bluuebunny/crossref_metadata_2025 huggingface dataset:
Deleterious effects of lymphocytes at the early stage of neurodegeneration in an animal model of amyotrophic lateral sclerosis
Authors: Tada Satoru , Okuno Tatsusada , Yasui Teruhito , Nakatsuji Yuji , Sugimoto Tomoyuki , Kikutani Hitoshi , Sakoda Saburo
Published: February 2011

Background

Non-neuronal cells, such as microglia and lymphocytes, are thought to be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). Previous studies have demonstrated neuroprotective effects of lymphocytes at the end stage of ALS, partly through induction of alternatively activated microglia (M2 microglia), which are neuroprotective. In this study, we investigated the role of lymphocytes in the early stage of the disease using an animal model of inherited ALS.

Methods

We established a transgenic mouse line overexpressing the familial ALS-associated G93A-SOD1 mutation (harboring a single amino acid substitution of glycine to alanine at codon 93) with depletion of the Rag2 gene (mSOD1/RAG2-/- mice), an animal model of inherited ALS lacking mature lymphocytes. Body weights, clinical scores and motor performance (hanging wire test) of mSOD1/RAG2-/- mice were compared to those of mutant human SOD1 transgenic mice (mSOD1/RAG2+/+ mice). Activation of glial cells in the spinal cords of these mice was determined immunohistochemically, and the expression of mRNA for various inflammatory and anti-inflammatory molecules was evaluated.

Results

Clinical onset in mSOD1/RAG2-/- mice was significantly delayed, and the number of lectin-positive cells in spinal cord was increased at the early stage of disease when compared to mSOD1/RAG2+/+ mice. Quantitative RT-PCR confirmed that mRNA for Ym1, an M2 microglial-related molecule, was significantly increased in mSOD1/RAG2-/- mouse spinal cords at the early disease stage.

Conclusions

Compared with mSOD1/RAG2+/+ mice, mSOD1/RAG2-/- mice displayed delayed onset and increased M2 microglial activation at the early stage of disease. Thus, lymphocytes at the early pathological phase of ALS display a deleterious effect via inhibition of M2 microglial activation.
A pseudotype baculovirus expressing the capsid protein of foot-and-mouth disease virus and a T-Cell immunogen shows enhanced immunogenicity in mice
Authors: Cao Yimei , Lu Zengjun , Sun Pu , Fu Yuanfang , Tian Feipeng , Hao Xiaofang , Bao Huifang , Liu Xiangtao , Liu Zaixin
Published: February 2011

Background

Foot-and-mouth disease (FMD) is a highly contagious disease of livestock which causes severe economic loss in cloven-hoofed animals. Vaccination is still a major strategy in developing countries to control FMD. Currently, inactivated vaccine of FMDV has been used in many countries with limited success and safety concerns. Development of a novel effective vaccine is must.

Methods

In the present study, two recombinant pseudotype baculoviruses, one expressing the capsid of foot-and-mouth disease virus (FMDV) under the control of a cytomegalovirus immediate early enhancer/promoter (CMV-IE), and the other the caspid plus a T-cell immunogen coding region under a CAG promoter were constructed, and their expression was characterized in mammalian cells. In addition, their immunogenicity in a mouse model was investigated. The humoral and cell-mediated immune responses induced by pseudotype baculovirus were compared with those of inactivated vaccine.

Results

Indirect immunofluorescence assay (IFA) and indirect sandwich-ELISA (IS-ELISA) showed both recombinant baculoviruses (with or without T-cell epitopes) were transduced efficiently and expressed target proteins in BHK-21 cells. In mice, intramuscular inoculation of recombinants with 1 × 109 or 1 × 1010 PFU/mouse induced the production of FMDV-specific neutralizing antibodies and gamma interferon (IFN-γ). Furthermore, recombinant baculovirus with T-cell epitopes had better immunogenicity than the recombinant without T-cell epitopes as demonstrated by significantly enhanced IFN-γ production (P < 0.01) and higher neutralizing antibody titer (P < 0.05). Although the inactivated vaccine produced the highest titer of neutralizing antibodies, a lower IFN-γ expression was observed compared to the two recombinant pseudotype baculoviruses.

Conclusions

These results indicate that pseudotype baculovirus-mediated gene delivery could be a alternative strategy to develop a new generation of vaccines against FMDV infection.
Genetic diversity of a Korean echovirus 5 isolate and response of the strain to five antiviral drugs
Authors: Park Kwisung , Song Jaehyoung , Baek Kyoungah , Lee Changgyun , Kim Donguk , Cho SamHyun , Park JoonSoo , Choi YoungJin , Kang Byunghak , Choi Hwajung , Cheon Doo-Sung
Published: February 2011

