bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antiviral Activity of Geneticin against Bovine Viral Diarrhoea Virus
Authors: Birk Alexander V , Dubovi Edward J , Zhang Xianchao , Szeto Hazel H 
Published: March 2015

Background: Aminoglycoside G418 is commonly used to generate stable replicons for RNA viruses, such as hepatitis C virus, West Nile virus, and bovine viral diarrhoea virus (BVDV). This precludes testing G418's own antiviral activities against those viruses. Here, we report antiviral activity of G418 against BVDV. Methods: Cell viability and virus yield reduction assays were used to investigate antiviral effects of G418 against BVDV. The expression of viral proteins and RNA were determined by western blot and real-time quantitive PCR, respectively. Results: We demonstrated that G418 (50% cytotoxicity concentration of 400 µg/ml) improved cell viability of Madin-Darby bovine kidney cells infected with a cytopathic strain of BVDV (NADL) in a dose-dependent manner with 50% effective concentration of 4 µg/ml. Interestingly, close structural analogues with known properties as translation inhibitors similar to G418 — kanamycin and gentamicin — had no antiviral activity against BVDV. In addition, G418 inhibits virus yield of two different strains of BVDV (NADL and NY-1) without affecting viral RNA replication and translation or viral NS3 protein processing. Conclusion: Our data indicate that antiviral activity of G418 could result from interference with either the assembly or release of active virus, rather than the regulation of viral translation and replication. Thus, we propose the use of chemical analogues of G418 as antiviral therapeutics for treatment of viral diseases associated with the Flaviviridae family, such as hepatitis C virus, dengue virus, yellow fever virus, West Nile virus and others.
Synthesis and Evaluation of N-Substituted Acridones as Antiviral Agents against Haemorrhagic Fever Viruses
Authors: Sepúlveda Claudia S , Fascio Mirta L , Mazzucco Maria B , Palacios Maite L Docampo , Pellón Rolando F , García Cybele C , D'Accorso Norma B , Damonte Elsa B 
Published: March 2015

Background: In the present study, a series of N-substituted acridone derivatives was synthesized and evaluated against two haemorrhagic fever viruses (HFV). Methods: Compounds were tested against Junin virus (JUNV), an arenavirus agent of Argentine haemorrhagic fever, and dengue virus (DENV), a flavivirus agent of the most prevalent arthropod-borne viral disease in humans. Results: Among tested compounds, two N-allyl acridones (derivatives 3c and 3f) elicited a potent and selective antiviral activity against JUNV (strain IV4454) and DENV-2 (strain NGC) with 50% effective concentration values between 2.5 and 5.5 µM, as determined by virus yield inhibition. No cytotoxicity was detected at concentrations up to 1,000 µM, resulting in selectivity indices > 181.8–400.0. Both acridones were effective against a wide spectrum of arenaviruses and the four serotypes of DENV. Furthermore, 3c and 3f failed to inactivate virus before cell infection as well as to induce a refractory state by cell pretreatment, indicating that the inhibitory effect was exerted through a blockade in virus multiplication during the infectious process. Conclusion: These data are the first demonstration that acridone derivatives have a potent antiviral activity that block in vitro multiplication of HFV belonging to Arenaviridae and Flaviviridae, such as JUNV and DENV.
Binding Modes of Two Novel Non-Nucleoside Reverse Transcriptase Inhibitors, YM-215389 and YM-228855, to HIV Type-1 Reverse Transcriptase
Authors: Kodama Eiichi , Orita Masaya , Masuda Naoyuki , Yamamoto Osamu , Fujii Masahiro , Ohgami Tetsuro , Kageyama Shunji , Ohta Mitsuaki , Hatta Toshifumi , Inoue Hiroshi , Suzuki Hiroshi , Sudo Kenji , Shimizu Yasuaki , Matsuoka Masao 
Published: March 2015

