bluuebunny/crossref_metadata_2025 huggingface dataset:
ME-609: A Treatment for Recurrent Herpes Simplex Virus Infections
Authors: Harmenberg Johan G , Awan Aftab R , Alenius Stefan , Ståhle Lars , Erlandsson Anna C , Lekare Gunilla , Flink Ola , Augustsson Elisabeth , Larsson Torbjörn , Wikström Ann-Charlotte , Stierna Pontus , Field Hugh J , Larsson Alf G , Öberg Bo
Published: March 2015

Studies in conventional murine models of HSV infection use immunologically naive animals. These models thus mimic primary infections rather than recurrent infections in humans. We have, therefore, used a newly developed mouse model that more closely mimics recurrent HSV infection in humans. In this model, the mice are infected, and zosteriform HSV-1 infection develops in the presence of a primed immune response using adoptive transfer of immunity (ATI) as we have described previously. Using the ATI mouse model, it has been shown that a more beneficial therapy for recurrent mucocutaneous HSV infection could be achieved by controlling both the viral replication and the inflammatory response to the virus. Topical treatment was initiated in this model at the time of first occurrence of symptoms and was given three times daily for 4 days. Topical treatment with ME-609 (which contains 5% acyclovir and 1% hydrocortisone) in the ATI mouse model was substantially more efficacious than 5% Zovirax® cream, 1% hydrocortisone or no treatment, respectively. The beneficial properties of ME-609 were also found to be superior to those of Zovirax cream when tested in the standard guinea pig model, representing a primary HSV infection. ME-609 represents a novel treatment principle of recurrent HSV infections and the present paper summarizes the preclinical and early clinical experience of ME-609.
Peptide Inhibitors of Hepatitis C Virus NS3 Protease
Authors: Portal-Núñez Sergio , González-Navarro Carlos J , García-Delgado Marina , Vizmanos José Luis , Lasarte Juan José , Borrás-Cuesta Francisco
Published: March 2015

Hepatitis C virus (HCV) is a highly prevalent virus and one of the major agents of chronic hepatitis. Since HCV NS3 protease is essential for the processing of HCV polyprotein, this protease is a target of choice to control HCV replication. Peptide inhibitors of NS3 were developed by selective amino acid replacement of six leader sequences, corresponding to regions of HCV polyprotein that are cleaved by NS3. The large numbers of potential 14-mer and 16-mer peptide inhibitors thus obtained were tested against NS3 using the fluorescent probe RETS1 and peptide cofactor SVVIVGRIILSGRA from NS4A protein. This afforded several peptide inhibitors with an IC50 of around 2 μM. These peptides may be good leading compounds for the development of peptidomimetics to control HCV replication in the treatment of chronic hepatitis C.
Treatment of Mannan-Enhanced Influenza B Virus Infections in Mice with Oseltamivir, Ribavirin and Viramidine
Authors: Smee Donald F , Wandersee Miles K , Wong Min-Hui , Bailey Kevin W , Sidwell Robert W
Published: March 2015

Mannan, a polysaccharide preparation from Saccharomyces cerevisiae, has previously been shown to enhance influenza virus replication in mice by inhibiting host defense collectins. The use of mannan in infections may serve to broaden the types of influenza viruses that can be studied in rodent infection models. When mannan was co-administered with influenza B/Sichuan/379/99 virus to mice, the animals died from the infection, whereas mice infected with only virus survived. Three types of influenza A (H1N1) and another influenza B (Hong Kong/330/01) virus infection were also enhanced by mannan, but not four types of influenza A (H3N2) viruses. Mannan was used at 0.16 or 0.5 mg/mouse for optimal disease-enhancing activity using influenza B/Sichuan/379/99 virus. Using this model, influenza B/Sichuan/379/99 infections were treated with oseltamivir, ribavirin or viramidine (the carboxamidine derivative of ribavirin). When oral gavage treatments started 4 h before virus and mannan challenge, oseltamivir was effective at 2.5, 5 and 10 mg/kg/day. Ribavirin was active at 20, 40 and 80 mg/kg/day. Viramidine was effective at 80 and 160 mg/kg/day but not at 40 mg/kg/day. Active drug doses improved lung consolidation scores and lung weights, with decreases in lung virus titres also noted. Arterial oxygen saturation values in treated groups were significantly better than those of the placebo group on days 7–11 of the infection. Oseltamivir (5 mg/kg/day) and ribavirin (40 mg/kg/day) were used alone and in combination to determine how late after infection they could be beneficially administered. Ribavirin alone was very effective (90–100% survival of mice) when treatments started as late as 3 days after infection. Forty percent survival was evident even when treatments started 4 days post-infection. Oseltamivir was active starting treatments 1 day after virus exposure, but lost considerable efficacy when treatments began after that time. The combination of ribavirin and oseltamivir appeared to be no better than ribavirin alone, due to the stronger beneficial effect of ribavirin in this model. The overall results demonstrate that mannan can be used to enhance certain non-lethal influenza virus infections sufficiently to allow antiviral studies.
Antiviral Therapy of Chronic Hepatitis B: Can We Clear the Virus and Prevent Drug Resistance?
Authors: Zoulim Fabien
Published: March 2015

Antiviral therapy of chronic HBV infection remains a clinical challenge. Once this infection has been-established, the viral genome persists for life, either as an integrated genome or as episomal covalently closed circular DNA (cccDNA). The latter is the source of renewed viral replication in case of immune depression or after antiviral drug withdrawal. The mechanisms of clearance of infected cells involve CD8+ cell-mediated cytolytic and non-cytolytic pathways. Antiviral therapy, using nucleoside analogues that inhibit the viral polymerase, induces a slow depletion of intrahepatic cccDNA. The persistence of low-grade viral replication under antiviral therapy may then lead to the selection of drug-resistant mutants. New assays have been developed to study the functional consequences of these polymerase mutations in terms of replication capacity and drug susceptibility. Together with the development of new HBV polymerase inhibitors and novel immunostimulatory approaches, this should lead to the design and evaluation of rational treatment combinations for a better control of viral replication and prevention of drug resistance.
Geldanamycin, a Potent and Specific Inhibitor of Hsp90, Inhibits Gene Expression and Replication of Human Cytomegalovirus
Authors: Basha Walid , Kitagawa Ryoko , Uhara Miho , Imazu Hiromi , Uechi Kouhei , Tanaka Junji
Published: March 2015

