bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of sildenafil and/or muscle derived stem cells on myocardial infarction
Authors: Wang Judy SC , Kovanecz Istvan , Vernet Dolores , Nolazco Gaby , Kopchok George E , Chow Sheryl L , White Rodney A , Gonzalez-Cadavid Nestor F
Published: August 2012

Background

Previous studies have shown that long-term oral daily PDE 5 inhibitors (PDE5i) counteract fibrosis, cell loss, and the resulting dysfunction in tissues of various rat organs and that implantation of skeletal muscle-derived stem cells (MDSC) exerts some of these effects. PDE5i and stem cells in combination were found to be more effective in non-MI cardiac repair than each treatment separately. We have now investigated whether sildenafil at lower doses and MDSC, alone or in combination are effective to attenuate LV remodeling after MI in rats.

Methods

MI was induced in rats by ligature of the left anterior descending coronary artery. Treatment groups were: “Series A”: 1) untreated; 2) oral sildenafil 3 mg/kg/day from day 1; and “Series B”: intracardiac injection at day 7 of: 3) saline; 4) rat MDSC (106cells); 5) as #4, with sildenafil as in #2. Before surgery, and at 1 and 4 weeks, the left ventricle ejection fraction(LVEF)was measured. LV sections were stained for collagen,myofibroblasts, apoptosis, cardiomyocytes, and iNOS, followed by quantitative image analysis.Western blots estimated angiogenesis and myofibroblast accumulation, as well as potential sildenafil tachyphylaxis by PDE 5 expression. Zymography estimated MMPs 2 and 9 in serum.

Results

As compared to untreated MI rats, sildenafil improved LVEF, reduced collagen, myofibroblasts, and circulating MMPs, and increased cardiac troponin T. MDSC replicated most of these effects and stimulated cardiac angiogenesis. Concurrent MDSC/sildenafil counteracted cardiomyocyte and endothelial cells loss, but did not improve LVEF or angiogenesis, and upregulated PDE 5.

Conclusions

Long-term oral sildenafil, or MDSC given separately, reduce the MI fibrotic scar and improve left ventricular function in this rat model. The failure of the treatment combination may be due to inducing overexpression of PDE5.
Rapid and selective separation for mixed proteins with thiol functionalized magnetic nanoparticles
Authors: Lee Soo Youn , Ahn Chi Young , Lee Jiho , Lee Jin Hyung , Chang Jeong Ho
Published: August 2012

Thiol group functionalized silica-coated magnetic nanoparticles (Si-MNPs@SH) were synthesized for rapid and selective magnetic field-based separation of mixed proteins. The highest adsorption efficiencies of binary proteins, bovine serum albumin (BSA; 66 kDa; pI = 4.65) and lysozyme (LYZ; 14.3 kDa; pI = 11) were shown at the pH values corresponding to their own pI in the single-component protein. In the mixed protein, however, the adsorption performance of BSA and LYZ by Si-MNPs@SH was governed not only by pH but also by the molecular weight of each protein in the mixed protein.
Photoluminescence enhancement of quantum dots on Ag nanoneedles
Authors: Ahmed Syed Rahin , Cha Hee Ryoung , Park Jung Youn , Park Enoch Y , Lee Dongyun , Lee Jaebeom
Published: August 2012

Noble metal nanostructure allows us to tune optical and electrical properties, which has high utility for real-world application. We studied surface plasmon-induced emission of semiconductor quantum dots (QDs) on engineered metallic nanostructures. Highly passive organic ZnS-capped CdSe QDs were spin-coated on poly-(methyl methacrylate)-covered Ag films, which brought QDs near the metallic surface. We obtained the enhanced electromagnetic field and reduced fluorescence lifetimes from CdSe/ZnS QDs due to the strong coupling of emitter wave function with the Ag plasmon resonance. Observed changes include a six-fold increase in the fluorescence intensity and striking reduction in fluorescence lifetimes of CdSe/ZnS QDs on rough Ag nanoneedle compared to the case of smooth surfaces. The advantages of using those nanocomposites are expected for high-efficiency light-emitting diodes, platform fabrication of biological and environmental monitoring, and high-contrast imaging.
Extending the scope of empirical mode decomposition by smoothing
Authors: Kim Donghoh , Kim Kyungmee O , Oh Hee-Seok
Published: August 2012

This article considers extending the scope of the empirical mode decomposition (EMD) method. The extension is aimed at noisy data and irregularly spaced data, which is necessary for widespread applicability of EMD. The proposed algorithm, called statistical EMD (SEMD), uses a smoothing technique instead of an interpolation when constructing upper and lower envelopes. Using SEMD, we discuss how to identify non-informative fluctuations such as noise, outliers, and ultra-high frequency components from the signal, and to decompose irregularly spaced data into several components without distortions.
Movement adds bite to the evolutionary morphology of mammalian teeth
Authors: David Polly P
Published: August 2012

Selection and constraints put limits on morphological evolution. Mammalian teeth are no exception, and the need for them to meet precisely exerts exacting constraints on a staggering array of developmental and functional factors that must be integrated to maintain their performance as they evolve. A study inBMC Evolutionary Biologydemonstrates that mandibular movement is an important component of this integration, and one that should not be neglected in the quantitiative study of the evolution of tooth morphology.

See research articlehttp://www.biomedcentral.com/1471-2148/12/146/
Brain leukocyte infiltration initiated by peripheral inflammation or experimental autoimmune encephalomyelitis occurs through pathways connected to the CSF-filled compartments of the forebrain and midbrain
Authors: Schmitt Charlotte , Strazielle Nathalie , Ghersi-Egea Jean-François
Published: August 2012

Background

Cerebrospinal fluid (CSF) has been considered as a preferential pathway of circulation for immune cells during neuroimmune surveillance. In order to evaluate the involvement of CSF-filled spaces in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis, we performed a time-course analysis of immune cell association with the CSF-containing ventricles, velae, and cisterns in two active models of this disease.