Background: YM-215389 and YM-228855 are thiazolidenebenzenesulfonamide (TBS) derivatives and novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) that inhibit not only wild-type, but also the K103N- and Y181C-substituted reverse transcriptase (RT) of HIV type-1 (HIV-1). Methods: To characterize the binding modes of the TBS derivatives in detail, the anti-HIV-1 activities of YM-215389 and YM-228855 against various NNRTI-resistant clones were examined. Docking studies with HIV-1 RT were also performed. Results: YM-215389, which effectively inhibits various NNRTI-resistant clones, interacted with L100, K103, V106 and Y318 through the benzene ring and with E138, V179, Y181, Y188 and W229 through the thiazole ring. A single amino acid substitution confers only moderate resistance to YM-215389; indeed, four amino acid substitutions (V106L, V108I, E138K and L214F) were necessary for high- level resistance. Although the activity of YM-228855, a derivative of YM-215389 that has two bulky and rigid cyano-moieties on the benzene ring, was 10x more potent against HIV-1 than YM-215389, its anti-HIV-1 activity was readily reduced with single substitutions as with Y181I and K103N. Conclusions: These results provide structural information for optimizing the TBS derivatives in an attempt to construct ideal NNRTIs that maintain anti-HIV-1 activity to various HIV-1 variants.
HIV Dynamics and Integrase Inhibitors
Authors: Murray John M 
Published: March 2015

The integrase inhibitor (INI) raltegravir has shown promising results in clinical trials to date, reducing second phase HIV RNA levels by 70% in comparison with standard regimens. These trial results have been limited by the 50 copies/ml detection limit of the HIV RNA assay and have not investigated the effect of an INI regimen on levels of latently infected cells. Mathematical models that duplicated previous raltegravir results were extended to estimate effects of an INI regimen on HIV RNA beyond second phase and on HIV DNA levels. Depending on assumptions underlying later phase HIV RNA generation and its interaction with latently infected cells, HIV RNA in later phases can be lower or show no difference with an INI, and similarly for HIV DNA. If latent infection is maintained by differentiation of stem cells with integrated HIV DNA, then an INI regimen will eventually have no added benefit. Other hypotheses that allow ongoing replication predict continually lower HIV RNA levels with an INI regimen, but this differential effect need not translate to a reduction in latent infection. Investigation of HIV RNA and HIV DNA levels with an INI will provide better understanding of how these components are generated and maintained under antiretroviral therapy.
Synthesis and Antiviral Evaluation of 4'-alkoxy Analogues of 9-(β-D-xylofuranosyl)adenine
Authors: Kubota Yutaka , Ishizaki Nobuhide , Kaneda Yuri , Haraguchi Kazuhiro , Odanaka Yuki , Tanaka Hiromichi , Kato Nobuyuki , Baba Masanori , Balzarini Jan 
Published: March 2015

Background: Motivated by the reported biological activity of 9-(β-D-xylofuranosyl)adenine (xylo-A), the synthesis of its 4'-alkoxy analogues was carried out. Methods: The starting material 9-(3-deoxy-β-D-glycero-pento–3-enofuranosyl)adenine (1) was prepared from adenosine. Compound 1 was converted to the 2',5'-bis-0–(tert-butyldimethylsilyl) derivative (2) and then to the N6-pivaloyl derivative (3). When 3 was reacted with meta- chloroperbenzoic acid in the presence of a series of alcohols, the β-D-isomer of the respective 4'-alkoxy derivative was obtained exclusively in high yield. Deprotection of these products led to the isolation of the desired 4'alkoxy analogues (8a-I) of xylo-A. Results: Antiviral evaluation revealed that none of these analogues showed inhibitory activity against a wide variety of DNA and RNA viruses. Conclusions: We assume that conformational difference of the sugar moiety of 8a-1 from that of xylo-A could be attributable to their inactivity.
Mesoionic Heterocyclic Compounds as Candidate Messenger RNA Cap Analogue Inhibitors of the Influenza Virus RNA Polymerase Cap-Binding Activity
Authors: Mickleburgh Ian , Geng Feng , Tiley Laurence 
Published: March 2015

