bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chemoprevention of Cigarette Smoke–Induced Alterations of MicroRNA Expression in Rat Lungs
Authors: Izzotti Alberto , Calin George A. , Steele Vernon E. , Cartiglia Cristina , Longobardi Mariagrazia , Croce Carlo M. , De Flora Silvio 
Published: January 2010

Abstract
We previously showed that exposure to environmental cigarette smoke (ECS) for 28 days causes extensive downregulation of microRNA expression in the lungs of rats, resulting in the overexpression of multiple genes and proteins. In the present study, we evaluated by microarray the expression of 484 microRNAs in the lungs of either ECS-free or ECS-exposed rats treated with the orally administered chemopreventive agents N-acetylcysteine, oltipraz, indole-3-carbinol, 5,6-benzoflavone, and phenethyl isothiocyanate (as single agents or in combinations). This is the first study of microRNA modulation by chemopreventive agents in nonmalignant tissues. Scatterplot, hierarchical cluster, and principal component analyses of microarray and quantitative PCR data showed that none of the above chemopreventive regimens appreciably affected the baseline microRNA expression, indicating potential safety. On the other hand, all of them attenuated ECS-induced alterations but to a variable extent and with different patterns, indicating potential preventive efficacy. The main ECS-altered functions that were modulated by chemopreventive agents included cell proliferation, apoptosis, differentiation, Ras activation, P53 functions, NF-κB pathway, transforming growth factor–related stress response, and angiogenesis. Some microRNAs known to be polymorphic in humans were downregulated by ECS and were protected by chemopreventive agents. This study provides proof-of-concept and validation of technology that we are further refining to screen and prioritize potential agents for continued development and to help elucidate their biological effects and mechanisms. Therefore, microRNA analysis may provide a new tool for predicting at early carcinogenesis stages both the potential safety and efficacy of cancer chemopreventive agents. Cancer Prev Res; 3(1); 62–72
Folate Deficiency Alters Hepatic and Colon MGMT and OGG-1 DNA Repair Protein Expression in Rats but Has No Effect on Genome-Wide DNA Methylation
Authors: Duthie Susan J. , Grant George , Pirie Lynn P. , Watson Amanda J. , Margison Geoffrey P. 
Published: January 2010

Abstract
Folate deficiency is implicated in human colon cancer. The effects of feeding rats a folate-deficient diet for 24 weeks on DNA damage (8-oxo-7,8-dihydroguanine), DNA repair [O6-methylguanine-DNA methyltransferase (MGMT) and 8-oxoguanine-DNA glycosylase (OGG-1) activity], and epigenetic parameters (genome-wide cytosine methylation and indices of cellular methylation status) were investigated. Relative to control diet, the folate-deficient diet resulted in significantly reduced levels of serum (∼80%; P &lt; 0.0001), whole blood (∼40%; P &lt; 0.0001), and tissue folate (between 25% and 60% depending on the tissue sampled; P &lt; 0.05); increased plasma total homocysteine (∼35%; P &lt; 0.05); and decreased S-adenosylmethionine to S-adenosylhomocysteine concentrations (∼11%; P &lt; 0.05). There was no significant change in the levels of 5-methyldeoxycytidine in liver or colon DNA, nor in the activity of liver DNA cytosine methyltransferase. However, there were significant increases in 8-oxo-7,8-dihydroguanine (P &lt; 0.001) in lymphocyte DNA and in levels of the DNA repair proteins OGG-1 (∼27%; P &lt; 0.03) and MGMT (∼25%; P &lt; 0.003) in the liver, but not in the colon. This may reflect the ability of the liver, but not the colon, to upregulate DNA repair enzymes in response to either elevated DNA damage or an imbalance in the nucleotide precursor pool. These results show that folate deficiency can significantly modulate DNA damage and DNA repair, providing mechanisms by which it plays a role in the etiology of human cancer. We speculate that the inability of colon tissue to respond to folate deficiency occurs in humans and may increase the potential for malignant transformation. Cancer Prev Res; 3(1); 92–100
Targeting Ornithine Decarboxylase for the Prevention of Nonmelanoma Skin Cancer in Humans
Authors: Elmets Craig A. , Athar Mohammad 
Published: January 2010

