Investigation of the interaction between non-small cell lung cancer cells and immortalised normal bronchial epithelial cells

Non-small cell lung cancer consists of a diverse range of molecular and pathological features. This may be due in part to the critical interaction between normal and lung cancer cells. Consequently resulting in ‘normal’ cells acting in a malignant fashion. This project aims to identify pathways responsible for this altered ‘normal’ behaviour.

Inflammatory meditated mechanisms of cisplatin resistance in non-small cell lung cancer

The majority of non-small cell lung cancer (NSCLC) patients present with advanced stage disease, where chemotherapy is usually the most common treatment option. While somewhat effective, patients treated with cisplatin-based chemotherapy will eventually develop resistance. Multiple pathways have been implicated in chemo-resistance, however the critical underlying mechanisms have yet to be elucidated. The aim of this project is to determine the role of inflammatory mediators in cisplatin resistance.

The emerging role of microRNAs in resistance to lung cancer treatments

One of the major challenges in the treatment of lung cancer is the development of drug resistance. This represents a major obstacle in the treatment of patients, limiting the efficacy of both conventional chemotherapy and biological therapies. Deciphering the mechanisms of resistance is critical to further understanding the multifactorial pathways involved, and in developing more specific targeted treatments. To date, numerous studies have reported the potential role of microRNAs (miRNAs) in resistance to various cancer treatments. MicroRNAs are a family of small non-coding RNAs that regulate gene expression by sequence-specific targeting of mRNAs causing translational repression or mRNA degradation. More than 1200 validated human miRNAs have been identified to date. While as little as one miRNA can regulate hundreds of targets, a single target can also be affected by multiple miRNAs. Evidence suggests that dysregulation of specific miRNAs may be involved in the acquisition of resistance to a number of cancer treatments, thereby modulating the sensitivity of cancer cells to such therapies. Therefore, targeting miRNAs may be an attractive strategy for developing novel and more effective individualized therapies, improving drug efficiency, and for predicting patient response to different treatments. In this review, we provide an overview on the role of miRNAs in resistance to current lung cancer therapies and novel biological agents.

Lung cancer stem cells: The root of resistance

In the absence of specific treatable mutations, platinum-based chemotherapy remains the gold standard of treatment for lung cancer patients. However, 5-year survival rates remain poor due to the development of resistance and eventual relapse. Resistance to conventional cytotoxic therapies presents a significant clinical challenge in the treatment of this disease. The cancer stem cell (CSC) hypothesis suggests that tumors are arranged in a hierarchical structure, with the presence of a small subset of stem-like cells that are responsible for tumor initiation and growth. This CSC population has a number of key properties such as the ability to asymmetrically divide, differentiate and self-renew, in addition to having increased intrinsic resistance to therapy. While cytotoxic chemotherapy kills the bulk of tumor cells, CSCs are spared and have the ability to recapitulate the heterogenic tumor mass. The identification of lung CSCs and their role in tumor biology and treatment resistance may lead to innovative targeted therapies that may ultimately improve clinical outcomes in lung cancer patients. This review will focus on lung CSC markers, their role in resistance and their relevance as targets for future therapies.

Epigenetics Underpinning DNA Damage Repair

Epigenetics is the study of heritable changes in gene expression that are not the result of genetic alterations. These changes include DNA methylation, histone modifications, or indeed microRNA expression. Chromatin is a tightly compacted DNA–protein complex that allows approximately two meters of DNA to be packaged inside a cell, only a few micrometers across. Although the resulting DNA structure is very stable, it is not very amiable to DNA-dependent processes, so mechanisms have to exist to allow processes such as transcription, replication, and DNA repair to occur. This chapter will look at how a cell responds to and deals with genomic instability at the epigenetic level and highlight how critical chromatin remodeling is for correct DNA repair and cell survival following DNA damage. This chapter will initially look at the DNA repair pathways that function in human cells and then at how the repair of DNA damage is controlled by epigenetics.