The effect of geldanamycin (GA), a specific inhibitor of heat shock protein 90 (Hsp90), on gene expression and replication of human cytomegalovirus (HCMV) was studied in human embryonic lung (HEL) fibroblasts. Kinetic analysis indicated that GA delayed synthesis of major immediate early (MIE), early and late viral proteins, and blocked a second tier of the synthesis of these proteins that occurred in untreated cells after 48 h post-infection (pi). Moreover, when HCMV-infected HEL cells were maintained with medium containing 40 nM GA for 6 days, with medium changes at 2-day intervals, the virus yield was reduced to an undetectable level. On a molecular level, the cellular kinase Akt and the transcription factor NFκB were activated in HCMV-infected cells within 30 min pi. NFκB was shown to be essential for MIE gene expression. However, in GA-treated cells, activation of both Akt and NFκB was greatly inhibited. Because LY294002, an inhibitor of cellular phosphatidylinositol 3-kinase (PI3-K), also prohibited HCMV-mediated activation of Akt and NFκB and synthesis of the MIE proteins, PI3-K signalling was necessary for expressing the MIE genes. These results suggest that the inhibitory effect of GA on HCMV replication is primarily caused by the disruption of the PI3-K signalling pathway, leading to the activation of NFκB, which plays a crucial role in expression of the critical MIE genes.
Evaluation of Chemical and Antiviral Properties of Essential Oils from South American Plants
Authors: Duschatzky Claudia B , Possetto Mirta L , Talarico Laura B , García Cybele C , Michis Fabiana , Almeida Norma V , de Lampasona Marina P , Schuff Carola , Damonte Elsa B
Published: March 2015

The essential oils of seven aromatic plants from Córdoba, San Luis and San Juan Provinces (Argentina) were isolated by steam distillation and analysed by a gas chromatography/mass spectrometry technique. The oils were screened for cytotoxicity and in vitro inhibitory activity against herpes simplex virus type 1 (HSV-1), dengue virus type 2 (DENV-2) and Junin virus (JUNV) by a virucidal test. The oils showed a variable virucidal action according to the virus. The better relationship between cytotoxicity and antivirus action was observed with the essential oils of Heterothalamus alienus and Buddleja cordobensis against JUNV, with virucidal concentration 50% (VC50) values of 44.2 and 39.0 ppm and therapeutic indices (cytotoxicity to virucidal activity ratio) of 3.3 and 4.0, respectively. The inhibitory action was exerted by a direct interaction of virions with the oils. Virions inactivated with B. cordobensis and H. alienus essential oil were not affected in their ability to bind to the host cell. The therapeutic indices shown by these essential oils in toto were very modest, but given the complexity of their chemical composition the future identification of the precise active principle may allow the elimination of cytotoxic components and increase the selectivity of the effective compound.
A Survey of Antiviral Drugs for Bioweapons
Authors: Goff Arthur J. , Paragas Jason
Published: March 2015

Smallpox (variola major), and the haemorrhagic fever viruses (filoviruses and arenaviruses) are classified as Category A biowarfare agents by the Centers for Disease Control. Category A agents pose a significant risk to public health and national security because they can be easily disseminated by aerosol, although with the exception of variola, they are not easily transmitted from person to person. An attack with these viruses would result in high morbidity and mortality and cause widespread panic. With the exception of smallpox and Argentine haemorrhagic fever virus, there are no vaccines or approved treatments to protect against these diseases. In this review we focus on promising prophylactic, therapeutic and disease modulating drugs (see Figure 1 for select chemical structures).
Antiviral Activity of Nucleoside Analogues against SARS-coronavirus (SARS-CoV)
Authors: Chu Chung K , Gadthula Srinivas , Chen Xin , Choo Hyunah , Olgen Sureyya , Barnard Dale L , Sidwell Robert W
Published: March 2015

The recent outbreak of severe acute respiratory syndrome (SARS), which is an acute respiratory illness, is caused by newly discovered SARS coronavirus (SARS-CoV). Herein we describe the antiviral activity of several classes of nucleoside analogues evaluated against SARS-CoV in Vero 76 cells, some of which exhibited moderate activity.
Carbohydrate-Binding Agents: A Potential Future Cornerstone for the Chemotherapy of Enveloped Viruses?
Authors: Balzarini Jan
Published: March 2015