Abstract
Bailey et al. report in this issue of the journal (beginning on page 35) one of the first successful trials of basal cell carcinoma (BCC) prevention. Oral α-difluoromethyl-dl-ornithine (DFMO) reduced new BCCs in patients with a prior history of nonmelanoma skin cancer. DFMO is an inhibitor of ornithine decarboxylase, a key enzyme in the polyamine biosynthetic pathway. This perspective on Bailey et al. discusses our knowledge of the contribution of polyamines to BCC pathogenesis, how this knowledge advanced the development of a new method to prevent BCCs, and prospects for future studies of DFMO in BCC prevention. Cancer Prev Res; 3(1); 8–11
One-Hit Effects and Cancer
Authors: Iniesta Maria D. , Chien Janet , Wicha Max , Merajver Sofia D. 
Published: January 2010

Abstract
This perspective on Bellacosa et al. (beginning on p. 48 in this issue of the journal) discusses the important biology of microscopically normal tissues in carriers of germ-line BRCA1 or BRCA2 mutations. The work of Bellacosa et al. is an important step toward discerning which pathways may be altered when one BRCA allele is inactivated. Cancer Prev Res; 3(1); 12–5
Negotiating an Exit: Existential, Interactional, and Cultural Obstacles to Disorder Disidentification
Authors: Howard Jenna 
Published: January 2010

This study highlights a population that has been largely overlooked in sociological research on labeling and identity: people who formerly identified with emotional disorder labels and have chosen to discard them (delabelers). My qualitative analysis of 40 delabelers'narratives explores processes of identification and disidentification by highlighting the tension between individuals' decision to discard their labeled identities and their simultaneous reluctance to relinquish these identities. I characterize this tension as the consequence of existential, interactional, and cultural obstacles to disidentification that are common to delabelers' narratives. These obstacles include both a fear of the consequences of dissociating with the label as well as an attachment to the identity, the community, and the cultural support associated with the disorder label.
Perceptions of Time, Cultural Boundaries and ‘Region’ in Early Indian Texts
Authors: Parasher-Sen Aloka 
Published: January 2010

Historiographical positions have hitherto suggested that historical regions be objectively encapsulated solely as entities of political control or, as regions with their present-day linguistic boundaries. This article takes an in-depth look at the way notions of time, history, space, boundaries and identities evolved in the early Indian textual traditions that impinged on how regions were continually in the process of making. Critical to the argument is the unveiling of theoretical underpinnings of the sources that modern historians use to reconstruct ancient historical regions, states and territories. Next, it highlights the boundaries of socio-cultural regions, as specified in the dominant literary tradition, to conclude that an inherent fluidity was manifested especially in the reckoning regions of exclusion. Stable definition of regions was, however, entwined in data emerging out of regional inscriptions that elaborated primarily on socio-economic mechanisms of control. In this case study, the early textual traditions culturally interlinked a locality and region to its large whole, whereas specific data from inscriptions projected more concrete realities of boundary, space and time. Conflict between the two modes of perceiving and documenting the past has to be reckoned with, so as not to project our modern concerns of ‘country’, ‘region’ and ‘history’ into the past.
A randomized, blinded, parallel-group, pilot trial of mycophenolate mofetil (CellCept) compared with interferon beta-1a (Avonex) in patients with relapsing-remitting multiple sclerosis
Authors: Frohman Elliot M. , Cutter Gary , Remington Gina , Gao Hongjiang , Rossman Howard , Weinstock-Guttman Bianca , Durfee Jacqueline E. , Conger Amy , Carl Ellen , Treadaway Katherine , Lindzen Eric , Salter Amber , Frohman Teresa C. , Shah Anjali , Bates Angela , Cox Jennifer L. , Dwyer Michael G. , Stuve Olaf , Greenberg Benjamin M. , Racke Michael K. , Zivadinov Robert 
Published: January 2010