Methods

Guinea-pig spinal cord homogenate-induced EAE in rat and myelin oligodendrocyte glycoprotein-induced EAE in mouse were used. Leukocyte distribution and phenotypes were investigated by immunohistochemistry in serial sections of brain areas of interest, as well as in CSF withdrawn from rat. Immune cells associated with the choroid plexuses were quantified.

Results

Freund’s adjuvant-induced peripheral inflammation in the absence of brain antigen led to a subtle but definite increase in the number of myeloid cells in the extraventricular CSF spaces. In both rats and mice, EAE was characterized by a sustained and initial infiltration of lymphocytes and monocytes within forebrain/midbrain fluid-filled compartments such as the velum interpositum and ambient cisterns, and certain basal cisterns. Leukocytes further infiltrated periventricular and pericisternal parenchymal areas, along perivascular spaces or following a downward CSF-to-tissue gradient. Cells quantified in CSF sampled from rats included lymphocytes and neutrophils. The distinctive pattern of cell distribution suggests that both the choroid plexus and the vessels lying in the velae and cisterns are gates for early leukocyte entry in the central nervous system. B-cell infiltration observed in the mouse model was restricted to CSF-filled extraventricular compartments.

Conclusion

These results identified distinctive velae and cisterns of the forebrain and midbrain as preferential sites of immune cell homing following peripheral and early central inflammation and point to a role of CSF in directing brain invasion by immune cells during EAE.
Viral-toxin interactions and Parkinson’s disease: poly(I:C) priming enhanced the neurodegenerative effects of paraquat
Authors: Bobyn Jessica , Mangano Emily N , Gandhi Anusha , Nelson Eric , Moloney Kerry , Clarke Melanie , Hayley Shawn
Published: August 2012

Background

Parkinson’s disease (PD) has been linked with exposure to a variety of environmental and immunological insults (for example, infectious pathogens) in which inflammatory and oxidative processes seem to be involved. In particular, epidemiological studies have found that pesticide exposure and infections may be linked with the incidence of PD. The present study sought to determine whether exposure to a viral mimic prior to exposure to pesticides would exacerbate PD-like pathology.

Methods

Mice received a supra-nigral infusion of 5 μg of the double-stranded RNA viral analog, polyinosinic: polycytidylic acid (poly(I:C)), followed 2, 7 or 14 days later by administration of the pesticide, paraquat (nine 10 mg/kg injections over three weeks).

Results

As hypothesized, poly(I:C) pre-treatment enhanced dopamine (DA) neuron loss in the substantia nigra pars compacta elicited by subsequent paraquat treatment. The augmented neuronal loss was accompanied by robust signs of microglial activation, and by increased expression of the catalytic subunit (gp91) of the NADPH oxidase oxidative stress enzyme. However, the paraquat and poly(I:C) treatments did not appreciably affect home-cage activity, striatal DA terminals, or subventricular neurogenesis.

Conclusions

These findings suggest that viral agents can sensitize microglial-dependent inflammatory responses, thereby rendering nigral DA neurons vulnerable to further environmental toxin exposure.
Avian influenza surveillance reveals presence of low pathogenic avian influenza viruses in poultry during 2009-2011 in the West Bengal State, India
Authors: Pawar Shailesh D , Kale Sandeep D , Rawankar Amol S , Koratkar Santosh S , Raut Chandrashekhar G , Pande Satish A , Mullick Jayati , Mishra Akhilesh C
Published: August 2012

Introduction

More than 70 outbreaks of the highly pathogenic avian influenza (HPAI) H5N1 have been reported in poultry in the western and north-eastern parts of India. Therefore, in view of the recent HPAI H5N1 outbreaks in poultry, active AI surveillance encompassing wild, resident, migratory birds and poultry was undertaken during 2009–2011 in the State of West Bengal.

Methods

A total of 5722 samples were collected from West Bengal; 3522 samples (2906 fecal droppings + 616 other environmental samples) were from migratory birds and 2200 samples [1604 tracheal, cloacal swabs, environmental samples, tissue samples + 596 blood (serum)] were from domestic ducks and poultry. All tracheal, cloacal and environmental samples were processed for virus isolation. Virus isolates were detected using hemagglutination assay and identified using hemagglutination inhibition (HI) and reverse transcriptase polymerase chain reaction (RT-PCR) assays. Sequencing and phylogenetic analysis of partial region of the hemagglutinin and neuraminidase genes was done. Intravenous pathogenicity index assays were performed in chickens to assess pathogenicity of AI virus isolates. Serum samples were tested for detection of antibodies against AI viruses using HI assay.

Results

A total of 57 AI H9N2, 15 AI H4N6 and 15 Newcastle Disease (NDV) viruses were isolated from chickens, from both backyard and wet poultry markets; AI H4N6 viruses were isolated from backyard chickens and domestic ducks. Characterization of AI H9N2 and H4N6 viruses revealed that they were of low pathogenicity. Domestic ducks were positive for antibodies against H5 and H7 viruses while chickens were positive for presence of antibodies against AI H9N2 and NDV.