Carbohydrate-binding agents (CBAs) inhibit HIV-1 and it is proposed that therapy with such agents may have important implications for the future of anti-HIV therapy. Examples of CBAs include the procaryotic cyanovirin-N (CV-N), plant lectins such as HHA, GNA, NPA, CA and UDA, the monoclonal antibody 2G12 directed against a glycan-containing epitope on HIV envelope gp120, and the mannose-specific non-peptidic antibiotic Pradimicin A, which inhibits the entry of HIV-1 into its target cells. CBAs prevent not only virus infection of susceptible cells, but also inhibit syncytia formation between persistently HIV-infected cells and uninfected lymphocytes. In addition, CBAs may also prevent DC-SIGN-mediated transmission of HIV to T-lymphocytes. Therefore, CBAs qualify as potential microbicide drugs. Long-term exposure of HIV to CBAs in cell culture results in the progressive deletion of N-glycans of HIV gp120 in an attempt of the virus to escape drug pressure. In this respect, the CBAs are endowed with a high genetic barrier. Multiple mutations at N-glycosylation sites are required before pronounced phenotypic drug resistance development becomes evident. CBA treatment of HIV may consist of a novel chemotherapeutic concept with a dual mechanism of antiviral action: a direct antiviral activity by preventing HIV entry and transmission to its target cells, and an indirect antiviral activity by forcing HIV to delete glycans in its gp120 envelope. The latter phenomenon will result in creating ‘holes’ in the protective glycan shield of the HIV envelope, whereby the immune system may become triggered to produce neutralizing antibodies against previously hidden immunogenic epitopes of gp120. If this concept can be proven in in vivo, low-molecular-weight non-peptidic CBAs such as Pradimycin A may become the cornerstone for the efficient treatment of infections of those viruses that require a glycosylated envelope (that is, HIV, but also hepatitis C virus) for entry into its target cells. In addition, influenza virus and coronavirus infections may also qualify to be treated by CBAs.
Los Alamos Hepatitis C Virus Sequence and Human Immunology Databases: An Expanding Resource for Antiviral Research
Authors: Hraber Peter T , Leach Robert W , Reilly Lee P , Thurmond James , Yusim Karina , Kuiken Carla
Published: March 2015

The hepatitis C virus (HCV) resource at Los Alamos (hcv.lanl.gov) provides access to multiple databases: one containing annotated sequences and the other a repository of immunogenic epitopes. They are derived from databases originally developed for HIV research (hiv.lanl.gov). HCV and HIV are RNA viruses with relatively compact genomes (around 10 kb) that are extraordinarily variable, both within and between hosts. This diversity requires methods to track and exclude variants from an individual infection or from epidemiologically related infections, and tools to analyse the variation. The HCV immunology database contains a curated inventory of immunogenic epitopes and information about their interaction with the host immune system, with associated retrieval and analysis tools. This interactive resource provides flexible retrieval tools for sequences, epitopes, clinical information, and metadata, as well as utilities for scientific data analysis, to investigators with internet access and a web browser. This paper describes the types of data and the services that these databases offer, the tools they provide, and their configuration and use. Examples of applications to clonal analysis for drug-resistance mutations are shown.
Los Alamos Hepatitis C Virus Sequence and Human Immunology Databases: An Expanding Resource for Antiviral Research
Authors: Hraber Peter T , Leach Robert W , Reilly Lee P , Thurmond James , Yusim Karina , Kuiken Carla
Published: March 2015

Owing to a printing error, Figure 3 was not aligned correctly on the page. The figure below has been corrected.

The publisher apologies for this error.

[Figure: see text]
Influenza a (H1N1) Virus Resistance to Cyanovirin-N Arises Naturally during Adaptation to Mice and by Passage in Cell Culture in the Presence of the Inhibitor
Authors: Smee Donald F , Wandersee Miles K , Checketts Melissa B , O'Keefe Barry R , Saucedo Carrie , Boyd Michael R , Mishin Vasiliy P , Gubareva Larisa V
Published: March 2015

Influenza A/New Caledonia/20/99 (H1N1) virus was studied for development of resistance to cyanovirin-N (CVN). CVN neutralizes virus infectivity by binding to specific high-mannose oligosaccharides on the viral haemagglutinin 1 (HA1) subunit. During virus adaptation to mice in the absence of CVN treatment the virus became resistant to CVN (CVN-MR virus), as did virus passaged in cell culture in the presence of CVN (CVN-R virus). The CVN-R virus possessed a single amino acid change at position 94a (Asn94aAsp) of HA1 that eliminated this glycosylation site. The CVN-MR virus at mouse passage 7 was a mixture of clones, consisting of a single mutation (Asp225Gly) and double mutations (Asn63Ser+Asp225Gly or Asn94a+Asp225Gly), eliminating glycosylation sites. CVN did not bind well to the CVN-R and CVN-MR viruses. Propagating these viruses in cells treated with 1 mM deoxymannojirimycin (dMJ, mannosidase inhibitor) increased sensitivity to CVN, suggesting that glycans attached at other sites on HA1 that typically are not high-mannosidic became so due to dMJ treatment. Further evaluation showed that the Asp225Gly mutant virus was sensitive to the inhibitor and did not kill mice or induce weight loss. The CVN-R virus was also avirulent to mice. The double-mutant CVN-MR viruses were resistant to CVN and caused deaths and severe weight loss in mice. CVN-R virus subjected to mouse adaptation acquired the 225 mutation and a lethal phenotype. Thus, the 225 mutation in the HA receptor-binding site in combination with a loss of glycan at Asn (63 or 94a) are important for mouse adaptation in this virus. The mutations reported here causing resistance to CVN are consistent with its known mode of action.
Cellular Pharmacology of 9-(β-D-1,3-dioxolan-4-yl) Guanine and its Lack of Drug Interactions with Zidovudine in Primary Human Lymphocytes
Authors: Hernandez-Santiago Brenda I , Obikhod Aleksandr , Fromentin Emilie , Hurwitz Selwyn J , Schinazi Raymond F
Published: March 2015

Amdoxovir, currently in Phase II clinical trials, is rapidly converted to 9-(β-D-1,3-dioxolan-4-yl)guanine (DXG) by adenosine deaminase in vitro and in humans. The cellular pharmacology of DXG in primary human lymphocytes, including dose-response relationships, intracellular half-life of DXG triphosphate (DXG-TP), and combination studies were determined. DXG produced high levels of DXG-TP with a long half-life (16 h) in activated human peripheral blood mononuclear cells. Since zidovudine (ZDV) and DXG select for different resistance mutations, co-formulation of the these two drugs is an attractive proposition. A combination study between DXG and ZDV showed no reduction of DXG-TP or ZDV-TP. Taken together, these results suggest that an appropriately designed DXG prodrug could be given once a day and that co-formulation with ZDV might be a possibility.
Antiviral Chemistry & Chemotherapy's Current Antiviral Agents FactFile (2nd Edition): Retroviruses and Hepadnaviruses
Authors: De Clercq Erik , Field Hugh J
Published: March 2015

