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Synergistic anti-tumor efficacy of immunogenic adenovirus ONCOS-102 (Ad5/3-D24-GM-CSF) and standard of care chemotherapy in preclinical mesothelioma model
No full textMalignant mesothelioma (MM) is a rare cancer type caused mainly by asbestos exposure. The median overall survival time of a mesothelioma cancer patient is less than 1-year from diagnosis. Currently there are no curative treatment modalities for malignant mesothelioma, however treatments such as surgery, chemotherapy and radiotherapy can help to improve patient prognosis and increase life expectancy. Pemetrexed-Cisplatin is the only standard of care (SoC) chemotherapy for malignant mesothelioma, but the median PFS/OS (progression-free survival/overall survival) from the initiation of treatment is only up to 12 months. Therefore, new treatment strategies against malignant mesothelioma are in high demand. ONCOS-102 is a dual targeting, chimeric oncolytic adenovirus, coding for human GM-CSF. The safety and immune activating properties of ONCOS-102 have already been assessed in phase 1 study (NCT01598129). In this preclinical study, we evaluated the antineoplastic activity of combination treatment with SoC chemotherapy (Pemetrexed, Cisplatin, Carboplatin) and ONCOS-102 in xenograft BALB/c model of human malignant mesothelioma. We demonstrated that ONCOS-102 is able to induce immunogenic cell death of human mesothelioma cell lines in vitro and showed anti-tumor activity in the treatment of refractory H226 malignant pleural mesothelioma (MPM) xenograft model. While chemotherapy alone showed no anti-tumor activity in the mesothelioma mouse model, ONCOS-102 was able to slow down tumor growth. Interestingly, a synergistic anti-tumor effect was seen when ONCOS-102 was combined with chemotherapy regimens. These findings give a rationale for the clinical testing of ONCOS-102 in combination with first-line chemotherapy in patients suffering from malignant mesothelioma
Controlling transduction and replication of oncolytic adenoviruses
No full textDespite progress in conventional cancer treatment regimes, metastatic disease essentially remains incurable and new treatment alternatives are needed. Virotherapy is a relatively novel approach in cancer treatment. It harnesses the natural ability of oncolytic viruses to kill the cells they proliferate in and to spread to neighboring cells, thereby amplifying the therapeutic effect of the initial input dose. The use of replicating, oncolytic viruses for cancer treatment necessitates introduction of various genetic modifications to the viral genome, thereby restraining replication exclusively to tumor cells and eventually obtaining selective eradication of the tumor without side effects to healthy tissue. Furthermore, various modifications can be applied to the viral capsid in hope of gaining effective transduction of target tissue. In other words, the entry of viruses into tumor tissue can be augmented by allowing the virus to utilize non-native receptors for entry. Genetic capsid modifications may also help to avoid some major hurdles in systemic delivery that ultimately lead to the rapid clearance of the virus from the blood and virus induced toxicity.
In addition to genetic modifications that alter the phenotype of the virus, some pharmacologic agents may be utilized to enhance the virus entry to target site. Liver kupffer cells (KC) are responsible for the majority of viral clearance after systemic viral delivery and they play a major role in adenovirus induced acute toxicity. The therapeutic window could possibly be widened by transiently depleting KCs, allowing smaller viral input doses and diminishing KC related toxicity.
The transductional efficacy of various capsid modified viruses was analyzed in vitro and in vivo in murine orthotopic breast cancer model. The effect of capsid modifications on the oncolytic efficacy, i.e. the ability of the viruses to kill cancer cells, was evaluated in vitro and in vivo in murine cancer models. We concluded that capsid modifications result in transductional enhancement, and that enhanced transduction translates into more potent oncolysis in vitro and in vivo. When KC depleting agents were used in vivo prior to viral injections, enhanced tumor transduction was seen, but this effect was not translated into enhanced antitumor activity.
