p = 0.028). Conclusion: Although young patients experience more LR than older ones, once LR occurs, young patients have a better outcome than the others. Possible hypotheses are: (1) more aggressive treatment in young patients after LR; (2) the treatment is better sustained in young patients; (3) biological differences in the characteristics of LR.
A Pilot Feasibility Study of TNFerade™ Biologic with Capecitabine and Radiation Therapy Followed by Surgical Resection for the Treatment of Rectal Cancer
Authors: Citrin Deborah , Camphausen Kevin , Wood Bradford J. , Quezado Martha , Denobile John , Pingpank James F. , Royal Richard E. , Alexander H. Richard , Seidel Geoffrey , Steinberg Seth M. , Shuttack Yvonne , Libutti Steven K.
Published: March 2011

Objective: The purpose of this pilot study was to evaluate the feasibility and tolerability of weekly intratumoral TNFerade™ injections combined with concurrent capecitabine and radiotherapy in the treatment of patients with locally advanced rectal cancer. Methods: Patients with T3, T4, or N+ rectal cancer received radiotherapy to a total dose of 50.4–54 Gy in combination with capecitabine 937.5 mg/m2 p.o. b.i.d. TNFerade™ at a dose of 4 × 1010 particle units was injected into the rectal tumor on the first day of radiotherapy and weekly for a total of 5 injections. Surgery was performed 5–10 weeks after the completion of chemoradiation. Results: Nine patients were enrolled in this pilot trial. The stage was cT2 in 2 patients, cT3 in 6 patients, cT4 in 1 patient, N– in 7 patients and N+ in 2 patients. Eight patients completed all treatments. Grade 3 hematologic toxicity was observed in 2 patients. There was no toxicity directly attributable to the injection procedure. A complete pathologic response was observed in 2 of 9 patients. Conclusions: This study demonstrates the feasibility of weekly intratumoral TNFerade™ injections during chemoradiotherapy for locally advanced rectal cancer. Pathologic responses with this combination compare favorably to published rates.
Extended Cytogenetic Maps of Sheep Chromosome 1 and Their Cattle and River Buffalo Homoeologues: Comparison with the OAR1 RH Map and Human Chromosomes 2, 3, 21 and 1q
Authors: Di Meo G.P. , Goldammer T. , Perucatti A. , Genualdo V. , Iannuzzi A. , Incarnato D. , Rebl A. , Di Berardino D. , Iannuzzi L.
Published: March 2011

Cytogenetic maps are useful tools for several applications, such as the physical anchoring of linkage and RH maps or genome sequence contigs to specific chromosome regions or the analysis of chromosome rearrangements. Recently, a detailed RH map was reported in OAR1. In the present study, we selected 38 markers equally distributed in this RH map for identification of ovine genomic DNA clones within the ovine BAC library CHORI-243 using the virtual sheep genome browser and performed FISH mapping for both comparison of OAR1 and homoeologous chromosomes BBU1q–BBU6 and BTA1–BTA3 and considerably extending the cytogenetic maps of the involved species-specific chromosomes. Comparison of the resulting maps with human-identified homology with HSA2q, HSA3, HSA21 and HSA1q reveals complex chromosome rearrangements differentiating human and bovid chromosomes. In addition, we identified 2 new small human segments from HSA2q and HSA3q conserved in the telomeric regions of OAR1p and homoeologous chromosome regions of BTA3 and BBU6, and OAR1q, respectively. Evaluation of the present OAR1 cytogenetic map and the OAR1 RH map supports previous RH assignments with 2 main exceptions. The 2 loci BMS4011 and CL638002 occupy inverted positions in these 2 maps.
Effects of Systemic Capsaicin Treatment on TRPV1 and Tachykinin NK1 Receptor Distribution and Function in the Nucleus of the Solitary Tract of the Adult Rat
Authors: Geraghty Dominic P. , Mazzone Stuart B. , Carter Candace , Kunde Dale A.
Published: March 2011