An outbreak of echovirus 5 (ECV 5) occurred in Korea in 2006, marking the first time this virus had been identified in the country since enterovirus surveillance began in 1993. Using a sample isolated from a young male patient with aseptic meningitis, we performed sequencing of the Korean ECV 5 strain and compared it with a prototype strain (Noyce). At the nucleotide level, the P1 region (85.3%) had the highest identity value; at the amino acid level, the P3 region (98.0%) had the highest identity value. The two strains shared all cleavage sites, with the exception of the VP1/2A site, which was TY/GA in the Noyce strain but TR/GA in the Korean ECV 5 isolate. In Vero cells infected with the Korean ECV 5 isolate, no cytotoxicity was observed in the presence of azidothymidine, acyclovir, amantadine, lamivudine, or ribavirin, when the drugs were administered at a CC50 value >100 μg/mL. Of the five drugs, only amantadine (IC50: 1 ± 0.42 μg/mL, TI: 100) and ribavirin (IC50: 22 ± 1.36 μg/mL, TI: 4.55) had any antiviral activity against the Korean ECV 5 isolate.
Japanese encephalitis virus infection induces changes of mRNA profile of mouse spleen and brain
Authors: Yang Yang , Ye Jing , Yang Xiaohong , Jiang Rong , Chen Huanchun , Cao Shengbo
Published: February 2011

Background

Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus, leading to an acute encephalitis and damage to the central nervous system (CNS). The mechanism of JEV pathogenesis is still unclear. DNA microarray analyses have been recently employed to detect changes in host gene expression, which is helpful to reveal molecular pathways that govern viral pathogenesis. In order to globally identify candidate host genes associated with JEV pathogenesis, a systematic mRNA profiling was performed in spleens and brains of JEV-infected mice.

Results

The results of microarray analysis showed that 437 genes in spleen and 1119 genes in brain were differentially expressed in response to JEV infection, with obviously upregulated genes like pro-inflammatory chemokines and cytokines, apoptosis-related proteases and IFN inducible transcription factors. And the significant pathways of differentially expressed genes are involved in cytokine-cytokine receptor interaction, natural killer cell mediated cytotoxicity, antigen processing and presentation, MAPK signaling, and toll-like receptor signaling, etc. The differential expression of these genes suggests a strong antiviral response of host but may also contribute to the pathogenesis of JEV resulting in encephalitis. Quantitative RT-PCR (RT-qPCR) assay of some selected genes further confirmed the results of microarray assay.

Conclusions

Data obtained from mRNA microarray suggests that JEV infection causes significant changes of mRNA expression profiles in mouse spleen and brain. Most of differentially expression genes are associated with antiviral response of host, which may provide important information for investigation of JEV pathogenesis and therapeutic method.
Isolation and identification of a bovine viral diarrhea virus from sika deer in china
Authors: Gao Yugang , Wang Shijie , Du Rui , Wang Quankai , Sun Changjiang , Wang Nan , Zhang Pengju , Zhang Lianxue
Published: February 2011

Background

Bovine viral diarrhea virus (BVDV) infections continue to cause significantly losses in the deer population. Better isolation and identification of BVDV from sika deer may contribute significantly to the development of prophylactic therapeutic, and diagnostic reagents as well as help in prevention and control of BVDV. However, isolation and identification of BVDV from sika deer is seldom reported in literature. In this study, we collected some samples according to clinical sign of BVDV to isolation and identification of BVDV from sika deer.

Results

we isolated a suspected BVDV strain from livers of an aborted fetus from sika deer in Changchun (China) using MDBK cell lines, named as CCSYD strain, and identified it by cytopathic effect (CPE), indirect immunoperoxidase test (IPX) and electron microscopy(EM). The results indicated that this virus was BVDV by a series of identification. The structural proteins E0 gene was cloned and sequenced. The obtained E0 gene sequence has been submitted to GenBank with the accession number: FJ555203. Alignment with other 9 strains of BVDV, 7 strains of classical swine fever virus (CSFV) and 3 strains of border disease virus(BDV) in the world, showed that the homology were 98.6%-84.8%, 76.0%-74.7%, 76.6%-77.0% for nucleotide sequence, respectively. The phylogenetic analysis indicated that new isolation and identification CCSYD strain belonged to BVDV1b.

Conclusion

To the best of our knowledge, this is the first report that BVDV was isolated and identified in sika deer. This current research contributes development new BVDV vaccine to prevent and control of BVD in sika deer.
Cytotoxicity screening of 23 engineered nanomaterials using a test matrix of ten cell lines and three different assays
Authors: Kroll Alexandra , Dierker Christian , Rommel Christina , Hahn Daniela , Wohlleben Wendel , Schulze-Isfort Christian , Göbbert Christian , Voetz Matthias , Hardinghaus Ferdinand , Schnekenburger Jürgen
Published: February 2011

Background

Engineered nanomaterials display unique properties that may have impact on human health, and thus require a reliable evaluation of their potential toxicity. Here, we performed a standardized in vitro screening of 23 engineered nanomaterials. We thoroughly characterized the physicochemical properties of the nanomaterials and adapted three classical in vitro toxicity assays to eliminate nanomaterial interference. Nanomaterial toxicity was assessed in ten representative cell lines.

Results

Six nanomaterials induced oxidative cell stress while only a single nanomaterial reduced cellular metabolic activity and none of the particles affected cell viability. Results from heterogeneous and chemically identical particles suggested that surface chemistry, surface coating and chemical composition are likely determinants of nanomaterial toxicity. Individual cell lines differed significantly in their response, dependent on the particle type and the toxicity endpoint measured.