Conclusions

In the current scenario of HPAI H5N1 outbreaks in West Bengal, this report shows presence of low pathogenic AI H9N2 and H4N6 viruses in chickens and domestic ducks during the period 2009–2011. This is the first report of isolation of H4N6 from India. Antibodies against AI H5 and H7 in ducks highlight the probable role of domestic ducks in the transmission of AI viruses. Human infections of H9N2 have been reported from China and Hong Kong. This necessitates implementation of prevention and control measures to limit the spread of AI viruses.
Functional analysis of the interferon-stimulated response element of porcine circovirus type 2 and its role during viral replication in vitro and in vivo
Authors: Gu Jinyan , Zhang Yu , Lian Xue , Sun Hailiang , Wang Jingman , Liu Weiting , Meng Gang , Li Peng , Zhu Dan , Jin Yuexin , Cao Ruibing
Published: August 2012

Background

Porcine circovirus type 2 (PCV2) is associated with post-weaning multi-systemic wasting syndrome (PMWS) in young weaned pigs. Immune stimulation was found to activate the replication of PCV2 and exacerbate the clinical outcome of the infection. Proper amount of interferon-α (IFN-α) is able to enhance PCV2 infection and production in Porcine kidney-15 (PK-15) cells when administered after inoculation.

Methods

In the present study, luciferase reporter assays, construction of mutant viruses, Analysis the replication efficiency and the response to IFN-α treatment in PK-15 cells and animal experiments were carried out to analyze the function of interferon-stimulated response element (ISRE) of PCV2 and its role during viral replication in vitro and in vivo.

Results

A functional viral ISRE sequence, 5′-CTGAAAACGAAAGA-3′, was identified in Rep gene promoter (Prep) of PCV2. PCV2 Prep is composed of two mini promoters, the proximal one span the sequence +1 to -106, containing an ISRE while the distal mini promoter is composed of three tandem GC box like sites locate at -85 to -194. It was demonstrated that viral ISRE is necessary for porcine IFN-α initiated luciferase expression enhancement and it plays an important role in affecting the replication efficiency of PCV2 in vivo and in vitro.

Conclusions

These findings provide a theoretical basis for the Phenomenon of immunostimulation is able to enhance PCV2 infection, and improve the understanding of the complicated mechanisms involved in the host and pathogen interactions of PCV2.
Green tea extract suppresses adiposity and affects the expression of lipid metabolism genes in diet-induced obese zebrafish
Authors: Hasumura Takahiro , Shimada Yasuhito , Kuroyanagi Junya , Nishimura Yuhei , Meguro Shinichi , Takema Yoshinori , Tanaka Toshio
Published: August 2012

Background

Visceral fat accumulation is one of the most important predictors of mortality in obese populations. Administration of green tea extract (GTE) can reduce body fat and reduce the risk of obesity-related diseases in mammals. In this study, we investigated the effects and mechanisms of GTE on adiposity in diet-induced obese (DIO) zebrafish.

Methods

Zebrafish at 3.5 to 4.5 months post-fertilization were allocated to four groups: non-DIO, DIO, DIO + 0.0025%GTE, and DIO + 0.0050%GTE. The non-DIO group was fed freshly hatched Artemia once daily (5 mg cysts/fish daily) for 40 days. Zebrafish in the three DIO groups were fed freshly hatched Artemia three times daily (60 mg cysts/fish daily). Zebrafish in the DIO + 0.0025%GTE and DIO + 0.0050%GTE groups were exposed to GTE after the start of feeding three times daily for 40 days.

Results

Three-dimensional microcomputed tomography analysis showed that GTE exposure significantly decreased the volume of visceral but not subcutaneous fat tissue in DIO zebrafish. GTE exposure increased hepatic expression of the lipid catabolism genes ACOX1 (acyl-coenzyme A oxidase 1, palmitoyl), ACADM (acyl-coenzyme A dehydrogenase, c-4 to c-12 straight chain), and PPARA (peroxisome proliferator-activated receptor alpha). GTE exposure also significantly decreased the visceral fat expression of SOCS3 (suppressor of cytokine signaling 3b) which inhibits leptin signaling.

Conclusions

The present results are consistent with those seen in mammals treated with GTE, supporting the validity of studying the effects of GTE in DIO zebrafish. Our results suggest that GTE exerts beneficial effects on adiposity, possibly by altering the expression of lipid catabolism genes and SOCS3.
Integrative transcriptome analysis suggest processing of a subset of long non-coding RNAs to small RNAs
Authors: Jalali Saakshi , Jayaraj Gopal Gunanathan , Scaria Vinod
Published: August 2012

Background

The availability of sequencing technology has enabled understanding of transcriptomes through genome-wide approaches including RNA-sequencing. Contrary to the previous assumption that large tracts of the eukaryotic genomes are not transcriptionally active, recent evidence from transcriptome sequencing approaches have revealed pervasive transcription in many genomes of higher eukaryotes. Many of these loci encode transcripts that have no obvious protein-coding potential and are designated as non-coding RNA (ncRNA). Non-coding RNAs are classified empirically as small and long non-coding RNAs based on the size of the functional RNAs. Each of these classes is further classified into functional subclasses. Although microRNAs (miRNA), one of the major subclass of ncRNAs, have been extensively studied for their roles in regulation of gene expression and involvement in a large number of patho-physiological processes, the functions of a large proportion of long non-coding RNAs (lncRNA) still remains elusive. We hypothesized that some lncRNAs could potentially be processed to small RNA and thus could have a dual regulatory output.

Results

Integration of large-scale independent experimental datasets in public domain revealed that certain well studied lncRNAs harbor small RNA clusters. Expression analysis of the small RNA clusters in different tissue and cell types reveal that they are differentially regulated suggesting a regulated biogenesis mechanism.

Conclusions

Our analysis suggests existence of a potentially novel pathway for lncRNA processing into small RNAs. Expression analysis, further suggests that this pathway is regulated. We argue that this evidence supports our hypothesis, though limitations of the datasets and analysis cannot completely rule out alternate possibilities. Further in-depth experimental verification of the observation could potentially reveal a novel pathway for biogenesis.