Transcriptional regulation of replicative oncolytic viruses is a prerequisite for virotherapy. Tumor or tissue specific promoters can be used to control the transcription of adenoviral early genes to gain cancer specific viral replication. Specific deletions in viral regions essential for virus replication in normal cells can further increase the safety by allowing viral genome replication in cancer cells featuring specific mutations. Genetically modified viruses were shown to be able to kill putative cancer stem cells that are thought to be responsible for post treatment relapses and metastasis. Further, pharmacologic intervention reduced viral replication and thereby might offer an additional safety switch in case viral replication related side effects are encountered.Huolimatta perinteisten syöpähoitojen parantumisesta levinnyttä syöpää ei voida parantaa, ja uusia tehokkaita hoitomuotoja tarvitaan. Onkolyyttisten eli syöpäsoluja tappavien adenovirusten käyttö on uusi lähestymistapa syövän hoidossa. Se perustuu adenovirusten kykyyn tappaa solut, joissa ne monistavat perimänsä ja tuottavat uusia viruspartikkeleita. Adenovirusten levitessä kasvaimessa naapurisoluihin niiden terapeuttinen vaikutus teoriassa moninkertaistuu. Virusten käyttö syövän hoidossa edellyttää viruksen perimän muokkaamista, jotta sen monistuminen rajoittuu syöpäsoluihin ja sivuvaikutuksilta normaalisoluissa vältytään. Lisäksi adenovirusten kykyä päästä kohdesoluihin voidaan parantaa muokkaamalla kuorta, jonka sisällä viruksen perimä on. Muokkaamalla viruksen kuorta voidaan myös osittain välttää immuunipuolustukseen liittyvä viruksen nopea poistaminen verenkierrosta ja samoin immuunipuolustukseen liittyvä mahdollinen akuutti toksisuus.
Erilaisilla adenoviruksen perimän muokkauksilla voidaan vaikuttaa siihen, missä soluissa adenoviruksen perimä monistuu ja uusia viruksia syntyy. Perimän monistumiselle ehdottoman tärkeiden geenien luentaa voidaan kontrolloida erityisillä promoottorialueilla, jotka toimivat ja siten sallivat geenien luennan vain syöpäsoluissa. Perimästä voidaan myös poistaa lyhyitä alueita sellaisista geeneistä, joiden toiminta on edellytys adenoviruksen perimän monistumiselle normaalisoluissa. Syöpäsoluissa on yleensä sellaisia muutoksia, jotka sallivat tällä tavalla muokattujen adenovirusten perimän monistamisen, tavallisissa soluissa ei.
Adenovirusten pääsyä kohdesoluihin voidaan kontrolloida myös kemiallisilla yhdisteillä. Ihmisen maksan kupfferinsolut ovat makrofageja, jotka vastaavat adenovirusten nopeasta poistamisesta verenkierrosta ja saattavat samalla aiheuttaa akuuttia toksisuutta. Tietyt yhdisteet estävät Kupfferinsoluja poistamasta adenoviruksia verenkierrosta, ja siten niin sanottua terapeuttista ikkunaa voidaan laajentaa. Toisin sanoen vaikuttamalla Kupfferinsoluihin adenoviruksia voidaan antaa vähemmän ja silti saavuttaa tyydyttävä taso adenoviruksen pääsyssä kohdesoluihin verenkierrosta. Myös adenovirusten leviämiseen kohdesolusta toiseen voidaan vaikuttaa. Viruksen perimän monistumiseen ja uusien virusten leviämiseen voi liittyä haittavaikutuksia etenkin ihmisissä, joiden immuunipuolustus on heikentynyt. Tietyt yhdisteet estävät adenovirusten pääsyä uusiin kohdesoluihin, pysäyttäen siten niiden lisääntymisen ihmisessä.