Conclusion

In vitro toxicity of the analyzed engineered nanomaterials cannot be attributed to a defined physicochemical property. Therefore, the accurate identification of nanomaterial cytotoxicity requires a matrix based on a set of sensitive cell lines and in vitro assays measuring different cytotoxicity endpoints.
Protein S blocks the extrinsic apoptotic cascade in tissue plasminogen activator/N-methyl D-aspartate-treated neurons via Tyro3-Akt-FKHRL1 signaling pathway
Authors: Guo Huang , Barrett Theresa M , Zhong Zhihui , Fernández José A , Griffin John H , Freeman Robert S , Zlokovic Berislav V
Published: February 2011

Background

Thrombolytic therapy with tissue plasminogen activator (tPA) benefits patients with acute ischemic stroke. However, tPA increases the risk for intracerebral bleeding and enhances post-ischemic neuronal injury if administered 3-4 hours after stroke. Therefore, combination therapies with tPA and neuroprotective agents have been considered to increase tPA's therapeutic window and reduce toxicity. The anticoagulant factor protein S (PS) protects neurons from hypoxic/ischemic injury. PS also inhibits N-methyl-D-aspartate (NMDA) excitotoxicity by phosphorylating Bad and Mdm2 which blocks the downstream steps in the intrinsic apoptotic cascade. To test whether PS can protect neurons from tPA toxicity we studied its effects on tPA/NMDA combined injury which in contrast to NMDA alone kills neurons by activating the extrinsic apoptotic pathway. Neither Bad nor Mdm2 which are PS's targets and control the intrinsic apoptotic pathway can influence the extrinsic cascade. Thus, based on published data one cannot predict whether PS can protect neurons from tPA/NMDA injury by blocking the extrinsic pathway. Neurons express all three TAM (Tyro3,Axl,Mer) receptors that can potentially interact with PS. Therefore, we studied whether PS can activate TAM receptors during a tPA/NMDA insult.

Results

We show that PS protects neurons from tPA/NMDA-induced apoptosis by suppressing Fas-ligand (FasL) production and FasL-dependent caspase-8 activation within the extrinsic apoptotic pathway. By transducing neurons with adenoviral vectors expressing the kinase-deficient Akt mutantAktK179Aand a triple FKHRL1 Akt phosphorylation site mutant (FKHRL1-TM), we show that Akt activation and Akt-mediated phosphorylation of FKHRL1, a member of the Forkhead family of transcription factors, are critical for FasL down-regulation and caspase-8 inhibition. Using cultured neurons from Tyro3, Axl and Mer mutants, we show that Tyro3, but not Axl and Mer, mediates phosphorylation of FHKRL1 that is required for PS-mediated neuronal protection after tPA/NMDA-induced injury.

Conclusions

PS blocks the extrinsic apoptotic cascade through a novel mechanism mediated by Tyro3-dependent FKHRL1 phosphorylation which inhibits FasL-dependent caspase-8 activation and can control tPA-induced neurotoxicity associated with pathologic activation of NMDA receptors. The present findings should encourage future studies in animal stroke models to determine whether PS can increase the therapeutic window of tPA by reducing its post-ischemic neuronal toxicity.
Morphological and functional alterations in adult boar epididymis: Effects of prenatal and postnatal administration of flutamide
Authors: Lydka Marta , Kopera-Sobota Ilona , Kotula-Balak Malgorzata , Chojnacka Katarzyna , Zak Dorota , Bilinska Barbara
Published: February 2011

Background

The dynamic cross-talk between epididymal cells is hormonally regulated and, in part, through direct cell-to-cell interactions. To date, no information is available regarding possible impact of anti-androgens on the proteins involved in the gap junctional communication within the boar epididymis. Thus, a question arised whether prenatal or postnatal exposure to an anti-androgen flutamide alters the expression of gap junction protein - connexin43 (Cx43) and androgen receptor (AR) expression in the caput, corpus and cauda epididymis and leads to delayed effects on morphology and function of adult pig epididymis.

Methods

First two experimental groups received flutamide prenatally on gestational days 20-28 and 80-88 (GD20 and GD80) and further two groups were exposed to flutamide postanatally on days 2-10 and 90-98 after birth (PD2 and PD90). Epididymides were collected from adult boars. Routine histology was performed using hematoxylin-eosin staining. The expression of Cx43 and AR were analyzed using immunohistochemistry and Western blotting. Both analyses were supported by quantitative approaches to demonstrate the variations of the expression levels following the treatment. Apoptotic cells were identified using TUNEL assay.

Results

Histological examination revealed differences in epididymal morphology of flutamide-exposed boars when compared to controls. Scarce spermatic content were seen within the corpus and cauda lumina of GD20, PD2 and PD90 groups. Concomitantly, frequency of epididymal cell apoptosis was significantly higher (p < 0.05) after exposure to flutamide at GD20. Moreover, in GD20, PD2, and PD90 groups, significantly lower AR expression (p < 0.05) was found in the principal and basal cells of the corpus and cauda regions, while in the stromal cells AR expression was significantly reduced (p < 0.05) along the epididymal duct. Concomitantly, a decrease in Cx43 expression (p < 0.05) was noticed in the stromal cells of the cauda region of GD20 and PD2 groups. This indicates high sensitivity of the stromal cells to androgen withdrawal.