Reviewers

This article was reviewed by Dr Rory Johnson (nominated by Fyodor Kondrashov), Dr Raya Khanin (nominated by Dr Yuriy Gusev) and Prof Neil Smalheiser. For full reviews, please go to the Reviewer’s comment section.
Evaluation of antigen detection and polymerase chain reaction for diagnosis of amoebic liver abscess in patients on anti-amoebic treatment
Authors: Jaiswal Virendra , Ghoshal Ujjala , Baijal Sanjay S , Mittal Balraj , Dhole Tapan N , Ghoshal Uday C
Published: August 2012

Background

Diagnosis of amoebic liver abscess (ALA) in patients on anti-amoebic drugs is difficult. There is scanty data on this issue using Entamoeba histolytica (E. histolytica) lectin antigen and polymerase chain reaction (PCR). We studied utility of lectin antigen, PCR, and IgG antibody in diagnosis of liver abscess in patients on anti-amoebic treatment. Liver aspirate of 200 patients, of which 170 had anti-amoebic drug prior to drainage, was tested for E. histolytica lectin antigen by (ELISA), PCR, bacterial culture, and serum IgG antibody by (ELISA). Classification of abscesses was based on result of anti-amoebic IgG antibody and bacterial culture, E. histolytica PCR and bacterial culture, and E. histolytica lectin antigen and bacterial culture.

Findings

Using anti-amoebic IgG antibody and bacterial culture, 136/200 (68.0%) were classified as ALA, 12/200 (6.0%) as pyogenic liver abscess (PLA), 29/200 (14.5%) as mixed infection, and 23/200 (11.5%) remained unclassified. Using amoebic PCR and bacterial culture 151/200 (75.5%) were classified as ALA, 25/200 (12.5%) as PLA, 16/200 (8.0%) as mixed infection, and 8/200 (4.0%) remained unclassified. With E. histolytica lectin antigen and bacterial culture, 22/200 (11.0%) patients were classified as ALA, 39/200 (19.5%) as PLA, 2/200 (1.0%) as mixed infection, and 137/200 (68.5%) remained unclassified.

Conclusions

E. histolytica lectin antigen was not suitable for classification of ALA patients who had prior anti-amoebic treatment. However, PCR may be used as alternative test to anti-amoebic antibody in diagnosis of ALA.
The suicide assessment scale: Psychometric properties of a Norwegian language version
Authors: Koldsland Bjørn Odd , Mehlum Lars , Mellesdal Liv Solrunn , Walby Fredrik A , Diep Lien M
Published: August 2012

Background

Rating scales are valuable tools in suicide research and can also be useful supplements to the clinical interview in suicide risk assessments. This study describes the psychometric properties of a Norwegian language version of the Suicide Assessment Scale Self-report version (SUAS-S).

Methods

Participants were fifty-two patients (mean age = 39.3 years, SD = 10.7) with major depression (53.8%), bipolar disorder (25.0%) and/or a personality disorder (63.5%) referred to a psychiatric outpatient clinic. The SUAS-S, the screening section of the Beck Scale for Suicidal Ideation (BSS-5), the Beck Depression Inventory (BDI), Beck’s Hopelessness Scale (BHS), the Symptom Check-List-90 R (SCL-90R) and the Clinical Global Impression for Severity of Suicidality (CGI-SS) were administered. One week later, the patients completed the SUAS-S a second time.

Results

Cronbach’s alpha for SUAS-S was 0.88 and the test–retest reliability was 0.95 (95% CI: 0.93– 0.97). SUAS-S was positively correlated with the BSS-5 (r = 0.66; 95% CI: 0.47–0.85) for the study sample as a whole and for the suicidal (r = 0.52) and non-suicidal groups (r = 0.50) respectively. There was no difference between the SUAS-S and the BSS-5 in the ability to identify suicidality. This ability was more pronounced when the suicide risk was high. There was a substantial intercorrelation between the score on the SUAS-S and the BDI (0.81) and the BHS (0.76). The sensitivity and specificity of the SUAS-S was explored and an appropriate clinical cut-off value was assessed.

Conclusions

The study revealed good internal consistency, test–retest reliability and concurrent validity for the Suicide Assessment Scale Self-report version. The discriminatory ability for suicidality was comparable to that of the BSS-5.
Molecular characterization of the hexose transporter gene in benznidazole resistant and susceptible populations of Trypanosoma cruzi
Authors: dos Santos Paula F , Ruiz Jerônimo C , Soares Rodrigo P P , Moreira Douglas S , Rezende Antônio M , Folador Edson L , Oliveira Guilherme , Romanha Alvaro J , Murta Silvane M F
Published: August 2012

Background

Hexose transporters (HT) are membrane proteins involved in the uptake of energy-supplying glucose and other hexoses into the cell. Previous studies employing the Differential Display technique have shown that the transcription level of the HT gene from T. cruzi (TcrHT) is higher in an in vitro- induced benznidazole (BZ)-resistant population of the parasite (17 LER) than in its susceptible counterpart (17 WTS).

Methods

In the present study, TcrHT has been characterized in populations and strains of T. cruzi that are resistant or susceptible to BZ. We investigated the copy number and chromosomal location of the gene, the levels of TcrHT mRNA and of TcrHT activity, and the phylogenetic relationship between TcrHT and HTs from other organisms.

Results

In silico analyses revealed that 15 sequences of the TcrHT gene are present in the T. cruzi genome, considering both CL Brener haplotypes. Southern blot analyses confirmed that the gene is present as a multicopy tandem array and indicated a nucleotide sequence polymorphism associated to T. cruzi group I or II. Karyotype analyses revealed that TcrHT is located in two chromosomal bands varying in size from 1.85 to 2.6 Mb depending on the strain of T. cruzi. The sequence of amino acids in the HT from T. cruzi is closely related to the HT sequences of Leishmania species according to phylogenetic analysis. Northern blot and quantitative real-time reverse transcriptase polymerase chain reaction analyses revealed that TcrHT transcripts are 2.6-fold higher in the resistant 17 LER population than in the susceptible 17 WTS. Interestingly, the hexose transporter activity was 40% lower in the 17 LER population than in all other T. cruzi samples analyzed. This phenotype was detected only in the in vitro- induced BZ resistant population, but not in the in vivo-selected or naturally BZ resistant T. cruzi samples. Sequencing analysis revealed that the amino acid sequences of the TcrHT from 17WTS and 17LER populations are identical. This result suggests that the difference in glucose transport between 17WTS and 17LER populations is not due to point mutations, but probably due to lower protein expression level.