Background: Mycophenolate mofetil (MMF, CellCept®) has been utilized as an antirejection agent in transplant recipients and in patients with myriad autoimmune disorders including multiple sclerosis (MS). Objective: To investigate radiographic and clinical safety involving monotherapy use of daily oral MMF (1 g b.i.d.) versus weekly intramuscular interferon beta 1a (Avonex ® at 30 mcg) in relapsing-remitting MS (RRMS). Methods: We organized a randomized, serial, 6-monthly, MRI-blinded, parallel-group multicenter pilot study to determine the safety of MMF versus interferon beta monotherapy in 35 untreated patients with RRMS, all of whom exhibited evidence of gadolinium (Gd) enhancement on a screening MRI of the brain. The primary outcome was the reduction in the cumulative mean number of combined active lesions (CAL), new Gd-enhancing lesions, and new T2 lesions on MRI analyses. Results: Both interferon beta and MMF appeared safe and well tolerated in the majority of patients. There was no difference between MMF therapy and the standard regimen of interferon beta therapy on the primary safety MRI endpoints of the study. However, the MMF group showed a trend toward a lower accumulation of combined active lesions, CAL, Gd and T2 lesions when compared with interferon beta treated patients. Conclusions: The results from this pilot study suggest that the application of MMF monotherapy in MS deserves further exploration.
A one-year prospective, randomized, placebo-controlled, quadruple-blinded, phase II safety pilot trial of combination therapy with interferon beta-1a and mycophenolate mofetil in early relapsing—remitting multiple sclerosis (TIME MS)
Authors: Remington Gina M. , Treadaway Katherine , Frohman Teresa , Salter Amber , Stüve Olaf , Racke Michael K. , Hawker Kathleen , Agosta Federica , Sormani Maria Pia , Filippi Massimo , Frohman Elliot M. 
Published: January 2010

Background: Mycophenolate mofetil (MMF) is an oral DNA base synthesis inhibitor with immunomodulatory effects on B cells, T cells, and macrophages. Objective: To conduct a safety and tolerability pilot study of interferon beta-1a (IFN-b1a) in combination with either placebo or oral MMF in multiple sclerosis (MS). Methods: Twenty-four treatment-naïve R—RMS patients participated in a one-year prospective, placebo-controlled, blinded, safety pilot clinical trial. Every patient injected weekly intramuscular interferon beta-1a. The cohort was then randomized (1 : 1) to either active oral MMF or identical-appearing placebo tablets. Clinical evaluations were assessed every 3 months, along with brain MRI scans performed at baseline and repeated every 60 days for one year. Comprehensive laboratory assessments were monitored for safety, along with adverse events. Results: In this small pilot investigation, no differences were identified between the two treatment groups with respect to patient-reported adverse events, MRI metrics, or laboratory abnormalities. Notwithstanding these observations, and the limited number of patients treated, trends appeared to favor the combination therapy regimen. Conclusions: The combination treatment regimen of interferon beta-1a and MMF appeared to be well tolerated in this pilot study. Despite the small sample size, therapeutic trends were observed in favor of combination therapy. An adequately powered controlled trial of MMF in MS appears warranted.
Standing variation and new mutations both contribute to a fast response to selection for flowering time in maize inbreds
Authors: Durand Eléonore , Tenaillon Maud I , Ridel Céline , Coubriche Denis , Jamin Philippe , Jouanne Sophie , Ressayre Adrienne , Charcosset Alain , Dillmann Christine 
Published: January 2010

AbstractBackgroundIn order to investigate the rate and limits of the response to selection from highly inbred genetic material and evaluate the respective contribution of standing variation and new mutations, we conducted a divergent selection experiment from maize inbred lines in open-field conditions during 7 years. Two maize commercial seed lots considered as inbred lines,F252 andMBS847, constituted two biological replicates of the experiment. In each replicate, we derived an Early and a Late population by selecting and selfing the earliest and the latest individuals, respectively, to produce the next generation.ResultsAll populations, except the EarlyMBS847, responded to selection despite a short number of generations and a small effective population size. Part of the response can be attributed to standing genetic variation in the initial seed lot. Indeed, we identified one polymorphism initially segregating in theF252 seed lot at a candidate locus for flowering time, which explained 35% of the trait variation within the LateF252 population. However, the model that best explained our data takes into account both residual polymorphism in the initial seed lots and a constant input of heritable genetic variation by new (epi)mutations. Under this model, values of mutational heritability range from 0.013 to 0.025, and stand as an upper bound compare to what is reported in other species.ConclusionsOur study reports a long-term divergent selection experiment for a complex trait, flowering time, conducted on maize in open-field conditions. Starting from a highly inbred material, we created within a few generations populations that strikingly differ from the initial seed lot for flowering time while preserving most of the phenotypic characteristics of the initial inbred. Such material is unique for studying the dynamics of the response to selection and its determinants. In addition to the fixation of a standing beneficial mutation associated with a large phenotypic effect, a constant input of genetic variance by new mutations has likely contributed to the response. We discuss our results in the context of the evolution and mutational dynamics of populations characterized by a small effective population size.
Molecular characterization of Legionella pneumophila-induced interleukin-8 expression in T cells
Authors: Takamatsu Reika , Teruya Hiromitsu , Takeshima Eriko , Ishikawa Chie , Matsumoto Kunihiro , Mukaida Naofumi , Li Jian-Dong , Heuner Klaus , Higa Futoshi , Fujita Jiro , Mori Naoki 
Published: January 2010