Background: An unusual feature of influenza viral messenger RNA (mRNA) synthesis is its dependence upon host cell mRNAs as a source of capped RNA primers. A crucial activity of the influenza polymerase is to steal these primers by binding and cleaving the caps from host mRNAs. The recent structural analysis of the cap-binding fragment of the influenza virus PB2 protein has highlighted the importance of the mesoionic properties of the N7-methylguanine (N7mG) component of the mRNA cap in this interaction. Methods: A series of mesoionic heterocycles with 5,6-fused ring systems analogous to the N7mG component of mRNA cap structures were synthesized and examined for the ability to inhibit the cap-binding activity of the influenza virus RNA polymerase complex using a bead-based in vitro cap-binding assay. Results: None of the compounds tested were able to significantly inhibit binding and subsequent endonucleolytic cleavage of a synthetic radiolabelled capped mRNA substrate by recombinant influenza virus polymerase in vitro. Conclusions: Compounds analogous to the mesoionic N7mG component of mRNA cap structures comprise a large class of potential inhibitors of the influenza virus polymerase. Although this preliminary assessment of a small group of related analogues was unsuccessful, further screening of this class of compounds is warranted.
Effect of Duration and Intensity of Ganciclovir Exposure on Lymphoblastoid Cell Toxicity
Authors: Janoly-Dumenil Audrey , Rouvet Isabelle , Bleyzac Nathalie , Bertrand Yves , Aulagner Gilles , Zabot Marie-Therese 
Published: March 2015

Introduction: Human cytomegalovirus infection is still a major complication after pediatric bone marrow transplantation and could be fatal in some cases. The toxicity of the drug in dividing transplanted haematopoietic cells combined with the suppression of cell growth caused by the virus remains a major problem in managing human cytomegalovirus infection. Methods: The aim of the current in vitro study was to evaluate the effect of the intensity (1–20 mg/l) and duration (1, 2, 7 or 14 days) of ganciclovir exposure on toxicity in B lymphoblastoid cells (using cell counting and viability measurements). Results: A correlation was found between the dose of ganciclovir exposure and a decrease in total cell number when duration exceeded 2 days (r2=0.92 and 0.93 after 7 and 14 days, respectively). High levels (20 mg/l) of ganciclovir were not more toxic than lowest levels (1 mg/l) for the shortest durations of ganciclovir exposure (1 and 2 days). Moreover, 50% cytotoxic concentrations markedly decreased with the duration of ganciclovir exposure (374–3 mg/l from 1 to 14 days respectively) after 14 days of culture. Conclusions: This in vitro study demonstrated for the first time that ganciclovir exhibited an in vitro duration-dependent toxicity on haematopoietic-derived cells when in vivo doses of the drug were used.
Design, synthesis, and anti-HIV-1 activity of 1-aromatic methyl-substituted 3-(3,5-dimethylbenzyl)uracil and N-3,5-dimethylbenzyl-substituted urea derivatives
Authors: Sakakibara Norikazu , Baba Masanori , Okamoto Mika , Toyama Masaaki , Demizu Yosuke , Misawa Takashi , Kurihara Masaaki , Irie Kohji , Kato Yoshihisa , Maruyama Tokumi 
Published: March 2015

Background A new series of 1-aromatic methyl-substituted 3-(3,5-dimethylbenzyl)uracil and N-3,5-dimethylbenzyl-substituted urea derivatives were synthesized and evaluated as non-nucleoside HIV-1 reverse transcriptase inhibitors. Methods A series of new 6-azido and 6-amino derivatives of 1-substituted-3-(3,5-dimethylbenzyl)uracils were synthesized using our previously reported method, and three acyclic derivatives were synthesized from urea. The anti-HIV-1 activities of these compounds were determined based on the inhibition of virus-induced cytopathogenicity in MT-4 cells. The cytotoxicities of the compounds were evaluated using the viability of mock-infected cells. Results Some of these compounds showed good-to-moderate activities against HIV-1 with half maximal effective concentration (EC50) values in the submicromolar or subnanomolar range. Compared with emivirine, compound 6-amino-3-(3,5-dimethylbenzyl)-1-(4-aminobenzyl)uracil showed significant anti-HIV-1 activity with an EC50 value of 10 nM and a high selectivity index of 1923. Preliminary structure–activity relationship studies and molecular modeling analyses were carried out to explore the major interactions between HIV-1 reverse transcriptase and the potent inhibitor 6-amino-3-(3,5-dimethylbenzyl)-1-(4-aminobenzyl)uracil; these results may be important for further development of this class of compounds as anti-HIV-1 agents. Conclusion The excellent activity of 6-amino-3-(3,5-dimethylbenzyl)-1-(4-aminobenzyl)uracil (EC50: 0.010 ± 0.006 µM, SI: >1923) may serve as the basis for conducting further investigations on the behavior of this class of compounds against drug-resistant mutants.
Burden of migraine related to menses: results from the AMPP study
Authors: Pavlović Jelena M , Stewart Walter F , Bruce Christa A , Gorman Jennifer A , Sun Haiyan , Buse Dawn C , Lipton Richard B 
Published: March 2015