There are at present exactly 25 compounds that have been formally approved for the treatment of retrovirus (that is HIV) infections: seven nucleoside reverse transcriptase inhibitors (NRTIs), one nucleotide reverse transcriptase inhibitor (NtRTI), four non-nucleoside reverse transcriptase inhibitors (NNRTIs), 10 protease inhibitors (PIs), one core-ceptor inhibitor (CRI), one fusion inhibitor (FI) and one integrase inhibitor (INI). Other compounds expected to be approved for the treatment of HIV infections in the near future are the NNRTI rilpivirine, the CRI vicriviroc and the INI elvitegravir. To obtain synergistic activity, enable lower dosage levels, thus minimizing toxic side effects, and particularly to reduce the risk of drug resistance development, common wisdom dictates that the HIV inhibitors should be used in drug combination regimens. Although, given the number of compounds available, the drug combinations that could be concocted are uncountable, only one triple-drug combination has so far been formulated as single pill to be taken orally once daily, namely Atripla® containing the NtRTI tenofovir disoproxil fumarate, the NRTI emtricitabine and the NNRTI efavirenz. Here, we document these approved compounds along with other HIV-active compounds and, for the first time, compounds whose principal activity is against hepatitis B virus. The logic of this new division being the enzymatic similarity between the reverse transcriptase of HIV and hepatitis B virus; the strategies for the development of antiviral agents to combat them have much in common.
Bevirimat: A Novel Maturation Inhibitor for the Treatment of HIV-1 Infection
Authors: Martin David E , Salzwedel Karl , Allaway Graham P
Published: March 2015

Existing antiretroviral treatments for HIV type-1 (HIV-1) disease are limited by problems of resistance and drug-drug interactions. Bevirimat is a novel HIV-1 maturation inhibitor with a mechanism of action that is distinct from other antiretroviral agents. Specific inhibiton of the final rate-limiting step in Gag processing by bevirimat prevents release of mature capsid protein from its precursor (CA-SP1), resulting in the production of immature, non-infectious virus particles. Bevirimat inhibits replication of both wild-type and drug-resistant HIV-1 isolates in vitro, achieving similar 50% inhibitory concentration values with both categories. Serial drug passage studies have identified six single amino acid substitutions that independently confer bevirimat resistance. These resistance mutations occur at or near the CA-SP1 cleavage site, which is not a known target for resistance to other antiretroviral drugs. Bevirimat has demonstrated a consistent pharmacokinetic profile in healthy volunteers and HIV-infected patients, with peak plasma concentrations attained approximately 1–3 h after dosing. Plasma concentrations decrease in a log-linear manner with a mean plasma elimination half-life of 58–80 h, supporting once-daily dosing. Animal studies suggest that elimination of bevirimat is primarily by hepatic glucuronidation and hepatobiliary excretion. There is minimal renal elimination, with <1% of the administered dose appearing in the urine. In responsive patients, bevirimat has demonstrated a robust dose-dependent reduction in viral load (>1.5 log10 copies/ml). Short-term administration (⩽14 days) of bevirimat is well tolerated, even when used in combination with other antiretroviral agents. Further studies to evaluate the long-term efficacy and tolerability of bevirimat are currently underway.
Anti-Hepatitis B Virus Activity in Vitro of Combinations of Tenofovir with Nucleoside/nucleotide Analogues
Authors: Zhu Yuao , Curtis Maria , Qi Xiaoping , Miller Michael D , Borroto-Esoda Katyna
Published: March 2015

Background:

Long-term management of some chronic hepatitis B patients might require combination therapy using drugs with distinct resistance profiles to sustain viral suppression and to reduce the resistance-associated failure. Tenofovir disoproxil fumarate (TDF), approved for hepatitis B virus (HBV) and HIV-1 treatment, is active against wild-type HBV and HBV containing YMDD mutations, which confer resistance to emtricitabine (FTC), lamivudine (3TC) and telbivudine (LdT) and contribute to entecavir (ETV) resistance. We therefore evaluated the in vitro anti-HBV activity of tenofovir (TFV), the active parent drug of TDF, combined with FTC, 3TC, ETV, LdT and adefovir (AFV).

Methods:

The anti-HBV activities of the compounds were tested using the AD38 cell line that expresses wild-type HBV from a tetracycline-controllable promoter. Intracellular HBV DNA levels were quantified using real-time PCR assay and cytotoxicities were assessed with XTT assays. The antiviral data of the drug combinations were evaluated using MacSynergy analyses on the basis of the Bliss independence model as well as isobologram analyses on the basis of the Loewe additivity theory.

Results:

All drug combinations tested, FTC+TFV, 3TC+TFV, ETV+TFV, LdT+TFV and AFV+TFV, showed additive antiviral interactions as analysed by MacSynergy. Isobologram analyses revealed that these combination pairs were additive, with the exception of FTC+TFV, which demonstrated slight synergistic activity. No cytotoxic or antagonistic effects were observed with any of the combinations tested.