Abstract

Background

Legionella pneumophila is the causative agent of human Legionnaire's disease. During infection, the bacterium invades macrophages and lung epithelial cells, and replicates intracellularly. However, little is known about its interaction with T cells. We investigated the ability of L. pneumophila to infect and stimulate the production of interleukin-8 (IL-8) in T cells. The objective of this study was to assess whether L. pneumophila interferes with the immune system by interacting and infecting T cells.

Results
Wild-type L. pneumophila and flagellin-deficient Legionella, but not L. pneumophila lacking a functional type IV secretion system Dot/Icm, replicated in T cells. On the other hand, wild-type L. pneumophila and Dot/Icm-deficient Legionella, but not flagellin-deficient Legionella or heat-killed Legionella induced IL-8 expression. L. pneumophila activated an IL-8 promoter through the NF-κB and AP-1 binding regions. Wild-type L. pneumophila but not flagellin-deficient Legionella activated NF-κB, p38 mitogen-activated protein kinase (MAPK), Jun N-terminal kinase (JNK), and transforming growth factor β-associated kinase 1 (TAK1). Transfection of dominant negative mutants of IκBα, IκB kinase, NF-κB-inducing kinase, TAK1, MyD88, and p38 MAPK inhibited L. pneumophila-induced IL-8 activation. Inhibitors of NF-κB, p38 MAPK, and JNK blocked L. pneumophila-induced IL-8 expression. In addition, c-Jun, JunD, cyclic AMP response element binding protein, and activating transcription factor 1, which are substrates of p38 MAPK and JNK, bound to the AP-1 site of the IL-8 promoter.

Conclusions
Taken together, L. pneumophila induced a flagellin-dependent activation of TAK1, p38 MAPK, and JNK, as well as NF-κB and AP-1, which resulted in IL-8 production in human T cells, presumably contributing to the immune response in Legionnaire's disease.
Corynebacterium diphtheriae invasion-associated protein (DIP1281) is involved in cell surface organization, adhesion and internalization in epithelial cells
Authors: Ott Lisa , Höller Martina , Gerlach Roman G , Hensel Michael , Rheinlaender Johannes , Schäffer Tilman E , Burkovski Andreas 
Published: January 2010

Abstract

Background

Corynebacterium diphtheriae, the causative agent of diphtheria, is well-investigated in respect to toxin production, while little is known about C. diphtheriae factors crucial for colonization of the host. In this study, we investigated the function of surface-associated protein DIP1281, previously annotated as hypothetical invasion-associated protein.

Results
Microscopic inspection of DIP1281 mutant strains revealed an increased size of the single cells in combination with an altered less club-like shape and formation of chains of cells rather than the typical V-like division forms or palisades of growing C. diphtheriae cells. Cell viability was not impaired. Immuno-fluorescence microscopy, SDS-PAGE and 2-D PAGE of surface proteins revealed clear differences of wild-type and mutant protein patterns, which were verified by atomic force microscopy. DIP1281 mutant cells were not only altered in shape and surface structure but completely lack the ability to adhere to host cells and consequently invade these.

Conclusions
Our data indicate that DIP1281 is predominantly involved in the organization of the outer surface protein layer rather than in the separation of the peptidoglycan cell wall of dividing bacteria. The adhesion- and invasion-negative phenotype of corresponding mutant strains is an effect of rearrangements of the outer surface.
Non-invasive evaluation of nigrostriatal neuropathology in a proteasome inhibitor rodent model of Parkinson's disease
Authors: Vernon Anthony C , Johansson Saga M , Modo Michel M 
Published: January 2010

Abstract

Background
Predominantly, magnetic resonance imaging (MRI) studies in animal models of Parkinson's disease (PD) have focused on alterations in T2 water 1H relaxation or 1H MR spectroscopy (MRS), whilst potential morphological changes and their relationship to histological or behavioural outcomes have not been appropriately addressed. Therefore, in this study we have utilised MRI to scan in vivo brains from rodents bearing a nigrostriatal lesion induced by intranigral injection of the proteasome inhibitor lactacystin.