Abstract

Background
Studies of the difference between menstrually associated and non-menstrually associated migraine are somewhat controversial. The majority of studies have focused on comparing menstrual to non-menstrual attacks rather than comparing study groups with different migraine diagnoses with respect to menstruation. As there is limited knowledge available on the overall impact and burden of migraine among groups of women with and without menstrually associated migraine our goal was to examine differences between these groups. We hypothesized that there would be greater burden of migraine related to menstruation and headache frequency in a population study across groups of women.

Methods
We analyzed data from the American Migraine Prevalence and Prevention (AMPP) Study, a longitudinal, US, population-based study. We included female respondents to the 2009 survey, aged 18 to 60, who met modified ICHD-2 criteria for migraine, were actively menstruating and fit one of three definitions based on the self-reported association of menses and migraine attacks: self-reported predominantly menstrual migraine (MM, attacks that only or predominantly occur at the time of menses), self-reported menstrually-associated migraine (MAM, attacks commonly associated with menses, but that also occur at other times of the month), and self-reported menstrually-unrelated migraine (MUM). These three groups were compared on characteristics and measures of headache impact and burden (Headache Impact Test– 6 item (HIT-6) and Migraine Disability Assessment Scale (MIDAS).

Results
There were 1,697 eligible subjects for this study in the following categories: MM (5.5%), MAM (53.8%), or MUM (40.7%). Women with MM had an older age of migraine onset. Those with predominantly menstrually-related attacks (MM) had fewer headache-days but appeared to be more impaired by attacks. HIT-6 and MIDAS scores were significantly higher for both the MM and MAM groups compared with the MUM groups; however, effects were more robust for MM than MAM.

Conclusions
Nearly 60% of women with migraine reported an association between migraine and menses. These women reported greater headache impact and migraine-related burden on functioning than those in whom migraines were not related to menstruation. Women with MM were more impaired by attacks while women with MAM had overall highest burden, likely due to experiencing migraines on additional days.
Protease-Activated Receptors in the Achilles Tendon–A Potential Explanation for the Excessive Pain Signalling in Tendinopathy
Authors: Christensen Jens , Alfredson Håkan , Andersson Gustav 
Published: March 2015

Background/Aim Tendinopathies are pathological conditions of tissue remodelling occurring in the major tendons of the body, accompanied by excessive nociceptive signalling. Tendinopathies have been shown to exhibit an increase in the number of mast cells, which are capable of releasing histamine, tryptase and other substances upon activation, which may play a role in the development of tendinopathies. This study set out to describe the distribution patterns of a family of receptors called protease-activated receptors (PARs) within the Achilles tendon. These four receptors (PAR1, PAR2, PAR3, PAR4) are activated by proteases, including tryptase released from mast cells, and are involved in fibrosis, hyperalgesia and neovascularisation, which are changes seen in tendinopathies. Method In order to study which structures involved in tendinopathy that these proteases can affect, biopsies from patients suffering of mid-portion Achilles tendinosis and healthy controls were collected and examined using immunohistochemistry. Tendon cells were cultured to study in vitro expression patterns. Results The findings showed a distribution of PARs inside the tendon tissue proper, and in the paratendinous tissue, with all four being expressed on nerves and vascular structures. Double staining showed co-localisation of PARs with nociceptive fibres expressing substance P. Concerning tenocytes, PAR2, PAR3, and PAR4, were found in both biopsies of tendon tissue and cultured tendon cells. Conclusions This study describes the expression patterns of PARs in the mid-portion of the Achilles tendon, which can help explain the tissue changes and increased pain signalling seen in tendinopathies. These findings also show that in-vitro studies of the effects of these receptors are plausible and that PARs are a possible therapeutic target in the future treatment strategies of tendinopathy.
Mechanisms of endocrine resistance in breast cancer: an overview of the proposed roles of noncoding RNA
Authors: Hayes Erin L , Lewis-Wambi Joan S 
Published: March 2015