Conclusion

The BZ resistant population 17 LER presents a decrease in glucose uptake in response to drug pressure.
Intra-articular corrective osteotomy for malunited Hoffa fracture: A case report
Authors: Iwai Takao , Hamada Masayuki , Miyama Takahide , Shino Konsei
Published: August 2012

Hoffa fracture, an isolated coronal plane fracture of the posterior aspect of the femoral condyle, is known as an unstable, intra-articular fracture, and therefore, operative treatment is recommended. However, insufficient open reduction or failure of fixation may lead to malunion. We performed intra-articular corrective osteotomy for a malunited Hoffa fracture in a 31-year-old man and obtained good functional and radiographic results. This report suggests that intra-articular corrective osteotomy for malunited Hoffa fracture offers a good outcome and should be considered as salvage treatment.
The semantics of Chemical Markup Language (CML) for computational chemistry : CompChem
Authors: Phadungsukanan Weerapong , Kraft Markus , Townsend Joe A , Murray-Rust Peter
Published: August 2012

This paper introduces a subdomain chemistry format for storing computational chemistry data called CompChem. It has been developed based on the design, concepts and methodologies of Chemical Markup Language (CML) by adding computational chemistry semantics on top of the CML Schema. The format allows a wide range of ab initio quantum chemistry calculations of individual molecules to be stored. These calculations include, for example, single point energy calculation, molecular geometry optimization, and vibrational frequency analysis. The paper also describes the supporting infrastructure, such as processing software, dictionaries, validation tools and database repositories. In addition, some of the challenges and difficulties in developing common computational chemistry dictionaries are discussed. The uses of CompChem are illustrated by two practical applications.
Adolescents with prenatal cocaine exposure show subtle alterations in striatal surface morphology and frontal cortical volumes
Authors: Roussotte Florence , Soderberg Lindsay , Warner Tamara , Narr Katherine , Lebel Catherine , Behnke Marylou , Davis-Eyler Fonda , Sowell Elizabeth
Published: August 2012

Background

Published structural neuroimaging studies of prenatal cocaine exposure (PCE) in humans have yielded somewhat inconsistent results, with several studies reporting no significant differences in brain structure between exposed subjects and controls. Here, we sought to clarify some of these discrepancies by applying methodologies that allow for the detection of subtle alterations in brain structure.

Methods

We applied surface-based anatomical modeling methods to magnetic resonance imaging (MRI) data to examine regional changes in the shape and volume of the caudate and putamen in adolescents with prenatal cocaine exposure (n = 40, including 28 exposed participants and 12 unexposed controls, age range 14 to 16 years). We also sought to determine whether changes in regional brain volumes in frontal and subcortical regions occurred in adolescents with PCE compared to control participants.

Results

The overall volumes of the caudate and putamen did not significantly differ between PCE participants and controls. However, we found significant (P <0.05, uncorrected) effects of levels of prenatal exposure to cocaine on regional patterns of striatal morphology. Higher levels of prenatal cocaine exposure were associated with expansion of certain striatal subregions and with contraction in others. Volumetric analyses revealed no significant changes in the volume of any subcortical region of interest, but there were subtle group differences in the volumes of some frontal cortical regions, in particular reduced volumes of caudal middle frontal cortices and left lateral orbitofrontal cortex in exposed participants compared to controls.

Conclusions

Prenatal cocaine exposure may lead to subtle and regionally specific patterns of regional dysmorphology in the striatum and volumetric changes in the frontal lobes. The localized and bidirectional nature of effects may explain in part the contradictions in the existing literature.
Human monocytes and macrophages differ in their mechanisms of adaptation to hypoxia
Authors: Fangradt Monique , Hahne Martin , Gaber Timo , Strehl Cindy , Rauch Roman , Hoff Paula , Löhning Max , Burmester Gerd-Rüdiger , Buttgereit Frank
Published: August 2012

Introduction

Inflammatory arthritis is a progressive disease with chronic inflammation of joints, which is mainly characterized by the infiltration of immune cells and synovial hyperproliferation. Monocytes migrate towards inflamed areas and differentiate into macrophages. In inflamed tissues, much lower oxygen levels (hypoxia) are present in comparison to the peripheral blood. Hence, a metabolic adaptation process must take place. Other studies suggest that Hypoxia Inducible Factor 1-alpha (HIF-1α) may regulate this process, but the mechanism involved for human monocytes is not yet clear. To address this issue, we analyzed the expression and function of HIF-1α in monocytes and macrophages, but also considered alternative pathways involving nuclear factor of kappa light polypeptide gene enhancer in B-cells (NFκB).

Methods

Isolated human CD14+ monocytes were incubated under normoxia and hypoxia conditions with or without phorbol 12-myristate 13-acetate (PMA) stimulation, respectively. Nuclear and cytosolic fractions were prepared in order to detect HIF-1α and NFκB by immunoblot. For the experiments with macrophages, primary human monocytes were differentiated into human monocyte derived macrophages (hMDM) using human macrophage colony-stimulating factor (hM-CSF). The effects of normoxia and hypoxia on gene expression were compared between monocytes and hMDMs using quantitative PCR (quantitative polymerase chain reaction).