Conclusions

The region-specific alterations in the epididymis morphology and scarce spermatic content within the lumina of the corpus and cauda indicate that flutamide can induce delayed effects on the epididymal function of the adult boar by decrease in AR protein levels that results in altered androgen signaling. This may cause disturbances in androgen-dependent processes including Cx43 (de)regulation, however, we can not exclude the possibility that in response to flutamide decreased Cx43 expression may represent one mechanism responsible for functional disturbance of the boar epididymis.
Phenotypic heterogeneity in mycobacterial stringent response
Authors: Ghosh Sayantari , Sureka Kamakshi , Ghosh Bhaswar , Bose Indrani , Basu Joyoti , Kundu Manikuntala
Published: February 2011

Background

A common survival strategy of microorganisms subjected to stress involves the generation of phenotypic heterogeneity in the isogenic microbial population enabling a subset of the population to survive under stress. In a recent study, a mycobacterial population of M. smegmatis was shown to develop phenotypic heterogeneity under nutrient depletion. The observed heterogeneity is in the form of a bimodal distribution of the expression levels of the Green Fluorescent Protein (GFP) as reporter with the gfp fused to the promoter of the rel gene. The stringent response pathway is initiated in the subpopulation with high rel activity.

Results

In the present study, we characterise quantitatively the single cell promoter activity of the three key genes, namely, mprA, sigE and rel, in the stringent response pathway with gfp as the reporter. The origin of bimodality in the GFP distribution lies in two stable expression states, i.e., bistability. We develop a theoretical model to study the dynamics of the stringent response pathway. The model incorporates a recently proposed mechanism of bistability based on positive feedback and cell growth retardation due to protein synthesis. Based on flow cytometry data, we establish that the distribution of GFP levels in the mycobacterial population at any point of time is a linear superposition of two invariant distributions, one Gaussian and the other lognormal, with only the coefficients in the linear combination depending on time. This allows us to use a binning algorithm and determine the time variation of the mean protein level, the fraction of cells in a subpopulation and also the coefficient of variation, a measure of gene expression noise.

Conclusions

The results of the theoretical model along with a comprehensive analysis of the flow cytometry data provide definitive evidence for the coexistence of two subpopulations with overlapping protein distributions.
Codon usage variability determines the correlation between proteome and transcriptome fold changes
Authors: Olivares-Hernández Roberto , Bordel Sergio , Nielsen Jens
Published: February 2011

Background

The availability of high throughput experimental methods has made possible to observe the relationships between proteome and transcirptome. The protein abundances show a positive but weak correlation with the concentrations of their cognate mRNAs. This weak correlation implies that there are other crucial effects involved in the regulation of protein translation, different from the sole availability of mRNA. It is well known that ribosome and tRNA concentrations are sources of variation in protein levels. Thus, by using integrated analysis of omics data, genomic information, transcriptome and proteome, we aim to unravel important variables affecting translation.

Results

We identified how much of the variability in the correlation between protein and mRNA concentrations can be attributed to the gene codon frequencies. We propose the hypothesis that the influence of codon frequency is due to the competition of cognate and near-cognate tRNA binding; which in turn is a function of the tRNA concentrations. Transcriptome and proteome data were combined in two analytical steps; first, we used Self-Organizing Maps (SOM) to identify similarities among genes, based on their codon frequencies, grouping them into different clusters; and second, we calculated the variance in the protein mRNA correlation in the sampled genes from each cluster. This procedure is justified within a mathematical framework.

Conclusions

With the proposed method we observed that in all the six studied cases most of the variability in the relation protein-transcript could be explained by the variation in codon composition.
Hybrid metabolic flux analysis: combining stoichiometric and statistical constraints to model the formation of complex recombinant products
Authors: Carinhas Nuno , Bernal Vicente , Teixeira Ana P , Carrondo Manuel JT , Alves Paula M , Oliveira Rui
Published: February 2011

Background

Stoichiometric models constitute the basic framework for fluxome quantification in the realm of metabolic engineering. A recurrent bottleneck, however, is the establishment of consistent stoichiometric models for the synthesis of recombinant proteins or viruses. Although optimization algorithms for in silico metabolic redesign have been developed in the context of genome-scale stoichiometric models for small molecule production, still rudimentary knowledge of how different cellular levels are regulated and phenotypically expressed prevents their full applicability for complex product optimization.

Results

A hybrid framework is presented combining classical metabolic flux analysis with projection to latent structures to further link estimated metabolic fluxes with measured productivities. We first explore the functional metabolic decomposition of a baculovirus-producing insect cell line from experimental data, highlighting the TCA cycle and mitochondrial respiration as pathways strongly associated with viral replication. To reduce uncertainty in metabolic target identification, a Monte Carlo sampling method was used to select meaningful associations with the target, from which 66% of the estimated fluxome had to be screened out due to weak correlations and/or high estimation errors. The proposed hybrid model was then validated using a subset of preliminary experiments to pinpoint the same determinant pathways, while predicting the productivity of independent cultures.

Conclusions

Overall, the results indicate our hybrid metabolic flux analysis framework is an advantageous tool for metabolic identification and quantification in incomplete or ill-defined metabolic networks. As experimental and computational solutions for constructing comprehensive global cellular models are in development, the contribution of hybrid metabolic flux analysis should constitute a valuable complement to current computational platforms in bridging the metabolic state with improved cell culture performance.
New-onset headache in an elderly man with uremia that improved only after correction of hyperphosphatemia ("uremic headache"): a case report
Authors: Razdan Sushil , Pandita KK , Chopra Vanilla , Koul Sanjay
Published: February 2011

Introduction

New-onset headaches in the elderly are usually secondary and rarely primary. We present the case of an elderly man with recent-onset headache due to uremic hyperphosphatemia and hypocalcemia. To the best of our knowledge, this is the first case report of its kind in the literature.