KAT5 (Tip60) is a potential therapeutic target in malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is a rare aggressive cancer of the pleura. Asbestos exposure (through inhalation) is the most well established risk factor for mesothelioma. The current standard of care for patients suffering from MPM is a combination of cisplatin and pemetrexed (or alternatively cisplatin and raltitrexed). Most patients, however, die within 24 months of diagnosis. New therapies are therefore urgently required for this disease. Lysine acetyltransferases (KATs) including KAT5 have been linked with the development of cisplatin resistance. This gene may therefore be altered in MPM and could represent a novel candidate target for intervention. Using RT-PCR screening the expression of all known KAT5 variants was found to be markedly increased in malignant tumors compared to benign pleura. When separated according to histological subtype, KAT5 was significantly overexpressed in both the sarcomatoid and biphasic subgroups for all transcript variants. A panel of MPM cell lines including the normal pleural cells LP9 and Met5A was screened for expression of KAT5 variants. Treatment of cells with a small molecule inhibitor of KAT5 (MG-149) caused significant inhibition of cellular proliferation (p<0.0001), induction of apoptosis and was accompanied by significant induction of pro-inflammatory cytokines/chemokines.

Epigenetic therapy in lung cancer and mesothelioma

Thoracic malignancies present a considerable global health burden with the incidence and mortality of both lung cancer and malignant pleural mesothelioma (MPM) increasing year on year. Survival rates are poor and treatment options are limited in these cancers. Several epigenetic modifications have been associated with the development of both of these diseases with alterations discriminating between MPM and adenocarcinoma (AC) of the lung. In addition, studies have suggested that epigenetic agents are effective in altering the cellular characteristics of lung and MPM cells in terms of proliferation and migration. Furthermore, it has been demonstrated that epigenetic therapy can alter a pathologically relevant gene expression profile, with one that is more associated with comparative normal tissue. Therefore agents, which target the epi-genomes of lung cancer and MPM, may provide a substantial therapeutic improvement when used in combination with current therapy or indeed benefit when used as a single treatment modality.

VEGF-mediated cell survival in non-small-cell lung cancer: implications for epigenetic targeting of VEGF receptors as a therapeutic approach

Aims: To evaluate the potential therapeutic utility of histone deacetylase inhibitors (HDACi) in targeting VEGF receptors in non-small-cell lung cancer. Materials & methods: Non-small-cell lung cancer cells were screened for the VEGF receptors at the mRNA and protein levels, while cellular responses to various HDACi were examined. Results: Significant effects on the regulation of the VEGF receptors were observed in response to HDACi. These were associated with decreased secretion of VEGF, decreased cellular proliferation and increased apoptosis which could not be rescued by addition of exogenous recombinant VEGF. Direct remodeling of the VEGFR1 and VEGFR2 promoters was observed. In contrast, HDACi treatments resulted in significant downregulation of the Neuropilin receptors. Conclusion: Epigenetic targeting of the Neuropilin receptors may offer an effective treatment for lung cancer patients in the clinical setting.

Mutational analysis of the insulin‑like growth factor 1 receptor tyrosine kinase domain in non-small cell lung cancer patients

The insulin‑like growth factor 1 receptor (IGF1R) pathway plays an important role in the pathogenesis of non‑small cell lung cancer (NSCLC) and also provides a mechanism of resistance to targeted therapies. IGF1R is therefore an ideal therapeutic target and several inhibitors have entered clinical trials. However, thus far the response to these inhibitors has been poor, highlighting the importance of predictive biomarkers to identify patient cohorts who will benefit from these targeted agents. It is well‑documented that mutations and/or deletions in the epidermal growth factor receptor (EGFR) tyrosine kinase (TK) domain predict sensitivity of NSCLC patients to EGFR TK inhibitors. Single‑nucleotide polymorphisms (SNPs) in the IGF pathway have been associated with disease, including breast and prostate cancer. The aim of the present study was to elucidate whether the IGF1R TK domain harbours SNPs, somatic mutations or deletions in NSCLC patients and correlates the mutation status to patient clinicopathological data and prognosis. Initially 100 NSCLC patients were screened for mutations/deletions in the IGF1R TK domain (exons 16‑21) by sequencing analysis. Following the identification of SNP rs2229765, a further 98 NSCLC patients and 866 healthy disease‑free control patients were genotyped using an SNP assay. The synonymous SNP (rs2229765) was the only aberrant base change identified in the IGF1R TK domain of 100 NSCLC patients initially analysed. SNP rs2229765 was detected in exon 16 and was found to have no significant association between IGF1R expression and survival. The GA genotype was identified in 53.5 and 49.4% of NSCLC patients and control individuals, respectively. No significant difference was found in the genotype (P=0.5487) or allele (P=0.9082) frequencies between the case and control group. The present findings indicate that in contrast to the EGFR TK domain, the IGF1R TK domain is not frequently mutated in NSCLC patients. The synonymous SNP (rs2229765) had no significant association between IGF1R expression and survival in the cohort of NSCLC patients.