Vanilloids including capsaicin and resiniferatoxin (RTX) have been identified as potential novel anti-inflammatory and analgesic compounds. We have previously shown that systemic capsaicin administration to neonatal rats evokes profound long-term alterations in transient receptor potential vanilloid 1 (TRPV1)- and neurokinin 1 (NK1) receptor-mediated respiratory responses in the commissural nucleus of the solitary tract (cNTS). Whether this effect of capsaicin is unique to developmentally immature animals is unknown. Therefore, in the present study, we investigated the effects of systemic capsaicin administration to adult rats on NK1 receptor binding sites, TRPV1 and NK1 immunoreactivity and function in the cNTS. Microinjection of capsaicin (1 nmol) or RTX (75 pmol) into the cNTS of vehicle-pretreated rats produced a profound bradypnoea (maximum change: –45 breaths·min–1) and a small increase in tidal volume (VT). Similarly, microinjection of the selective NK1 receptor agonists [Sar9, Met(O2)11]substance P (SP; 66 pmol) and septide (20 pmol) decreased respiratory frequency and increased VT. Thirteen to 18 days after systemic administration of capsaicin (125 mg·kg–1 s.c.), the bradypnoeic responses to both capsaicin and RTX were absent (p < 0.05), indicative of sensory neuron ablation/desensitisation. Systemic capsaicin pretreatment significantly (p < 0.05) reduced the density of both [125I]Bolton-Hunter SP binding sites (NK1 receptors) and NK1 receptor immunoreactivity in the cNTS, but did not alter the respiratory responses evoked by microinjection of [Sar9, Met(O2)11]SP and septide into this region. These studies show that systemic capsaicin administration reduces NK1 receptor density in the cNTS without adversely affecting NK1 receptor function at this site. We speculate that adult rats may be more resistant than neonatal rats to the neuroplastic effects of systemic capsaicin administration.
Possible Role of Phosphoinositide-3-Kinase in Mx1 Protein Translation and Antiviral Activity of Interferon-Omega-Stimulated HeLa Cells
Authors: Seo Youngjun , Kim Mihee , Choi Minjoung , Kim Sunhee , Park Kidae , Oh Ilung , Chung Seungtae , Suh Hongwon , Hong Seunghwa , Park Suenie
Published: March 2011

Interferon ω (IFN-ω), a cytokine released during innate immune activation, is well known for promoting direct antiviral responses; however, the possible signal pathways that are initiated by IFN-ω binding to the type I IFN receptors have not been fully studied. Here, we provide evidence that activation of phosphoinositide-3-kinase/protein kinase B (PI3K/Akt) signaling plays a pivotal role in the generation of IFN-ω-mediated biological responses. We found that LY294002 (PI3K inhibitor)-attenuated antiviral activities are induced by IFN-ω treatment. Although such effects of LY294002 are unrelated to regulatory activities on IFN-ω-dependent Mx1 (myxovirus resistance 1) or Mx2 gene transcriptional regulation, translation of Mx1 protein, which was known as a key mediator of cell-autonomous antiviral resistance, was significantly reduced by PI3K inhibition. Further studies showed that PI3K inhibition using LY294002 leads to a decrease in PI3K substrate Akt and mitogen-activated protein kinase extracellular signal-regulated kinase and p38 phosphorylation/activation. In addition, although LY294002 was not able to reduce STAT1 activation, we found that the mammalian target of rapamycin (mTOR)/p70 S6 kinase pathway was significantly attenuated by inhibition of the PI3K/Akt signaling pathway. These results indicate that the PI3K/Akt pathway is a common and central integrator for antiviral responses in IFN-ω signaling via its regulatory effects on mTOR that are required for initiation of mRNA translation of Mx genes.
Risk Indicators for Erosive Tooth Wear in Brazilian Preschool Children
Authors: Murakami Christiana , Oliveira Luciana Butini , Sheiham Aubrey , Nahás Pires Corrêa Maria Salete , Haddad Ana Estela , Bönecker Marcelo
Published: March 2011