Case presentation

We present the case of a 70-year-old Indian man with chronic kidney disease whose new-onset headache improved only when his hyperphosphatemia and hypocalcemia were corrected. He had diffuse, dense calcification of tentorium cerebelli and falx due to hyperphosphatemia.

Conclusions

This case report reinforces the importance of identifying the cause of a new-onset headache, particularly in the elderly, and treating it before blaming a tension headache or primary headache as the cause.
Evaluation of chronic lymphocytic leukemia by BAC-based microarray analysis
Authors: Schultz Roger A , Delioukina Maria , Gaal Karl , Bedell Victoria , Smith David D , Forman Stephen J , McDaniel Lisa D , Ballif Blake C , Shaffer Lisa G , Slovak Marilyn L
Published: February 2011

Background

Chronic lymphocytic leukemia (CLL) is a highly variable disease with life expectancies ranging from months to decades. Cytogenetic findings play an integral role in defining the prognostic significance and treatment for individual patients.

Results

We have evaluated 25 clinical cases from a tertiary cancer center that have an established diagnosis of CLL and for which there was prior cytogenetic and/or fluorescencein situhybridization (FISH) data. We performed microarray-based comparative genomic hybridization (aCGH) using a bacterial artificial chromosome (BAC)-based microarray designed for the detection of known constitutional genetic syndromes. In 15 of the 25 cases, aCGH detected all copy number imbalances identified by prior cytogenetic and/or FISH studies. For the majority of those not detected, the aberrations were present at low levels of mosaicism. Furthermore, for 15 of the 25 cases, additional abnormalities were detected. Four of those cases had deletions that mapped to intervals implicated in inherited predisposition to CLL. For most cases, aCGH was able to detect abnormalities present in as few as 10% of cells. Although changes in ploidy are not easily discernable by aCGH, results for two cases illustrate the detection of additional copy gains and losses present within a mosaic tetraploid cell population.

Conclusions

Our results illustrate the successful evaluation of CLL using a microarray optimized for the interrogation of inherited disorders and the identification of alterations with possible relevance to CLL susceptibility.
Distinct influences of tandem repeats and retrotransposons on CENH3 nucleosome positioning
Authors: Gent Jonathan I , Schneider Kevin L , Topp Christopher N , Rodriguez Carmen , Presting Gernot G , Dawe R Kelly
Published: February 2011

Background

Unique structural characteristics of centromere chromatin enable it to support assembly of the kinetochore and its associated tensions. The histone H3 variant CENH3 (centromeric histone H3) is viewed as the key element of centromere chromatin and its interaction with centromere DNA is epigenetic in that its localization to centromeres is not sequence-dependent.

Results

In order to investigate what influence the DNA sequence exerts on CENH3 chromatin structure, we examined CENH3 nucleosome footprints on maize centromere DNA. We found a predominant average nucleosome spacing pattern of roughly 190-bp intervals, which was also the dominant arrangement for nucleosomes genome-wide. For CENH3-containing nucleosomes, distinct modes of nucleosome positioning were evident within that general spacing constraint. Over arrays of the major ~156-bp centromeric satellite sequence (tandem repeat) CentC, nucleosomes were not positioned in register with CentC monomers but in conformity with a striking ~10-bp periodicity of AA/TT dimers within the sequence. In contrast, nucleosomes on a class of centromeric retrotransposon (CRM2) lacked a detectable AA/TT periodicity but exhibited tightly phased positioning.

Conclusions

These data support a model in which general chromatin factors independent of both DNA sequence and CENH3 enforce roughly uniform centromeric nucleosome spacing while allowing flexibility in the mode in which nucleosomes are positioned. In the case of tandem repeat DNA, the natural bending effects related to AA/TT periodicity produce an energetically-favourable arrangement consistent with conformationally rigid nucleosomes and stable chromatin at centromeres.
Protecting HIV information in countries scaling up HIV services: a baseline study
Authors: Beck Eduard J , Mandalia Sundhiya , Harling Guy , Santas Xenophon M , Mosure Debra , Delay Paul R
Published: February 2011

Background

Individual‐level data are needed to optimize clinical care and monitor and evaluate HIV services. Confidentiality and security of such data must be safeguarded to avoid stigmatization and discrimination of people living with HIV. We set out to assess the extent that countries scaling up HIV services have developed and implemented guidelines to protect the confidentiality and security of HIV information.

Methods

Questionnaires were sent to UNAIDS field staff in 98 middle‐ and lower‐income countries, some reportedly with guidelines (G‐countries) and others intending to develop them (NG‐countries). Responses were scored, aggregated and weighted to produce standard scores for six categories: information governance, country policies, data collection, data storage, data transfer and data access. Responses were analyzed using regression analyses for associations with national HIV prevalence, gross national income per capita, OECD income, receiving US PEPFAR funding, and being a G‐ or NG‐country. Differences between G‐ and NG‐countries were investigated using non‐parametric methods.

Results

Higher information governance scores were observed for G‐countries compared with NG‐countries; no differences were observed between country policies or data collection categories. However, for data storage, data transfer and data access, G‐countries had lower scores compared with NG‐countries. No significant associations were observed between country score and HIV prevalence, per capita gross national income, OECD economic category, and whether countries had received PEPFAR funding.