Conclusions:

The combination of TFV with FTC, 3TC, ETV, LdT or AFV had additive to slightly synergistic anti-HBV effects in vitro. These results support the use of TDF as a component in combination regimens with currently available anti-HBV nucleoside analogues.
Synthesis and Antiviral Activity of 6-Benzoyl-Benzoxazolin-2-One and 6-Benzoyl-Benzothiazolin-2-One Derivatives
Authors: Van derpoorten Kim , Ucar Huseyin , Andrei Graciela , Snoeck Robert , Balzarini Jan , De Clercq Erik , Poupaert Jacques H
Published: March 2015

The synthesis and antiviral activity of an original series of 6-benzoyl-benzoxazolin-2-one and 6-benzoyl-benzothiazolin-2-one derivatives are described. Several compounds were found to have a selective inhibitory activity against human cytomegalovirus (HCMV) and varicella-zoster virus (VZV) in vitro, being inactive against a variety of other DNA and RNA viruses. 6-(3-fluorobenzoyl)benzoxazolin-2-one, 6-(3-fluorobenzoyl)benzothiazolin-2-one, 6-(3-bromobenzoyl)benzothiazolin-2-one, 6-(3-iodobenzoyl)benzothiazolin-2-one, 3-methyl-6-(3-fluorobenzoyl)benzothiazolin-2-one, 3-benzyl-6-benzoyl-benzothiazolin-2-one, 3-benzyl-6-(3-fluorobenzoyl)benzothiazolin-2-one and 3-benzoyl-6-(3-fluorobenzoyl)benzothiazolin-2-one were the most active of the series against HCMV and VZV with a selectivity index (CC50/IC50) ranging from 10 to 20. They displayed similar activity against thymidine kinase competent (TK+) and deficient (TK−) VZV strains, and also proved to be active against clinical HCMV isolates that were resistant to ganciclovir (GCV). Time-of-addition experiments revealed a site of interaction with the HCMV replicative cycle that may be close or similar to that of GCV and cidofovir (HPMPC). The compounds showed poor, if any, activity against herpes simplex virus type 1 (HSV-1) and HSV-2, and were not inhibitory against human immunodeficiency virus and other DNA and RNA viruses. Therefore, these compounds may represent a novel lead for the development of specific HCMV and VZV drugs.
Anti-Herpesvirus Activities and Cytotoxicities of 2-Thiopyrimidine Nucleoside Analogues in Vitro
Authors: Shigeta S , Mori S , Kira T , Takahashi K , Kodama E , Konno K , Nagata T , Kato H , Wakayama T , Koike N , Saneyoshi M
Published: March 2015

Twenty 2-thiopyrimidine nucleoside analogues were synthesized and examined for inhibitory activity against herpes simplex virus (HSV) type 1 and 2, varicella-zoster virus (VZV), human cytomegalovirus (HCMV) and thymidine kinase-deficient HSV (HSV-TK) replication in vitro. 2-thiouracil (thymine) arabinoside, 2′-deoxy-2-thiouridine (or 2-thiothymidine) and their 5-halogenated derivatives showed anti-HSV activity in both RPMI8226 (human B-lymphoblastoid cells) and MRC-5 (human embryo lung cells). 2′-deoxy-5-halogenated-2-thiocytidines were also inhibitory against HSV, whereas 2-thiocytosine arabinoside and its derivatives were not inhibitory against HSV replication, except 5-bromo and 5-iodo congeners (TN-31, TN-32). Substitution of the halogen atom at the 5-position of the pyrimidine rings to an atom with a higher molecular weight increased anti-HSV and VZV activities, except for the anti-HSV activity of 2-thiouracil arabinosides. 2′-deoxy-5-methyl-, and 2′-deoxy-5-iodo-2-thiouridines (TN-17, TN-44) showed the most potent anti-HSV activity, and 2′-deoxy-5-chloro- and 2′-deoxy-5-bromo-2-thiocytidines were potent inhibitors of VZV replication. However, none of the compounds inhibited HCMV and HSV-TK− replication. TN-31 and TN-32 were shown to inhibited HCMV and HSV-TK− as well as HSV and VZV replication. The cytotoxicity of the 2-thiopyrimidine nucleoside analogues was less than that of the 2-oxy-congeners of the compounds (5-iodo-2′-deoxyuridine, 5-iodo-2′-deoxycytidine, thymine arabinoside and cytosine arabinoside). The selectivity index of 2′-deoxy-5-iodo-2-thiouridine (TN-44) was higher than that of 5-iodo-deoxyuridine. TN-17 and TN-44 were not cytotoxic to resting or stimulated human peripheral blood mononuclear cells at 400 μ, although TN-32 was cytotoxic at a concentration of 20 μ.
Unusual Examples of Sophisticated Iron Technology in the Heating Systems of Roman Imperial Baths
Authors: Amici Carla Maria
Published: March 2015

In Roman imperial times, metallurgy reached a high degree of specialization and complexity. The use of iron extended even to building technology, leading to some very particular results, achieving a sophisticated mastery of the technology with a complete understanding of metal properties, in a social and economic context characterized by large financial resources and a high level of creativity applied to architectural projects. A still unpublished device was found in the construction of several floors in the Villa of Giulia, Augustus' daughter, in Ventotene (Italy). In the thermal area, the concrete floors of the bath tubs are supported by an iron grid held in place by vertical iron posts strongly fixed in the underfloor, allowing both widespread hot air circulation and support for superimposed loads. A curvilinear metal grid supported by metal hooks was also used to obtain a tile-line vault, creating an interspace for the circulation of hot air in calidaria; a careful analysis of the remains of two vaulted systems in Villa Adriana, Tivoli (Italy), allows a clear reconstruction of this device. The building process was difficult and complex, requiring careful planning and great accuracy in execution. However, after nearly a century of experimentation, it is possible to propose the hanging ceiling built over the calidarium of the Baths of Caracalla in Rome as the most imposing example of the grid system ever realized.
Cumulative inflammatory burden is independently associated with increased arterial stiffness in patients with psoriatic arthritis: a prospective study
Authors: Shen Jiayun , Shang Qing , Li Edmund K , Leung Ying-Ying , Kun Emily W , Kwok Lai-Wa , Li Martin , Li Tena K , Zhu Tracy Y , Yu Cheuk-Man , Tam Lai-Shan
Published: March 2015

Introduction

The aim of this study was to examine whether the cumulative inflammatory burden is associated with an increase in arterial stiffness in a prospective cohort of psoriatic arthritis (PsA) patients.