Results

We demonstrate, using primary human monocytes and hMDM, that the localization of transcription factor HIF-1α during the differentiation process is shifted from the cytosol (in monocytes) into the nucleus (in macrophages), apparently as an adaptation to a low oxygen environment. For this localization change, protein kinase C alpha/beta 1 (PKC-α/β1 ) plays an important role. In monocytes, it is NFκB1, and not HIF-1α, which is of central importance for the expression of hypoxia-adjusted genes.

Conclusions

These data demonstrate that during differentiation of monocytes into macrophages, crucial cellular adaptation mechanisms are decisively changed.
Endotoxemia and mortality prediction in ICU and other settings: underlying risk and co-detection of gram negative bacteremia are confounders
Authors: Hurley James C , Guidet Bertrand , Offenstadt Georges , Maury Eric
Published: August 2012

Introduction

The interdependence between endotoxemia, gram negative (GN) bacteremia and mortality has been extensively studied. Underlying patient risk and GN bacteremia types are possible confounders of the relationship.

Methods

Published studies with ≥10 patients in either ICU or non-ICU settings, endotoxemia detection by limulus assay, reporting mortality proportions and ≥1 GN bacteremia were included. Summary odds ratios (OR) for mortality were derived across all studies by meta-analysis for the following contrasts: sub-groups with either endotoxemia (group three), GN bacteremia (group two) or both (group one) each versus the group with neither detected (group four; reference group). The mortality proportion for group four is the proxy measure of study level risk within L'Abbé plots.

Results

Thirty-five studies were found. Among nine studies in an ICU setting, the OR for mortality was borderline (OR <2) or non-significantly increased for groups two (GN bacteremia alone) and three (endotoxemia alone) and patient group one (GN bacteremia and endotoxemia co-detected) each versus patient group four (neither endotoxemia nor GN bacteremia detected). The ORs were markedly higher for group one versus group four (OR 6.9; 95% confidence interval (CI), 4.4 -to 11.0 when derived from non-ICU studies. The distributions of Pseudomonas aeruginosa and Escherichia coli bacteremias among groups one versus two are significantly unequal.

Conclusions

The co-detection of GN bacteremia and endotoxemia is predictive of increased mortality risk versus the detection of neither but only in studies undertaken in a non-ICU setting. Variation in GN bacteremia species types and underlying risk are likely unrecognized confounders in the individual studies.
Analysis of CLIP and iCLIP methods for nucleotide-resolution studies of protein-RNA interactions
Authors: Sugimoto Yoichiro , König Julian , Hussain Shobbir , Zupan Blaž , Curk Tomaž , Frye Michaela , Ule Jernej
Published: August 2012

UV cross-linking and immunoprecipitation (CLIP) and individual-nucleotide resolution CLIP (iCLIP) are methods to study protein-RNA interactions in untreated cells and tissues. Here, we analyzed six published and two novel data sets to confirm that both methods identify protein-RNA cross-link sites, and to identify a slight uridine preference of UV-C-induced cross-linking. Comparing Nova CLIP and iCLIP data revealed that cDNA deletions have a preference for TTT motifs, whereas iCLIP cDNA truncations are more likely to identify clusters of YCAY motifs as the primary Nova binding sites. In conclusion, we demonstrate how each method impacts the analysis of protein-RNA binding specificity.
Clinicopathologic Characteristics of Angioimmunoblastic T-Cell Lymphoma: Analysis of the International Peripheral T-Cell Lymphoma Project
Authors: Federico Massimo , Rudiger Thomas , Bellei Monica , Nathwani Bharat N. , Luminari Stefano , Coiffier Bertrand , Harris Nancy L. , Jaffe Elaine S. , Pileri Stefano A. , Savage Kerry J. , Weisenburger Dennis D. , Armitage James O. , Mounier Nicholas , Vose Julie M.
Published: August 2012

Purpose

The International Peripheral T-Cell Lymphoma Project was undertaken to better understand the subtypes of T-cell and natural killer (NK) –cell lymphomas.

Patients and Methods

Angioimmunoblastic T-cell lymphoma (AITL) was diagnosed according to the 2001 WHO criteria by a central review process consisting of panels of expert hematopathologists. Clinical, pathologic, immunophenotyping, treatment, and survival data were correlated.

Results

Of 1,314 patients, 243 (18.5%) were diagnosed with AITL. At presentation, generalized lymphadenopathy was noted in 76% of patients, and 89% had stages III to IV disease. Skin rash was observed in 21% of patients. Hemolytic anemia and hypergammoglobulinemia occurred in 13% and 30% of patients, respectively. Five-year overall and failure-free survivals were 33% and 18%, respectively. At presentation, prognostic models were evaluated, including the standard International Prognostic Index, which comprised the following factors: age ≥ 60 years, stages III to IV disease, lactic dehydrogenase (LDH) > normal, extranodal sites (ENSs) > one, and performance status (PS) ≥ 2; the Prognostic Index for Peripheral T-Cell Lymphoma, comprising: age ≥ 60 years, PS ≥ 2, LDH > normal, and bone marrow involvement; and the alternative Prognostic Index for AITL (PIAI), comprising: age > 60 years, PS ≥ 2, ENSs > one, B symptoms, and platelet count < 150 × 109/L. The simplified PIAI had a low-risk group (zero to one factors), with 5-year survival of 44%, and a high-risk group (two to five factors), with 5-year survival of 24% (P = .0065).

Conclusion

AITL is a rare clinicopathologic entity characterized by an aggressive course and dismal outcome with current therapies.
Bendamustine in Combination With Rituximab for Previously Untreated Patients With Chronic Lymphocytic Leukemia: A Multicenter Phase II Trial of the German Chronic Lymphocytic Leukemia Study Group
Authors: Fischer Kirsten , Cramer Paula , Busch Raymonde , Böttcher Sebastian , Bahlo Jasmin , Schubert Jöerg , Pflüger Karl H. , Schott Silke , Goede Valentin , Isfort Susanne , von Tresckow Julia , Fink Anna-Maria , Bühler Andreas , Winkler Dirk , Kreuzer Karl-Anton , Staib Peter , Ritgen Matthias , Kneba Michael , Döhner Hartmut , Eichhorst Barbara F. , Hallek Michael , Stilgenbauer Stephan , Wendtner Clemens-Martin
Published: August 2012

Purpose

We investigated the safety and efficacy of bendamustine and rituximab (BR) in previously untreated patients with chronic lymphocytic leukemia (CLL).