Conclusions

Few countries, including G‐countries, had developed comprehensive guidelines on protecting the confidentiality and security of HIV information. Countries must develop their own guidelines, using established frameworks to guide their efforts, and may require assistance in adapting, adopting and implementing them.
Three methods for mitigating airwaves in shallow water marine controlled-source electromagnetic data
Authors: Chen Jiuping , Alumbaugh David L.
Published: February 2011

In the past several years, marine controlled-source electromagnetic (MCSEM) techniques have been applied successfully in deep water (depth > 1 km) for oil and gas exploration. The application of this technology in shallow water is challenged, however, because of “airwaves” that mask the signal from the target reservoir at depth. Based upon the understanding that an airwave is a lateral wave, which can be analytically expressed in a dual-half-space resistivity model, we propose three airwave-mitigation approaches to reduce the effects of these airwaves on MCSEM data. In the EM “x-bucking” approach, the effect of the airwaves can be “bucked” out from two measurements by using the analytic expression of the airwave. The frequency derivative (dE/dFreq) approach takes advantages of the unique characteristics of the airwaves in frequency domain, enhancing the reservoir signals while suppressing the airwave. The magnetotelluric (MT) stripping method uses the plane-wave feature of the airwaves and subtraction of the lateral wave electric component, which is obtained from measured marine MT impedance and controlled-source electromagnetics (CSEM) data, to generate a new data set in which the effects of the airwaves are removed substantially. By comparing the detectability, which is defined as the ratio of inline Ex fields between a reservoir model and a corresponding baseline model, for a reservoir target in deep water versus shallow water with a moderate 2D bathymetry, we show that the effects of the airwaves in shallow water can be reduced in the data, leading to greater reservoir detectability. In addition, these approaches have been applied successfully to a real shallow water MCSEM data set in which the detectability to the deeper resistive basement is enhanced.
Successful Multifold Dose Escalation of Anti-GD2 Monoclonal Antibody 3F8 in Patients With Neuroblastoma: A Phase I Study
Authors: Kushner Brian H. , Kramer Kim , Modak Shakeel , Cheung Nai-Kong V.
Published: February 2011

Purpose

Pain can hinder immunotherapy with anti-GD2 monoclonal antibodies (MoAbs) like 3F8. Heat-modified 3F8 (HM3F8) lacks effector functions and could mask GD2 or cross-reactive epitopes on nerves, thereby preventing a subsequent dose of unmodified 3F8 from activating pain fibers. We hypothesized that 3F8 dose escalation is possible without increased analgesic requirements in patients pretreated with HM3F8.

Patients and Methods

Thirty patients with resistant neuroblastoma (NB) received one to two cycles of 3F8 plus granulocyte-macrophage colony-stimulating factor. 3F8 dosing began at 20 mg/m2/d and increased by 20 mg/m2/d in the absence of dose-limiting toxicity (DLT). Premedication included analgesics, antihistamines, and 5-minute infusions of HM3F8. On the basis of experience with 3F8 10 mg/m2/d in prior protocols, the DLT of pain was defined as more than seven doses of opioids administered within 2 hours. Opioid use was compared with a contemporary control group treated with 3F8 20 mg/m2/d but no HM3F8. Disease response was assessed.

Results

Treatment was administered in the outpatient setting. Dose escalation stopped at 160 mg/m2/d because of drug supply limitations; even through this dosage level, analgesic requirements were similar to historical controls, and there were no DLTs. Analgesic requirements at 3F8 dosage levels through 80 mg/m2/d were significantly less compared with controls. Anti-NB activity occurred at all dosages.

Conclusion

Multifold dose escalation of 3F8 is feasible. The findings can be interpreted as compatible with the possibility that HM3F8 can modify toxicity without blunting anti-NB activity. This pain control strategy may help achieve dose escalation with other anti-GD2 MoAbs.
Can This Patient Be Discharged Home? Factors Associated With At-Home Death Among Patients With Cancer
Authors: Alonso-Babarro Alberto , Bruera Eduardo , Varela-Cerdeira María , Boya-Cristia María Jesús , Madero Rosario , Torres-Vigil Isabel , De Castro Javier , González-Barón Manuel
Published: February 2011

Purpose

The purpose of this study was to identify factors associated with at-home death among patients with advanced cancer and create a decision-making model for discharging patients from an acute-care hospital.

Patients and Methods

We conducted an observational cohort study to identify the association between place of death and the clinical and demographic characteristics of patients with advanced cancer who received care from a palliative home care team (PHCT) and of their primary caregivers. We used logistic regression analysis to identify the predictors of at-home death.

Results

We identified 380 patients who met the study inclusion criteria; of these, 245 patients (64%) died at home, 72 (19%) died in an acute-care hospital, 60 (16%) died in a palliative care unit, and three (1%) died in a nursing home. Median follow-up was 48 days. We included the 16 variables that were significant in univariate analysis in our decision-making model. Five variables predictive of at-home death were retained in the multivariate analysis: caregiver's preferred place of death, patients' preferred place of death, caregiver's perceived social support, number of hospital admission days, and number of PHCT visits. A subsequent reduced model including only those variables that were known at the time of discharge (caregivers' preferred place of death, patients' preferred place of death, and caregivers' perceived social support) had a sensitivity of 96% and a specificity of 81% in predicting place of death.