Tutkimuksessamme totesimme onkolyyttisten adenovirusten kuoren muokkauksen parantavan niiden pääsyä syöpäsoluihin ja syöpäsolujen tappamistehokkuutta sekä in vitro soluviljelmissä, että in vivo hiiren rintasyöpämalleissa. Erilaiset turvallisuutta lisäävät perimän muokkaukset eivät merkittävästi huonontaneet virusten tehokkuutta ja muokatut virukset kykenivät tappamaan jopa niin sanottuja syövän kantasoluja, joiden uskotaan olevan syöpien synnyn ja hoidettujen syöpien uusiutumisen taustalla. Lisäksi totesimme, että erilaisilla yhdisteillä voidaan lisätä adenovirusten pääsyä kohdesoluihin ja toisaalta hallita virusten leviämistä ihmisessä mahdollisten viruksen monistumiseen liittyvien haittavaikutusten ilmetessä.ei saavutettav
Betonisten julkisivurakenteiden lisä- ja seurantakuntotutkimukset
Get PDFOpinnäytetyön tavoitteena oli luoda Insinööritoimisto Lauri Mehto Oy:lle selkeä, yhtenäinen ohjeistus lisä- ja seurantakuntotutkimuksien teosta. Opinnäytetyössä Mehtolle luotiin prosessikuvaukset, yhtenäiset ohjekortit sekä malliraporttipohja lisä- ja seurantakuntotutkimuksien teosta. Lisäksi luotiin lyhyt ohjeistus tilaajille lisä- ja seurantakuntotutkimuksista.
Työ toteutettiin kirjallisuuskatsauksena ja haastattelututkimuksena. Lisäksi tehtiin casetarkastelu viidelle eri kohteelle. Tarkasteluun valittiin neljä Mehton kuntotutkimuskohdetta, joihin oli tehty Mehton toimesta sekä peruskuntotutkimus että sen jälkeen lisä- tai seurantakuntotutkimuksia. Lisäksi tarkasteltu tehtiin yhdestä kuvitteellisesta kohteesta, jossa tarkasteltiin ns. ”elinkaarimallin” mukaista kuntotutkimusta.
Tarkastelluissa case-esimerkeissä tilaajan saamat hyödyt lisä- ja seurantakuntotutkimuksista voidaan jakaa karkeasti kahteen kategoriaan: kustannushyötyihin ja käyttö- turvallisuuteen liittyviin hyötyihin. Kaikissa tarkastelluissa case-esimerkeissä tilaaja sai kustannushyötyä lisä- tai seurantakuntotutkimuksen tekemisestä. Lisäksi kolmessa tapauksessa tilaaja sai myös lisää tietoa kohteen käyttöturvallisuudesta.
Jatkossa Mehton lisä- ja seurantakuntotutkimukset pystytään tekemään yhtenäisen selkeän ohjeistuksen perusteella. Tämä auttaa vakioimaan kuntotutkimusraporttien muotoa ja varmistamaan kuntotutkimuksien tasalaatuisuutta, tutkijasta riippumatta. Lisäksi jatkossa pystytään vielä nykyistä paremmin huomioimaan se, minkälaisia tietoja tilaajat kokevat tarvitsevansa lisä- ja seurantakuntotutkimuksilta.The aim of this Master’s thesis was to create clear and coherent guidelines for additional and monitoring condition investigations. Process descriptions and homogeneous instruction cards as well as model reports for additional and monitoring condition investigations were created for the client company of this work, Engineering Office Lauri Mehto Oy (later called Mehto). In addition, a short guide about additional and monitoring condition investigations for Mehto’s clients was also written.
The work was carried out by literature review and in interviews. A closer case -review was conducted on five different condition investigation cases. Four condition investigation cases were selected from the condition investigations Mehto had conducted. These condition investigation cases included a basic condition investigation and additional or monitoring condition investigation(s) carried out by Mehto. A fifth case -review was carried out on a hypothetical case which concerned condition investigations carried out using a life-cycle model.
In the case examples the benefits to the client can be roughly divided into two categories: cost - benefits and safety -benefits. In all four real case examples the client received a cost -benefit from ordering the additional or monitoring condition investigation. In three of the cases the client also received information about the safety of the building under scrutiny.
In the future Mehto’s additional and monitoring condition investigations will be compiled with coherent and clear guidelines. This will help to standardize the format of the condition investigation reports and ensure the coherence of condition investigations, regardless of the investigator. In the future Mehto will be able to consider the client’s needs for additional and monitoring condition investigation reports
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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