Patients and Methods

In all, 117 patients, age 34 to 78 years, 46.2% of patients at Binet stage C, and 25.6% of patients age 70 years or older received BR chemoimmunotherapy for first-line treatment of CLL. Bendamustine was administered at a dose of 90 mg/m2 on days 1 and 2 combined with 375 mg/m2 rituximab on day 0 of the first course and 500 mg/m2 on day 1 during subsequent courses for up to six courses.

Results

Overall response rate was 88.0% (95% CI, 80.7% to 100.0%) with a complete response rate of 23.1% and a partial response rate of 64.9%. Ninety percent of patients with del(11q), 94.7% with trisomy 12, 37.5% with del(17p), and 89.4% with unmutated IGHV status responded to treatment. After a median observation time of 27.0 months, median event-free survival was 33.9 months, and 90.5% of patients were alive. Grade 3 or 4 severe infections occurred in 7.7% of patients. Grade 3 or 4 adverse events for neutropenia, thrombocytopenia, and anemia were documented in 19.7%, 22.2%, and 19.7% of patients, respectively.

Conclusion

Chemoimmunotherapy with BR is effective and safe in patients with previously untreated CLL.
Targeting the Hepatocyte Growth Factor–cMET Axis in Cancer Therapy
Authors: Blumenschein George R. , Mills Gordon B. , Gonzalez-Angulo Ana M.
Published: August 2012

The hepatocyte growth factor (HGF) and its receptor, the transmembrane tyrosine kinase cMET, promote cell proliferation, survival, motility, and invasion as well as morphogenic changes that stimulate tissue repair and regeneration in normal cells but can be co-opted during tumor growth. MET overexpression, with or without gene amplification, has been reported in a variety of human cancers, including breast, lung, and GI malignancies. Furthermore, high levels of HGF and/or cMET correlate with poor prognosis in several tumor types, including breast, ovarian, cervical, gastric, head and neck, and non–small-cell lung cancers. Gene amplification and protein overexpression of cMET drive resistance to epidermal growth factor receptor family inhibitors, both in preclinical models and in patients. It is increasingly apparent that the HGF-cMET axis signaling network is complex, and rational combinatorial therapy is needed for optimal clinical efficacy. Better understanding of HGF-cMET axis signaling and the mechanism of action of HGF-cMET inhibitors, along with the identification of biomarkers of response and resistance, will lead to more effective targeting of this pathway for cancer therapy.
Do Socially Deprived Urban Areas Have Lesser Supplies of Cancer Care Services?
Authors: Lamont Elizabeth B. , He Yulei , Subramanian S.V. , Zaslavsky Alan M.
Published: August 2012

Purpose

Area social deprivation is associated with unfavorable health outcomes of residents across the full clinical course of cancer from the stage at diagnosis through survival. We sought to determine whether area social factors are associated with the area health care supply.

Patients and Methods

We studied the area supply of health services required for the provision of guideline-recommended care for patients with breast cancer and colorectal cancer (CRC) in each of the following three distinct clinical domains: screening, treatment, and post-treatment surveillance. We characterized area social factors in 3,096 urban zip code tabulation areas by using Census Bureau data and the health care supply in the corresponding 465 hospital service areas by using American Hospital Association, American Medical Association, and US Food and Drug Administration data. In two-level hierarchical models, we assessed associations between social factors and the supply of health services across areas.

Results

We found no clear associations between area social factors and the supply of health services essential to the provision of guideline recommended breast cancer and CRC care in urban areas. The measures of health service included the supply of physicians who facilitate screening, treatment, and post-treatment care and the supply of facilities required for the same services.

Conclusion

Because we found that the supply of types of health care required for the provision of guideline-recommended cancer care for patients with breast cancer and CRC did not vary with markers of area socioeconomic disadvantage, it is possible that previously reported unfavorable breast cancer and CRC outcomes among individuals living in impoverished areas may have occurred despite an apparent adequate area health care supply.
Validation of a Prognostic Model and the Impact of Mutations in Patients With Lower-Risk Myelodysplastic Syndromes
Authors: Bejar Rafael , Stevenson Kristen E. , Caughey Bennett A. , Abdel-Wahab Omar , Steensma David P. , Galili Naomi , Raza Azra , Kantarjian Hagop , Levine Ross L. , Neuberg Donna , Garcia-Manero Guillermo , Ebert Benjamin L.
Published: August 2012

Purpose

A subset of patients with myelodysplastic syndromes (MDS) who are predicted to have lower-risk disease as defined by the International Prognostic Scoring System (IPSS) demonstrate more aggressive disease and shorter overall survival than expected. The identification of patients with greater-than-predicted prognostic risk could influence the selection of therapy and improve the care of patients with lower-risk MDS.

Patients and Methods

We performed an independent validation of the MD Anderson Lower-Risk Prognostic Scoring System (LR-PSS) in a cohort of 288 patients with low- or intermediate-1 IPSS risk MDS and examined bone marrow samples from these patients for mutations in 22 genes, including SF3B1, SRSF2, U2AF1, and DNMT3A.