The aim of this study was to assess the prevalence and risk indicators for erosive tooth wear (ETW) in Brazilian preschool children. A total of 967 children aged 3–4 years were examined. ETW was assessed using a modified version of the index recommended by O’Brien [London, Her Majesty’s Stationary Office, 1994]. The 16 examiners were trained and calibrated. Hierarchical logistic regression was applied to investigate the association between ETW and socio-economic, environmental, nutritional and behavioural factors, as well as factors related to the child’s characteristics. ETW was present in 51.6% of children. Most lesions were confined to enamel (93.9%) and involved over two thirds of the tooth surface’s area (82%). There were no significant associations between ETW and socio-economic, environmental and nutritional variables. ETW was significantly associated with soft drink intake twice or 3 or more times a day (p = 0.043 and 0.023, respectively), frequent reported gastro-oesophageal reflux (p = 0.005) and age (p = 0.003). In conclusion, there was a high prevalence of ETW in the preschool children examined, and the risk indicators were frequent consumption of soft drinks, reported gastro-oesophageal reflux and age.
Effects of anti-factor VIII inhibitor antibodies on factor VIIa/tissue factor-catalysed activation and inactivation of factor VIII
Authors: Yada Koji , Ogiwara Kenichi , Shibata Masaru , Shima Midori , Nogami Keiji
Published: March 2011

Factor (F)VIIa/tissue factor (TF) rapidly activates FVIII activity by proteolysis at Arg372 and Arg740, and subsequently inactivates FVIIIa activity by proteolysis at Arg336, although this activation is weaker than that by thrombin. The effects of anti-FVIII inhibitor antibodies on these reactions remain unknown, however. In this study, 13 of anti-FVIII inhibitor antibodies recognising the A2 or C2 domain were prepared. None of them, irrespective of epitope specificity, significantly affected FVIIa/TFcatalysed FVIII activation in one-stage clotting assays. Anti-A2 and anti-C2 type 2 antibodies had little effect on the inactivation phase. Anti-C2 type 1 antibodies, however, modulated inactivation by 40–60% of that seen with control IgG, suggesting that the activity of FVIIIa generated by FVIIa/TF persisted in the presence of this specific type of inhibitor. SDS-PAGE analysis demonstrated that all antibodies had little effect on FVIIa/TF-catalyzed proteolysis at Arg372 and Arg740. Anti-C2 type 1, however, significantly delayed cleavage at Arg336 in dose-dependent manners. Neither anti-A2 nor anti-C2 type 2 affected this reaction, and the findings were consistent with the results of the functional assays. In addition, anti-C2 monoclonal antibodies with type 1 and 2 demonstrated similar patterns of reaction as the anti-C2 polyclonal antibodies in FVIIa/TF-mediated FVIII mechanisms. We demonstrated that FVIIa/TF activated FVIII even in the presence of anti-FVIII antibodies, but inactivation patterns appeared to depend on inhibitor type. It could be important to determine the characteristic of these inhibitor antibodies for prediction of their effects on FVIIa-related FVIII reactions, and the results could have significant therapeutic implications.

Note: An account of this work was presented at the 51st annual meeting of the American Society of Hematology, 2009, New Orleans, LA, USA. This work was supported by grants for MEXT KAKENHI 21591370 in Japan and Bayer Hemophilia Award program.
Incidence and Predictors of Myocardial Infarction After Transient Ischemic Attack
Authors: Burns Joseph D. , Rabinstein Alejandro A. , Roger Veronique L. , Stead Latha G. , Christianson Teresa J.H. , Killian Jill M. , Brown Robert D.
Published: March 2011

Background and Purpose—

Coronary artery disease is the leading cause of death after TIA. Reliable estimates of the risk of MI after TIA, however, are lacking.

Methods—

Our purpose was to determine the incidence of and risk factors for MI after TIA. We cross-referenced preexisting incidence cohorts from the Rochester Epidemiology Project for TIA (1985–1994) and MI (1979–2006) to identify all community residents with incident MI after incident TIA. Incidence of MI after TIA was determined using Kaplan–Meier life-table methods. This was compared to the age-, sex-, and period-specific MI incidences in the general population. Proportional hazards regression analysis was used to examine associations between clinical variables and the occurrence of MI after TIA.

Results—

Average annual incidence of MI after TIA was 0.95%. Relative risk for incident MI in the TIA cohort compared to the general population was 2.09 (95% CI, 1.52–2.81). This was highest in patients younger than 60 years old (relative risk, 15.1; 95% CI, 4.11–38.6). Increasing age (hazard ratio, 1.51 per 10 years; 95% CI, 1.14–2.01), male sex (hazard ratio, 2.19; 95% CI, 1.18–4.06), and the use of lipid-lowering therapy at the time of TIA (hazard ratio, 3.10; 95% CI, 1.20–8.00) were independent risk factors for MI after TIA.