Methods

In total, 72 PsA patients were followed for a median of 6.5 years. Cumulative inflammatory burden was represented by the cumulative averages of repeated measures of erythrocyte sedimentation rate (ca-ESR) and C-reactive protein (ca-CRP). Brachial-ankle pulse wave velocity (PWV) was measured at the last visit. We also included 47 healthy controls for PWV assessment.

Results

PWV was significantly higher in PsA patients compared with healthy controls after adjustment for age, gender and body weight (1466 ± 29 cm/s versus 1323 ± 38 cm/s, P = 0.008). PsA patients were divided into two groups based on whether their PWV value is ≥1450 cm/s (High PWV group, N = 38) or <1450 cm/s (Low PWV group, N = 34). The High PWV group had a significantly higher ca-ESR (29 (19 to 44) versus 18 (10 to 32) mm/1st hour, P = 0.005) and ca-CRP (0.7 (0.3 to 1.4) versus 0.4 (0.2 to 0.7) mg/dl, P = 0.029). Using regression analysis, high ca-ESR (defined as ≥75th percentile: 37 mm/1st hour) was associated with a higher likelihood of being in the High PWV group (odds ratio (OR): 9.455 (1.939 to 46.093), P = 0.005, adjusted for baseline clinical and cardiovascular risk factors; and 9.111 (1.875 to 44.275), P = 0.006, adjusted for last visit parameters).

Conclusions

Cumulative inflammatory burden, as reflected by ca-ESR, was associated with increased arterial stiffness in PsA patients even after adjustment for cardiovascular risk factors, emphasizing the important role of chronic inflammation in accelerating the development of cardiovascular risks in PsA patients.
Head-to-head comparison of the safety of tocilizumab and tumor necrosis factor inhibitors in rheumatoid arthritis patients (RA) in clinical practice: results from the registry of Japanese RA patients on biologics for long-term safety (REAL) registry
Authors: Sakai Ryoko , Cho Soo-Kyung , Nanki Toshihiro , Watanabe Kaori , Yamazaki Hayato , Tanaka Michi , Koike Ryuji , Tanaka Yoshiya , Saito Kazuyoshi , Hirata Shintaro , Amano Koichi , Nagasawa Hayato , Sumida Takayuki , Hayashi Taichi , Sugihara Takahiko , Dobashi Hiroaki , Yasuda Shinsuke , Sawada Tetsuji , Ezawa Kazuhiko , Ueda Atsuhisa , Fujii Takao , Migita Kiyoshi , Miyasaka Nobuyuki , Harigai Masayoshi ,   for the REAL Study Group
Published: March 2015

Introduction

The objective of this study was to directly compare the safety of tocilizumab (TCZ) and TNF inhibitors (TNFIs) in rheumatoid arthritis (RA) patients in clinical practice.

Methods

This prospective cohort study included RA patients starting TCZ [TCZ group, n = 302, 224.68 patient-years (PY)] or TNFIs [TNFI group, n = 304, 231.01 PY] from 2008 to 2011 in the registry of Japanese RA patients on biologics for long-term safety registry. We assessed types and incidence rates (IRs) of serious adverse events (SAEs) and serious infections (SIs) during the first year of treatment. Risks of the biologics for SAEs or SIs were calculated using the Cox regression hazard analysis.

Results

Patients in the TCZ group had longer disease duration (P <0.001), higher disease activity (P = 0.019) and more frequently used concomitant corticosteroids (P <0.001) than those in the TNFI group. The crude IR (/100 PY) of SIs [TCZ 10.68 vs. TNFI 3.03; IR ratio (95% confidence interval [CI]), 3.53 (1.52 to 8.18)], but not SAEs [21.36 vs. 14.72; 1.45 (0.94 to 2.25)], was significantly higher in the TCZ group compared with the TNFI group. However, after adjusting for covariates using the Cox regression hazard analysis, treatment with TCZ was not associated with higher risk for SAEs [hazard ratio (HR) 1.28, 95% CI 0.75 to 2.19] or SIs (HR 2.23, 95% CI 0.93 to 5.37).

Conclusions

The adjusted risks for SAEs and SIs were not significantly different between TCZ and TNFIs, indicating an influence of clinical characteristics of the patients on the safety profile of the biologics in clinical practice.
CD4 T-cell transcriptome analysis reveals aberrant regulation of STAT3 and Wnt signaling pathways in rheumatoid arthritis: evidence from a case–control study
Authors: Ye Hua , Zhang Jing , Wang Jun , Gao Yanyan , Du Yan , Li Chun , Deng Minghua , Guo Jianping , Li Zhanguo
Published: March 2015

Introduction

Rheumatoid arthritis (RA) is a systemic autoimmune disease in which T cells play a pivotal role in the pathogenesis. Knowledge in terms of the CD4 T-cell transcriptome in RA is limited. The aim of this study was to examine the whole-genome transcription profile of CD4 T cells in RA by comparing patients with RA to healthy controls.

Methods

Peripheral blood CD4 T cells were isolated from 53 RA patients with active disease and 45 healthy individuals; 13 cases and 10 controls were enrolled in microarray analysis. The remaining 40 cases and 35 controls were recruited as an independent cohort for the validation study. Bioinformatics was performed on Gene Ontology (GO), gene-gene interaction networks, and pathway analysis. The gene modules, by combining the results from GO, gene networks, and pathway analysis, were selected for further validation.