Results
Lactacystin induced parkinsonian-like behaviour, characterised by impaired contralateral forelimb grip strength and increased contralateral circling in response to apomorphine. T2-weighted MRI, 3-weeks post-lesion, revealed significant morphological changes in PD-relevant brain areas, including the striatum and ventral midbrain in addition to a decrease in T2 water 1H relaxation in the substantia nigra (SN), but not the striatum. Post-mortem histological analyses revealed extensive dopaminergic neuronal degeneration and α-synuclein aggregation in the SN. However, extensive neuronal loss could also be observed in extra-nigral areas, suggesting non-specific toxicity of lactacystin. Iron accumulation could also be observed throughout the midbrain reflecting changes in T2. Importantly, morphological, but not T2 relaxivity changes, were significantly associated with both behavioural and histological outcomes in this model.

Conclusions
A pattern of morphological changes in lactacystin-lesioned animals has been identified, as well as alterations in nigral T2 relaxivity. The significant relationship of morphological changes with behavioural and histological outcomes in this model raises the possibility that these may be useful non-invasive surrogate markers of nigrostriatal degeneration in vivo.
The Plasmodium falciparum merozoite surface protein-1 19 KD antibody response in the Peruvian Amazon predominantly targets the non-allele specific, shared sites of this antigen
Authors: Sutton Patrick L , Clark Eva H , Silva Claudia , Branch OraLee H 
Published: January 2010

Abstract

Background

Plasmodium falciparum re-emerged in Iquitos, Peru in 1994 and is now hypoendemic (< 0.5 infections/person/year). Purportedly non-immune individuals with discrete (non-overlapping) P. falciparum infections can be followed using this population dynamic. Previous work demonstrated a strong association between this population's antibody response to Pf MSP1-19KD and protection against febrile illness and parasitaemia. Therefore, some selection for Pf MSP1-19KD allelic diversity would be expected if the protection is to allele-specific sites of Pf MSP1-19KD. Here, the potential for allele-specific polymorphisms in this population is investigated, and the allele-specificity of antibody responses to Pf MSP1-19KD are determined.

Methods
The 42KD region in Pf MSP1 was genotyped from 160 individual infections collected between 2003 and 2007. Additionally, the polymorphic block 2 region of Pfmsp1 (Pfmsp1-B2) was genotyped in 781 infection-months to provide a baseline for population-level diversity. To test whether Pf MSP1-19KD genetic diversity had any impact on antibody responses, ELISAs testing IgG antibody response were performed on individuals using all four allele-types of Pf MSP1-19KD. An antibody depletion ELISA was used to test the ability of antibodies to cross-react between allele-types.

Results
Despite increased diversity in Pfmsp1-B2, limited diversity within Pfmsp1-42KD was observed. All 160 infections genotyped were Mad20-like at the Pfmsp1-33KD locus. In the Pfmsp1-19KD locus, 159 (99.4%) were the Q-KSNG-F haplotype and 1 (0.6%) was the E-KSNG-L haplotype. Antibody responses in 105 individuals showed that Q-KNG and Q-TSR alleles generated the strongest immune responses, while Q-KNG and E-KNG responses were more concordant with each other than with those from Q-TSR and E-TSR, and vice versa. The immuno-depletion ELISAs showed all samples responded to the antigenic sites shared amongst all allelic forms of Pf MSP1-19KD.

Conclusions
A non-allele specific antibody response in Pf MSP1-19KD may explain why other allelic forms have not been maintained or evolved in this population. This has important implications for the use of Pf MSP1-19KD as a vaccine candidate. It is possible that Peruvians have increased antibody responses to the shared sites of Pf MSP1-19KD, either due to exposure/parasite characteristics or due to a human-genetic predisposition. Alternatively, these allelic polymorphisms are not immune-specific even in other geographic regions, implying these polymorphisms may be less important in immune evasion that previous studies suggest.