Conclusion

Asking a few simple patient- and family-centered questions may help to inform the decision regarding the best place for end-of-life care and death.
Prospective Multicenter Phase II Trial of Systemic ADH-1 in Combination With Melphalan via Isolated Limb Infusion in Patients With Advanced Extremity Melanoma
Authors: Beasley Georgia M. , Riboh Jonathan C. , Augustine Christina K. , Zager Jonathan S. , Hochwald Steven N. , Grobmyer Stephen R. , Peterson Bercedis , Royal Richard , Ross Merrick I. , Tyler Douglas S.
Published: February 2011

Purpose

Isolated limb infusion (ILI) with melphalan (M-ILI) dosing corrected for ideal body weight (IBW) is a well-tolerated treatment for patients with in-transit melanoma with a 29% complete response rate. ADH-1 is a cyclic pentapeptide that disrupts N-cadherin adhesion complexes. In a preclinical animal model, systemic ADH-1 given with regional melphalan demonstrated synergistic antitumor activity, and in a phase I trial with M-ILI it had minimal toxicity.

Patients and Methods

Patients with American Joint Committee on Cancer (AJCC) stage IIIB or IIIC extremity melanoma were treated with 4,000 mg of ADH-1, administered systemically on days 1 and 8, and with M-ILI corrected for IBW on day 1. Drug pharmacokinetics and N-cadherin immunohistochemical staining were performed on pretreatment tumor. The primary end point was response at 12 weeks determined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria.

Results

In all, 45 patients were enrolled over 15 months at four institutions. In-field responses included 17 patients with complete responses (CRs; 38%), 10 with partial responses (22%), six with stable disease (13%), eight with progressive disease (18%), and four (9%) who were not evaluable. Median duration of in-field response among the 17 CRs was 5 months, and median time to in-field progression among 41 evaluable patients was 4.6 months (95% CI, 4.0 to 7.1 months). N-cadherin was detected in 20 (69%) of 29 tumor samples. Grade 4 toxicities included creatinine phosphokinase increase (four patients), arterial injury (one), neutropenia (one), and pneumonitis (one).

Conclusion

To the best of our knowledge, this phase II trial is the first prospective multicenter ILI trial and the first to incorporate a targeted agent in an attempt to augment antitumor responses to regional chemotherapy. Although targeting N-cadherin may improve melanoma sensitivity to chemotherapy, no difference in response to treatment was seen in this study.
American Society of Clinical Oncology Executive Summary of the Clinical Practice Guideline Update on the Role of Bone-Modifying Agents in Metastatic Breast Cancer
Authors: Van Poznak Catherine H. , Temin Sarah , Yee Gary C. , Janjan Nora A. , Barlow William E. , Biermann J. Sybil , Bosserman Linda D. , Geoghegan Cindy , Hillner Bruce E. , Theriault Richard L. , Zuckerman Dan S. , Von Roenn Jamie H.
Published: February 2011

Purpose

To update the recommendations on the role of bone-modifying agents in the prevention and treatment of skeletal-related events (SREs) for patients with metastatic breast cancer with bone metastases.

Methods

A literature search using MEDLINE and the Cochrane Collaboration Library identified relevant studies published between January 2003 and November 2010. The primary outcomes of interest were SREs and time to SRE. Secondary outcomes included adverse events and pain. An Update Committee reviewed the literature and re-evaluated previous recommendations.

Results

Recommendations were modified to include a new agent. A recommendation regarding osteonecrosis of the jaw was added.

Recommendations

Bone-modifying agent therapy is only recommended for patients with breast cancer with evidence of bone metastases; denosumab 120 mg subcutaneously every 4 weeks, intravenous pamidronate 90 mg over no less than 2 hours, or zoledronic acid 4 mg over no less than 15 minutes every 3 to 4 weeks is recommended. There is insufficient evidence to demonstrate greater efficacy of one bone-modifying agent over another. In patients with a calculated serum creatinine clearance of more than 60 mg/min, no change in dosage, infusion time, or interval of bisphosphonate administration is required. Serum creatinine should be monitored before each dose. All patients should receive a dental examination and appropriate preventive dentistry before bone-modifying agent therapy and maintain optimal oral health. Current standards of care for cancer bone pain management should be applied at the onset of pain, in concert with the initiation of bone-modifying agent therapy. The use of biochemical markers to monitor bone-modifying agent use is not recommended.
TET2 Mutations Improve the New European LeukemiaNet Risk Classification of Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study
Authors: Metzeler Klaus H. , Maharry Kati , Radmacher Michael D. , Mrózek Krzysztof , Margeson Dean , Becker Heiko , Curfman John , Holland Kelsi B. , Schwind Sebastian , Whitman Susan P. , Wu Yue-Zhong , Blum William , Powell Bayard L. , Carter Thomas H. , Wetzler Meir , Moore Joseph O. , Kolitz Jonathan E. , Baer Maria R. , Carroll Andrew J. , Larson Richard A. , Caligiuri Michael A. , Marcucci Guido , Bloomfield Clara D.
Published: February 2011

Purpose

To determine the frequency of TET2 mutations, their associations with clinical and molecular characteristics and outcome, and the associated gene- and microRNA-expression signatures in patients with primary cytogenetically normal acute myeloid leukemia (CN-AML).