Conclusions—

Average annual incidence of MI after TIA is ≈1%, approximately double that of the general population. The relative risk increase is especially high in patients younger than 60 years old. These data are useful for identifying subgroups of patients with TIA at highest risk for subsequent MI.
Longitudinal Changes of Resting-State Functional Connectivity During Motor Recovery After Stroke
Authors: Park Chang-hyun , Chang Won Hyuk , Ohn Suk Hoon , Kim Sung Tae , Bang Oh Young , Pascual-Leone Alvaro , Kim Yun-Hee
Published: March 2011

Background and Purpose—

Functional MRI (fMRI) studies could provide crucial information on the neural mechanisms of motor recovery in patients with stroke. Resting-state fMRI is applicable to patients with stroke who are not capable of proper performance of the motor task. In this study, we explored neural correlates of motor recovery in patients with stroke by investigating longitudinal changes in resting-state functional connectivity of the ipsilesional primary motor cortex (M1).

Methods—

A longitudinal observational study using repeated fMRI experiments was conducted in 12 patients with stroke. Resting-state fMRI data were acquired 4 times over a period of 6 months. Patients participated in the first session of fMRI shortly after onset and thereafter in subsequent sessions at 1, 3, and 6 months after onset. Resting-state functional connectivity of the ipsilesional M1 was assessed and compared with that of healthy subjects.

Results—

Compared with healthy subjects, patients demonstrated higher functional connectivity with the ipsilesional frontal and parietal cortices, bilateral thalamus, and cerebellum. Instead, functional connectivity with the contralesional M1 and occipital cortex were decreased in patients with stroke. Functional connectivity between the ipsilesional and contralesional M1 showed the most asymmetry at 1 month after onset to the ipsilesional side. Functional connectivity of the ipsilesional M1 with the contralesional thalamus, supplementary motor area, and middle frontal gyrus at onset was positively correlated with motor recovery at 6 months after stroke.

Conclusions—

Resting-state fMRI elicited distinctive but comparable results with previous task-based fMRI, presenting complementary and practical values for use in the study of patients with stroke.
Особенности военной разведки России на мусульманском Востоке (1856-1890-е гг.)
Authors: Педагогический О.А.
Published: March 2011

Estimating military secret service on moslem the East, it is necessary to mark that there were both positive moments in its organization and negative. On the extent of the second half XIX century the secret service structures of empire were in the process of construction of the structure and searches of the most acceptable methods of work, completed only at the beginning of XX century. Military secret service on the moslem East carried in an examined period sporadic character and activated as far as a necessity. erefore, in spite of relatively permanent receipt of information about a region, this process was not to the end well-organized. The lacks of work of secret service agents were also the absence of the special preparation and rivalry with the representatives of foreign Ministry. Offcial, unoffcial and temporal soldiery agents, and also staff of territorial departments, were engaged in military secret service. It is possible to select four forms of its realization: reconnaissances, military-scientic expeditions, military-diplomatic missions, secret-service secret service. They closely interlaced between itself, and in military and peaceful time had the different filling.
Русский театр в Израиле: сто лет вместе
Authors: Левитан Ольга
Published: March 2011

The article explores the history of the Russian Theatre in Israel as an inseparable part of Israeli theatre life: Russian Jews had a decisive role in the foundation of Israeli theatre and in the very beginning of Hebrew theatre in Palestine and in Moscow, and for decades the main Israeli artists introduced themselves as pupils of Vachtangov and Stanislavsky. In addition, a specific sensitiveness to Russian cultural tradition made a serious impact on Israeli theatre school and repertoire policy. The article discusses the phenomenon of enduring connections between Israeli and Russian theatres. The discussion is based on original archive research, and it includes first publication of a variety of data and documents as well as the analysis of different aspects of the intercultural Israeli-Russian dialogue.
Trends of Calculated and Simulated Actual Evaporation in the Yangtze River Basin
Authors: Wang Yanjun , Liu Bo , Su Buda , Zhai Jianqing , Gemmer Marco
Published: March 2011

Actual evaporation in the Yangtze River basin is calculated by the complementary relationship approach—that is, the advection–aridity (AA) model with parameter validation from 1961 to 2007—and simulated by the general circulation model (GCM) ECHAM5–Max Planck Institute Ocean Model (MPI-OM) from 1961 to 2000. Trends of annual and seasonal estimated actual evaporation and air temperature, net radiation, saturation vapor pressure deficit, wind speed, and precipitation are examined by the linear regression method and nonparametric Mann–Kendall test. The stepwise regression method is used to analyze the significance to reference evapotranspiration of independent variables.