Results

The CD4 T cells showed 1,496 differentially expressed (DE) genes in RA patients relative to healthy individuals. GO analysis revealed that the DE genes were enriched in immune response, T-cell response, apoptosis process, and Wnt receptor signaling. Pathway analysis also identified that ‘Wnt signaling pathway’ was differentially regulated between two groups (P = 2.78 × 10−10). By gene-gene network analysis, we found that the DE genes were enriched in T-cell receptor (TCR), JAK-STAT signaling, and Wnt signaling pathway. By gene module analysis, we found that a number of DE genes overlapped in the three different analyses. In total, 23 genes were selected for further validation, and nine genes were confirmed. Of these, four genes (SOCS3, CBL, IFNAR1, and PIK3CA) were involved in STAT3 (signal transducer and activator of transcription 3) signaling, and three genes (CBL, KLF9, and CSNK2A1) were involved in the Wnt signaling pathway. Additionally, several zinc finger transcription factors (ZEB1, ZNF292, and ZNF644) were confirmed.

Conclusions

We report here the first case–control study of the CD4 T-cell transcriptome profile in RA. Our data provide evidence that CD4 T cells from patients with RA have abnormal functional networks in STAT3 signaling and Wnt signaling. Our results also suggest that the aberrant expression of several zinc finger transcription factors (ZEB1, ZNF292, and ZNF644) may be potential pathogenic factors for RA.
Intracellular free radical production by peripheral blood T lymphocytes from patients with systemic sclerosis: role of NADPH oxidase and ERK1/2
Authors: Amico Donatella , Spadoni Tatiana , Rovinelli Marina , Serafini Marta , D’Amico Giovanna , Campelli Nadia , Svegliati Baroni Silvia , Gabrielli Armando
Published: March 2015

Introduction

Abnormal oxidative stress has been described in systemic sclerosis (SSc) and previous works from our laboratory demonstrated an increased generation of reactive oxygen species (ROS) by SSc fibroblasts and monocytes. This study investigated the ability of SSc T lymphocytes to produce ROS, the molecular pathway involved, and the biological effects of ROS on SSc phenotype.

Methods

Peripheral blood T lymphocytes were isolated from serum of healthy controls or SSc patients by negative selection with magnetic beads and activated either with PMA or with magnetic beads coated with anti-CD3 and anti-CD28 antibodies. Intracellular ROS generation was measured using a DCFH-DA assay in a plate reader fluorimeter or by FACS analysis. CD69 expression and cytokine production were analyzed by FACS analysis. Protein expression was studied using immunoblotting techniques and mRNA levels were quantified by real-time PCR. Cell proliferation was carried out using a BrdU incorporation assay.

Results

Peripheral blood T lymphocytes from SSc patients showed an increased ROS production compared to T cells from healthy subjects. Since NADPH oxidase complex is involved in oxidative stress in SSc and we found high levels of gp91phox in SSc T cells, SSc T cells were incubated with chemical inhibititors or specific siRNAs against gp91phox. Inhibition of NADPH oxidase partially reverted CD69 activation and proliferation rate increase, and significantly influenced cytokine production and ERK1/2 activation.

Conclusions

SSc T lymphocityes are characterized by high levels of ROS, generated by NADPH oxidase via ERK1/2 phosphorylation, that are essential for cell activation, proliferation, and cytokine production. These data confirm lymphocytes as key cellular players in the pathogenesis of systemic sclerosis and suggest a crucial link between ROS and T cell activation.
Characterization of menstrual stem cells: angiogenic effect, migration and hematopoietic stem cell support in comparison with bone marrow mesenchymal stem cells
Authors: Alcayaga-Miranda Francisca , Cuenca Jimena , Luz-Crawford Patricia , Aguila-Díaz Carolina , Fernandez Ainoa , Figueroa Fernando E , Khoury Maroun
Published: March 2015

Introduction

Stem cells isolated from menstrual fluid (MenSCs) exhibit mesenchymal stem cell (MSCs)-like properties including multi-lineage differentiation capacity. Besides, menstrual fluid has important advantages over other sources for the isolation of MSCs, including ease of access and repeated sampling in a noninvasive manner. Such attributes allow the rapid culture of MenSCs in numbers that are sufficient for therapeutical doses, at lower cell passages.

Methods

In this study, we advance the characterization of MenSC populations in comparison to bone marrow derived mesenchymal stem cells (BM-MSCs) with regards to proliferation, lineage differentiation, migration potential, secretion profile and angiogenic properties in vitro and in a matrigel plug assay in mice. We additionally tested their ability to support hematopoietic stem cell (HSC) expansion in vitro.

Results

The phenotypic analysis of MenSCs revealed a profile largely similar to the BM-MSCs with the exception of a higher expression of the adhesion molecule CD49a (alpha1-integrin). Furthermore, the fibroblast colony forming units (CFU-F) from MenSCs yielded a 2 to 4 fold higher frequency of progenitors and their in vitro migration capacity was superior to BM-MSCs. In addition, MenSCs evidenced a superior paracrine response to hypoxic conditions as evidenced by the secretion of vascular endothelial growth factor and basic fibroblast growth factor and also improved angiogenic effect of conditioned media on endothelial cells. Furthermore, MenSCs were able to induce angiogenesis in a matrigel plug assay in vivo. Thus, an 8-fold increase in hemoglobin content was observed in implanted plugs containing MenSCs compared to BM-MSCs. Finally, we demonstrated, for the first time, the capacity of MenSCs to support the ex-vivo expansion of HSCs, since higher expansion rates of the CD34 + CD133+ population as well as higher numbers of early progenitor (CFU-GEMM) colonies were observed in comparison to the BM source.

Conclusions

We present evidence showing superiority of MenSCs with respect to several functional aspects, in comparison with BM-MSCs. However, the impact of such properties in their use as adult-derived stem cells for regenerative3 medicine remains to be clarified.
Role of breast cancer inhibitors on diabetes mellitus– an in silico approach
Authors: Rampogu Shailima DV
Published: March 2015

Background

Breast cancer and diabetes mellitus type-2 are two of the major diseases, which cause death to the women worldwide. Around 16% of the breast cancer patients also suffer from diabetes mellitus. It has been noted that the risk of occurrence of the breast cancer is more in patients suffering from diabetes mellitus.