Results

The LR-PSS successfully stratified patients with lower-risk MDS into three risk categories with significant differences in overall survival (20% in category 1 with median of 5.19 years [95% CI, 3.01 to 10.34 years], 56% in category 2 with median of 2.65 years [95% CI, 2.18 to 3.30 years], and 25% in category 3 with median of 1.11 years [95% CI, 0.82 to 1.51 years]), thus validating this prognostic model. Mutations were identified in 71% of all samples, and mutations associated with a poor prognosis were enriched in the highest-risk LR-PSS category. Mutations of EZH2, RUNX1, TP53, and ASXL1 were associated with shorter overall survival independent of the LR-PSS. Only EZH2 mutations retained prognostic significance in a multivariable model that included LR-PSS and other mutations (hazard ratio, 2.90; 95% CI, 1.85 to 4.52).

Conclusion

Combining the LR-PSS and EZH2 mutation status identifies 29% of patients with lower-risk MDS with a worse-than-expected prognosis. These patients may benefit from earlier initiation of disease-modifying therapy.
Murine Anti-GD2 Monoclonal Antibody 3F8 Combined With Granulocyte-Macrophage Colony-Stimulating Factor and 13-Cis-Retinoic Acid in High-Risk Patients With Stage 4 Neuroblastoma in First Remission
Authors: Cheung Nai-Kong V. , Cheung Irene Y. , Kushner Brian H. , Ostrovnaya Irina , Chamberlain Elizabeth , Kramer Kim , Modak Shakeel
Published: August 2012

Purpose

Anti-GD2 monoclonal antibody (MoAb) combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) has shown efficacy against neuroblastoma (NB). Prognostic variables that could influence clinical outcome were explored.

Patients and Methods

One hundred sixty-nine children diagnosed with stage 4 NB (1988 to 2008) were enrolled onto consecutive anti-GD2 murine MoAb 3F8 ± GM-CSF ± 13-cis-retinoic acid (CRA) protocols after achieving first remission (complete remission/very good partial remission). Patients enrolled in regimen A (n = 43 high-risk [HR] patients) received 3F8 alone; regimen B (n = 41 HR patients), 3F8 + intravenous GM-CSF + CRA, after stem-cell transplantation (SCT); and regimen C (n = 85), 3F8 + subcutaneous GM-CSF + CRA, 46 of 85 after SCT, whereas 28 of 85 required additional induction therapy and were deemed ultra high risk (UHR). Marrow minimal residual disease (MRD) was measured by quantitative reverse transcription polymerase chain reaction. Survival probability was calculated by the Kaplan-Meier method, and prognostic variables were analyzed by multivariate Cox regression model.

Results

At 5 years from the start of immunotherapy, progression-free survival (PFS) improved from 44% for HR patients receiving regimen A to 56% and 62% for those receiving regimens B and C, respectively. Overall survival (OS) was 49%, 61%, and 81%, respectively. PFS and OS of UHR patients were 36% and 75%, respectively. Relapse was mostly at isolated sites. Independent adverse prognostic factors included UHR (PFS) and post–cycle two MRD (PFS and OS), whereas the prognostic factors for improved outcome were missing killer immunoglobulin-like receptor ligand (PFS and OS), human antimouse antibody response (OS), and regimen C (OS).

Conclusion

Retrospective analysis of consecutive trials from a single center demonstrated that MoAb 3F8 + GM-CSF + CRA is effective against chemotherapy-resistant marrow MRD. Its positive impact on long-term survival can only be confirmed definitively by randomized studies.
Bortezomib-Based Graft-Versus-Host Disease Prophylaxis in HLA-Mismatched Unrelated Donor Transplantation
Authors: Koreth John , Stevenson Kristen E. , Kim Haesook T. , McDonough Sean M. , Bindra Bhavjot , Armand Philippe , Ho Vincent T. , Cutler Corey , Blazar Bruce R. , Antin Joseph H. , Soiffer Robert J. , Ritz Jerome , Alyea Edwin P.
Published: August 2012

Purpose

HLA-mismatched unrelated donor (MMUD) hematopoietic stem-cell transplantation (HSCT) is associated with increased graft-versus-host disease (GVHD) and impaired survival. In reduced-intensity conditioning (RIC), neither ex vivo nor in vivo T-cell depletion (eg, antithymocyte globulin) convincingly improved outcomes. The proteasome inhibitor bortezomib has immunomodulatory properties potentially beneficial for control of GVHD in T-cell-replete HLA-mismatched transplantation.

Patients and Methods

We conducted a prospective phase I/II trial of a GVHD prophylaxis regimen of short-course bortezomib, administered once per day on days +1, +4, and +7 after peripheral blood stem-cell infusion plus standard tacrolimus and methotrexate in patients with hematologic malignancies undergoing MMUD RIC HSCT. We report outcomes for 45 study patients: 40 (89%) 1-locus and five (11%) 2-loci mismatches (HLA-A, -B, -C, -DRB1, or -DQB1), with a median of 36.5 months (range, 17.4 to 59.6 months) follow-up.

Results

The 180-day cumulative incidence of grade 2 to 4 acute GVHD was 22% (95% CI, 11% to 35%). One-year cumulative incidence of chronic GVHD was 29% (95% CI, 16% to 43%). Two-year cumulative incidences of nonrelapse mortality (NRM) and relapse were 11% (95% CI, 4% to 22%) and 38% (95% CI, 24% to 52%), respectively. Two-year progression-free survival and overall survival were 51% (95% CI, 36% to 64%) and 64% (95% CI, 49% to 76%), respectively. Bortezomib-treated HLA-mismatched patients experienced rates of NRM, acute and chronic GVHD, and survival similar to those of contemporaneous HLA-matched RIC HSCT at our institution. Immune recovery, including CD8+ T-cell and natural killer cell reconstitution, was enhanced with bortezomib.

Conclusion

A novel short-course, bortezomib-based GVHD regimen can abrogate the survival impairment of MMUD RIC HSCT, can enhance early immune reconstitution, and appears to be suitable for prospective randomized evaluation.