Results show that a significant decreasing trend in annual reference evaporation is caused by a significant decline in wind speed. The annual actual evaporation decreases in the upper and midlower Yangtze reaches; more significantly in the AA model [–9.3 mm (10 yr)−1] than in the GCM [−3.6 mm (10 yr)−1]. Significant negative trends are found in spring and autumn, but they show reverse trends in summer and winter within the two methods, which is caused by the different contributors to the seasonal actual evaporation in the two methods.

Decreasing net radiation is the main contributor to annual and spring actual evaporation in the two methods. Decreasing precipitation and net radiation are the main contributors to decreasing autumn actual evaporation in the AA model and the GCM. Increasing net radiation and decreasing precipitation are the main contributors to summer and winter actual evaporation in the GCM. Decreasing net radiation and increasing precipitation are the main contributors to decreasing summer and increasing winter actual evaporation in the AA model.
On North American Decadal Climate for 2011–20
Authors: Hoerling Martin , Hurrell James , Kumar Arun , Terray Laurent , Eischeid Jon , Pegion Philip , Zhang Tao , Quan Xiaowei , Xu TaiYi
Published: March 2011

The predictability of North American climate is diagnosed by taking into account both forced climate change and natural decadal-scale climate variability over the next decade. In particular, the “signal” in North American surface air temperature and precipitation over 2011–20 associated with the expected change in boundary conditions related to future anthropogenic greenhouse gas (GHG) forcing, as well as the “noise” around that signal due to internally generated ocean–atmosphere variability, is estimated. The structural uncertainty in the estimate of decadal predictability is diagnosed by examining the sensitivity to plausible scenarios for the GHG-induced change in boundary forcing, the model dependency of the forced signals, and the dependency on methods for estimating internal decadal noise. The signal-to-noise analysis by the authors is thus different from other published decadal prediction studies, in that this study does not follow a trajectory from a particular initial state but rather considers the statistics of internal variability in comparison with the GHG signal. The 2011–20 decadal signal is characterized by surface warming over the entire North American continent, precipitation decreases over the contiguous United States, and precipitation increases over Canada relative to 1971–2000 climatological conditions. The signs of these forced responses are robust across different sea surface temperature (SST) scenarios and the different models employed, though the amplitude of the response differs. The North American decadal noise is considerably smaller than the signal associated with boundary forcing, implying a potential for high forecast skill for 2011–20 North American climate even for prediction methods that do not attempt to initialize climate models. However, the results do suggest that initialized decadal predictions, which seek to forecast externally forced signals and also constrain the internal variability, could potentially improve upon uninitialized methods in regions where the external signal is small relative to internal variability.
Optimal Sampling of Units in Three-Level Cluster Randomized Designs
Authors: Konstantopoulos Spyros
Published: March 2011

Field experiments with nested structures assign entire groups such as schools to treatment and control conditions. Key aspects of such cluster randomized experiments include knowledge of the intraclass correlation structure and the sample sizes necessary to achieve adequate power to detect the treatment effect. The units at each level of the hierarchy have a cost associated with them, however, and thus, researchers need to take budget and costs into account when designing their studies. This article uses analysis of covariance and provides methods for computing power within an optimal design framework that incorporates costs of units at different levels and covariate effects for three-level cluster randomized balanced designs. The optimal sample sizes are a function of the variances at each level and the cost of each unit. Overall, the results suggest that when units at higher levels become more expensive, the researcher should sample units at lower levels. The covariates affect the sampling of units and the power estimates. Fewer units need to be sampled at levels where covariates explain considerable proportions of the variance.
Virus-Host Interactions in HIV Pathogenesis
Authors: Levy J.A.
Published: March 2011