Methods

Owing to this, the present article deals with an objective of using the breast cancer inhibitors for the diabetes drug target– 1ADS. Ten breast cancer inhibitors were drawn using Marvin Sketch. The docking was performed using Molegro software (Molegro Virtual Docker, MVD).

Results

The docking wizard generated 50 poses with the highest Mol Dock score −131.649.

Conclusion

This investigation successfully evaluated the effect of breast cancer inhibitors on diabetes mellitus, providing a new dimension in endocrine research.
Effect of cell immobilization and pH on Scheffersomyces stipitis growth and fermentation capacity in rich and inhibitory media
Authors: Portugal-Nunes Diogo , Sànchez i Nogué Violeta , Pereira Susana R , Craveiro Sandra C , Calado António J , Xavier Ana MRB
Published: March 2015

Background

A wide range of value-added products can potentially be produced by bioprocessing hardwood spent sulfite liquors (HSSLs) that are by-products of pulp and paper industry with a high pentose sugar content. However, besides sugars, HSSLs contain considerable amounts of sulfonated lignin derivatives and acetic acid that inhibit the metabolic activity of most microorganisms. Scheffersomyces stipitis is a yeast with high capacity to ferment the pentose sugar xylose under appropriate microaerophilic conditions but it has limited tolerance to HSSL inhibitors. In the present study, cultivations of suspended and immobilized S. stipitis were compared in terms of growth capacity and by-product formation using rich medium and HSSL to investigate whether the immobilization of cells in calcium alginate beads could be a protection against inhibitors while favoring the presence of microaerophilic conditions.

Results

Whereas cell immobilization clearly favored the fermentative metabolism in rich medium, pH control was found to play a more important role than cell immobilization on the ethanol production efficiency from bio-detoxified HSSL (bdHSSL), leading to an improvement of 1.3-fold on the maximum ethanol productivity than using suspended cells. When immobilization and pH control were applied simultaneously, the ethanol yield improved by 1.3-fold with unchanged productivity, reaching 0.26 g ethanol.(g glucose + xylose)−1. Analysis of the immobilized beads inside revealed that the cells had grown in the opposite direction of the cortex.

Conclusions

Immobilization and pH control at 5.5, when applied simultaneously, have a positive impact on the fermentative metabolism of S. stipitis, improving the ethanol production efficiency. For the first time light microscopic analysis of the beads suggested that the nutrient and mass transfer limitations played a more important role in the fermentation than a possible protective role against inhibitors.
The New Woman: Sexology, Literary Modernism, and the Trans Feminine Remainder
Authors: Heaney Emma
Published: March 2015

This article begins by tracing the figure of gender inversion from Karl Heinrich Ulrichs's mid-nineteenth-century celebration of the “woman's soul confined in a man's body” to Edward Carpenter's early twentieth-century disavowal of the effeminate “of the extreme type,” whose gender nonconformity confirms the normativity of the mass of “normal” masculine homosexuals. Carpenter's disavowal voices both an orientalist distaste for the “mincing effeminacy” of British colonial subjects and an affirmation of the “somewhat masculine” women who are pursuing their rights in “civilized nations.” This article argues that this freighted figure of inversion obscures the theories of embodiment found in sexological case studies themselves, which ground the experience of sex in sociality and sensation. The sexological invert provides the foundation for a trans feminine stock character that modernist novels install to represent the cultural redefinition of “woman” and “man” in the early twentieth century. Aldous Huxley's Farcical History of Richard Greenow is an orienting example of this tendency. Jean Genet's Notre-Dame-des-Fleurs, in contrast, reflects a modernist current grounded in queer and trans street culture. The novel's heroine, the queen Divine, recalls the theories of embodiment outlined in the case study narratives. Ultimately, the “New Woman” demonstrates that sexology provides the narrative template for the twentieth-century medical diagnostic for transsexuality. From the early twentieth century, novels disseminate this abstract and singular definition of transsexuality and also recover the various and complex narratives of sexed embodiment first found in the case studies.
The Cemetery as Public Space: Spoon River Anthology and Act 3 of Our Town
Authors: Klaver Elizabeth
Published: March 2015

The cemetery is often portrayed in literary and cultural works as a heterotopic site for the other, awash in gothic or melodramatic features. This essay argues that Spoon River Anthology by Edgar Lee Masters and act 3 of Thornton Wilder's Our Town offer something quite different, a cemetery that invites people to use it as public space. After a historical overview of the American burial ground, the essay positions the cemetery in the current debate on public space. As the epitaphs of Spoon River and act 3 of Our Town typify, the cemetery is a contested site, open to constant negotiation and redefinition by the people who use it.
A Review of Angus Deaton's The Great Escape: Health, Wealth, and the Origins of Inequality
Authors: Weil David N.
Published: March 2015

This book explores the relationship between the material standard of living and health, both across countries and over time. Above all, Deaton is interested in the question of whether income growth contributes significantly to better health. His answer is no: saving lives in poor countries is not expensive, and there are many episodes of massive health improvements in the absence of income growth. As an alternative, he argues that the cross-sectional correlation between health and income is induced by variation in institutional quality, while over time, parallel improvements in income and health have been a result of advancing knowledge. (JEL E23, I12, I14, I15, O15, O47)
Robert E. Lucas Jr.'s Collected Papers on Monetary Theory
Authors: Sargent Thomas J.
Published: March 2015

This paper is a critical review of and a reader's guide to a collection of papers by Robert E. Lucas, Jr. about fruitful ways of using general equilibrium theories to understand measured economic aggregates. These beautifully written and wisely argued papers integrated macroeconomics, microeconomics, finance, and econometrics in ways that restructured big parts of macroeconomic research. (JEL A31, E00, E13, E50)