Patients and Methods

Four-hundred twenty-seven patients with CN-AML were analyzed for TET2 mutations by polymerase chain reaction and direct sequencing and for established prognostic gene mutations. Gene- and microRNA-expression profiles were derived using microarrays.

Results

TET2 mutations, found in 23% of patients, were associated with older age (P < .001) and higher pretreatment WBC (P = .04) compared with wild-type TET2 (TET2-wt). In the European LeukemiaNet (ELN) favorable-risk group (patients with CN-AML who have mutated CEBPA and/or mutated NPM1 without FLT3 internal tandem duplication [FLT3-ITD]), TET2-mutated patients had shorter event-free survival (EFS; P < .001) because of a lower complete remission (CR) rate (P = .007), and shorter disease-free survival (DFS; P = .003), and also had shorter overall survival (P = .001) compared with TET2-wt patients. TET2 mutations were not associated with outcomes in the ELN intermediate-I–risk group (CN-AML with wild-type CEBPA and wild-type NPM1 and/or FLT3-ITD). In multivariable models, TET2 mutations were associated with shorter EFS (P = .004), lower CR rate (P = .03), and shorter DFS (P = .05) only among favorable-risk CN-AML patients. We identified a TET2 mutation-associated gene-expression signature in favorable-risk but not in intermediate-I–risk patients and found distinct mutation-associated microRNA signatures in both ELN groups.

Conclusion

TET2 mutations improve the ELN molecular-risk classification in primary CN-AML because of their adverse prognostic impact in an otherwise favorable-risk patient subset. Our data suggest that these patients may be candidates for alternative therapies.
Phase II Trial of Pemetrexed and Bevacizumab in Patients With Recurrent or Metastatic Head and Neck Cancer
Authors: Argiris Athanassios , Karamouzis Michalis V. , Gooding William E. , Branstetter Barton F. , Zhong Shilong , Raez Luis E. , Savvides Panayiotis , Romkes Marjorie
Published: February 2011

Purpose

We hypothesized that bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), will potentiate the activity of pemetrexed, a multitargeted antifolate, in squamous cell carcinoma of the head and neck (SCCHN).

Patients and Methods

Patients with previously untreated, recurrent, or metastatic SCCHN were treated with pemetrexed 500 mg/m2 and bevacizumab 15 mg/kg given intravenously every 21 days with folic acid and B12 supplementation until disease progression. Primary end point was time-to-progression (TTP). DNA was isolated from whole blood samples for the detection of polymorphisms in thymidylate synthase, methylenetetrahydrofolate reductase (MTHFR), and VEGF.

Results

Forty patients were enrolled. The median TTP was 5 months, and the median overall survival (OS) was 11.3 months. In 37 evaluable patients, the overall response rate was 30%, including a complete response rate of 5%, and the disease control rate was 86%. Grade 3 to 5 bleeding events occurred in six patients (15%): four were grade 3, and two were fatal. Other serious toxicities in 10% or more of patients included neutropenia (10%) and infection (12.5%). One patient died of sepsis after receiving eight cycles of therapy. For the MTHFR A1298C (rs1801131) single nucleotide polymorphisms, homozygote patients with AA had worse OS (P = .034).

Conclusion

The addition of bevacizumab to pemetrexed resulted in promising efficacy outcomes in SCCHN. Bleeding events were frequent but some may have been due to natural history of disease. Polymorphisms in MTHFR may offer potential for treatment individualization.
Calcitropic Hormones and IGF-I Are Influenced by Dietary Protein
Authors: Dubois-Ferrière Victor , Brennan Tara C. , Dayer Romain , Rizzoli René , Ammann Patrick
Published: February 2011

Elderly men and women with protein deficiencies have low levels of circulating IGF-I, and it is likely this contributes to reduced bone formation and increased bone resorption. We hypothesized that calcitropic hormones are involved in this effect and are affected by dietary protein. We therefore investigated the influence of a low-protein diet on the PTH-1,25-dihydroxyvitamin D3 [1,25(OH)2D3] axis and IGF-I in rats, using pamidronate to block resorption that normally contributes to mineral homeostasis. We fed 6-month-old Sprague Dawley female rats isocaloric diets containing 2.5% or 15% casein for 2 wk. Pamidronate was then administered sc (0.6 mg/kg/) for 5 d. Blood samples were collected at different time points. Serum 1,25(OH)2D3, IGF-I, PTH, calcium, and phosphorus were determined in all rats; vertebral bone strength and histomorphometric analysis were performed in rats subject to the longest low-protein diets. We found 2 wk of low protein increased PTH levels, decreased 1,25(OH)2D3, calcium, and IGF-I, suggesting that increased PTH compensates for low-protein-induced decreases in 1,25(OH)2D3. Pamidronate augmented the increased PTH after 8 wk of low protein and prevented the 1,25(OH)2D3 decrease. IGF-I remained low. Protein malnutrition induced decreases in relative bone volume and trabecular thickness, which was prevented by pamidronate. Maximal load was reduced by protein restriction, but rescued by pamidronate. In summary, the low protein diet resulted in hyperparathyroidism, a reduction in circulating levels of IGF-I, and reduced 1,25(OH)2D3 despite hyperparathyroidism. Blocking resorption resulted in further increases in PTH and improved microarchitecture and biomechanical properties, irrespective of vitamin D status or protein intake.