AbstractEndocrine therapies such as tamoxifen and aromatase inhibitors are the standard treatment options for estrogen receptor-positive breast cancer patients. However, resistance to these agents has become a major clinical obstacle. Potential mechanisms of resistance to endocrine therapies have been identified, often involving enhanced growth factor signaling and changes in the expression or action of the estrogen receptor, but few studies have addressed the role of noncoding RNA (ncRNA). Two important types of ncRNA include microRNA (miRNA) and long noncoding RNA (lncRNA). miRNAs are small RNA molecules that regulate gene expression via translational inhibition or degradation of mRNA transcripts, while lncRNAs are larger RNA molecules that have been shown to play a role in multiple cellular maintenance functions such as protein scaffolding, chromatin looping, and regulation of mRNA stability. Both miRNA and lncRNA have recently impacted the field of breast cancer research as important pieces in the mechanistic puzzle of the genes and pathways involved in breast cancer development and progression. This review serves as an overview of the roles of miRNA and lncRNA in breast cancer progression and the development of endocrine resistance. Ideally, future experiments in the field should include identification of ncRNAs that could be potential therapeutic targets in endocrine-resistant tumors, as well as ncRNA biomarkers that facilitate more tumor-specific treatment options for endocrine-resistant breast cancer patients.
Relative benefit-risk comparing diclofenac to other traditional non-steroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors in patients with osteoarthritis or rheumatoid arthritis: a network meta-analysis
Authors: van Walsem Anneloes , Pandhi Shaloo , Nixon Richard M , Guyot Patricia , Karabis Andreas , Moore R Andrew 
Published: March 2015

Abstract
Introduction
There is argument over the benefits and risks of drugs for treating chronic musculoskeletal pain. This study compared the efficacy, safety, and tolerability of diclofenac, ibuprofen, naproxen, celecoxib, and etoricoxib for patients with pain caused by osteoarthritis (OA) or rheumatoid arthritis (RA).

Methods
A systematic literature review used Medline and EMBASE to identify randomised controlled trials. Efficacy outcomes assessed included: pain relief measured by visual analogue scale (VAS); Western Ontario McMaster Universities Arthritis Index (WOMAC) VAS or WOMAC Likert scale; physical functioning measured by WOMAC VAS or Likert scale; and patient global assessment (PGA) of disease severity measured on VAS or 5-point Likert scale. Safety outcomes included: Antiplatelet Trialists’ Collaboration (APTC), major cardiovascular (CV) and major upper gastrointestinal (GI) events, and withdrawals. Data for each outcome were synthesized by a Bayesian network meta-analysis (NMA). For efficacy assessments, labelled doses for OA treatment were used for the base case while labelled doses for RA treatment were also included in the sensitivity analysis. Pooled data across dose ranges were used for safety.

Results
Efficacy, safety, and tolerability data were found for 146,524 patients in 176 studies included in the NMA. Diclofenac (150 mg/day) was likely to be more effective in alleviating pain than celecoxib (200 mg/day), naproxen (1000 mg/day), and ibuprofen (2400 mg/day), and similar to etoricoxib (60 mg/day); a lower dose of diclofenac (100 mg/day) was comparable to all other treatments in alleviating pain. Improved physical function with diclofenac (100 and 150 mg/day) was mostly comparable to all other treatments. PGA with diclofenac (100 and 150 mg/day) was likely to be more effective or comparable to all other treatments. All active treatments were similar for APTC and major CV events. Major upper GI events with diclofenac were lower compared to naproxen and ibuprofen, comparable to celecoxib, and higher than etoricoxib. Risk of withdrawal with diclofenac was lower compared to ibuprofen, similar to celecoxib and naproxen, and higher than etoricoxib.

Conclusions
The benefit-risk profile of diclofenac was comparable to other treatments used for pain relief in OA and RA; benefits and risks vary in individuals and need consideration when making treatment decisions.