The challenge of controlling HIV infection involves an understanding of the heterogeneity of the virus, its wide cellular host range, its primary routes of transmission, and the immunologic and intrinsic cellular factors that can prevent its transmission and replication. Identification of HIV-infected individuals who have survived more than 10 years without signs of the infection and without therapy encourages studies examining the natural mechanisms for resistance to infection and disease. Within the immune system, emphasis should be given to the innate or natural response that appears within minutes of the infection and offers the optimal time for controlling HIV. All these parameters in HIV pathogenesis underline the information needed to develop optimal anti-HIV therapies and an effective AIDS vaccine.
Effect of Traditional Chinese Medicinal Herbs on Candida spp. from Patients with HIV/AIDS
Authors: Liu X. , Han Y. , Peng K. , Liu Y. , Li J. , Liu H.
Published: March 2011

As an opportunistic infection, candidiasis is common among individuals infected with HIV. About 90% of patients develop oral and/or oropharyngeal candidiasis in various stages of AIDS. Triazole antifungal agents, such as fluconazole and itraconazole, are considered to be first-choice agents for treatment and prevention because of their relatively low side effects and high effectiveness on mucosal infections. However, with prolonged exposure to azoles, drug resistance becomes a challenge for clinicians and patients alike. In traditional Chinese medicine, more than 300 herbs have been discovered to have “pesticidal” activities, and some of these have been used as antifungal agents in clinical practice for many years. Crude extracts from a number of medicinal herbs have been shown to exhibit antifungal activities in vitro. These include cortex moutan, cortex pseudolaricis, rhizoma alpiniae officinarum, rhizoma coptidis, clove and cinnamon, anemarrhena cortex phellodendri, ramulus cinnamomi, and Chinese gall. The effective anti- Candida principals were identified to be berberine, palmatine, allincin, pseudolaric acid A and B, magnolol, honokiol, and galangin. Thus, traditional Chinese medicinal herbs provide abundant choices for the treatment of refractory candidiasis commonly seen in HIV/AIDS patients. However, there remains a need for further screening of effective extracts and for study of the antifungal mechanisms involved. Importantly, ahead of clinical application, the safety of these compounds must be firmly established.
Immune Reconstitution Inflammatory Syndrome
Authors: Tappuni A.R.
Published: March 2011

Immune reconstitution inflammatory syndrome (IRIS) is a phenomenon observed in patients recovering from immunodeficiency. The clinical presentation of IRIS involves the unmasking of covert infections or the worsening of overt conditions. Several causes and pathways have been suggested, most recognizing an inflammatory flare component occurring in the context of rapid immune reconstitution. In HIV-infected patients, IRIS inadvertently occurs as the consequence of successful antiretroviral therapy, and it is affiliated with improvement of the immune function, complicating the course of the disease and presenting treatment challenges to clinicians. The pathogenesis of IRIS is poorly understood, but in recovering HIV patients, its initiation and progression seem to be primarily linked to an increase in CD4+ T-helper and CD8+ T-suppressor cell count and a reduction in T-regulatory cells, all endorsed by exaggerated cytokine release and activity. The clinical presentation of IRIS is usually atypical. The manifestations depend on the trigger antigen, which can be an infective agent (viable or nonviable), a host antigen, or a tumor antigen. Most IRIS cases are self-limiting, but a few cases can be overwhelming and life-threatening; hence, early recognition is important. In most cases, there is no need to discontinue the antiretroviral therapy, although in the more severe cases, other clinical intervention may be necessary.
Mucosal Fluids and Biomarkers of Clinical Disease
Authors: Johnson N.W. , Malamud D. , Reznik D. , Speicher D.J. , Phelan J.
Published: March 2011

Diagnostic tests for a range of oral and systemic diseases using fluids sampled from the mouth are under intense investigation and are increasingly being used. Methods exist for identification of HIV antibody and nucleic acid and for other viral infections of the mouth, such as Kaposi sarcoma herpes virus or human herpesvirus-8, which may coexist with HIV. A number of commercial test kits are available, with variable evidence of sensitivity, specificity, and utility. There is intense research on sophisticated but potentially facile handheld in-office devices for many disease markers. Challenges to their uptake require well-designed studies on their practical reliability and utility, with appropriate controls. A range of ethical, social, and political issues need to be addressed in such studies.