A review on green building in Vietnam

Following market reforms in 1986 Vietnam has transformed from a poor closed economy to a low middle income economy. Like other developing countries, economic growth has placed significant pressure on both infrastructure and environment, particularly the pressure of increasing housing demand, energy consumption, and waste and pollution management. In response to the development challenges and the green movement globally, the government has initiated actions to promote green building to promote more sustainable development. However, green building adoption in Vietnam is still criticised as being slow and lacking governmental support. This paper proposes that promoting green building could solve three inter-connected challenges hindering sustainable development, and provides a comparative review of progress.

Working Ethically in Child Protection

Rather than a single focus on assessing risk and diagnosing deficit, this book recognises that our child protection systems bear down disproportionately on those from disadvantaged and marginalised communities and argues that what is needed is real support and practical assistance for poor and vulnerable parents and children. It uses real-world case examples to illustrate the relevant ethical and practice principles, and ways in which students and practitioners can practise ethically when dealing with complex, multi-faceted issues.

A unified construction of space-time codes with optimal rate-diversity tradeoff

The problem of constructing space-time (ST) block codes over a fixed, desired signal constellation is considered. In this situation, there is a tradeoff between the transmission rate as measured in constellation symbols per channel use and the transmit diversity gain achieved by the code. The transmit diversity is a measure of the rate of polynomial decay of pairwise error probability of the code with increase in the signal-to-noise ratio (SNR). In the setting of a quasi-static channel model, let n(t) denote the number of transmit antennas and T the block interval. For any n(t) <= T, a unified construction of (n(t) x T) ST codes is provided here, for a class of signal constellations that includes the familiar pulse-amplitude (PAM), quadrature-amplitude (QAM), and 2(K)-ary phase-shift-keying (PSK) modulations as special cases. The construction is optimal as measured by the rate-diversity tradeoff and can achieve any given integer point on the rate-diversity tradeoff curve. An estimate of the coding gain realized is given. Other results presented here include i) an extension of the optimal unified construction to the multiple fading block case, ii) a version of the optimal unified construction in which the underlying binary block codes are replaced by trellis codes, iii) the providing of a linear dispersion form for the underlying binary block codes, iv) a Gray-mapped version of the unified construction, and v) a generalization of construction of the S-ary case corresponding to constellations of size S-K. Items ii) and iii) are aimed at simplifying the decoding of this class of ST codes.

Expected Performance of the ATLAS Experiment - Detector, Trigger and Physics

A detailed study is presented of the expected performance of the ATLAS detector. The reconstruction of tracks, leptons, photons, missing energy and jets is investigated, together with the performance of b-tagging and the trigger. The physics potential for a variety of interesting physics processes, within the Standard Model and beyond, is examined. The study comprises a series of notes based on simulations of the detector and physics processes, with particular emphasis given to the data expected from the first years of operation of the LHC at CERN.

Multiple contour extraction from graylevel images using an artificial neural network

For active contour modeling (ACM), we propose a novel self-organizing map (SOM)-based approach, called the batch-SOM (BSOM), that attempts to integrate the advantages of SOM- and snake-based ACMs in order to extract the desired contours from images. We employ feature points, in the form of ail edge-map (as obtained from a standard edge-detection operation), to guide the contour (as in the case of SOM-based ACMs) along with the gradient and intensity variations in a local region to ensure that the contour does not "leak" into the object boundary in case of faulty feature points (weak or broken edges). In contrast with the snake-based ACMs, however, we do not use an explicit energy functional (based on gradient or intensity) for controlling the contour movement. We extend the BSOM to handle extraction of contours of multiple objects, by splitting a single contour into as many subcontours as the objects in the image. The BSOM and its extended version are tested on synthetic binary and gray-level images with both single and multiple objects. We also demonstrate the efficacy of the BSOM on images of objects having both convex and nonconvex boundaries. The results demonstrate the superiority of the BSOM over others. Finally, we analyze the limitations of the BSOM.

Diasporakysymyksiä kansainvälisessä yhteisössä. Esimerkkinä Venäjän politiikka ja lapsikiistat Suomessa.

Pro gradu -tutkielmassani tarkastelen diasporia ja niihin kohdistuvaa kansainvälistä sääntelyä. Diasporilla tarkoitan valtion rajojen ulkopuolella asuvia ihmisiä, joilla on jokin, esimerkiksi etninen tai kieliside tuohon valtioon. Valtiolla puolestaan voi olla jokin intressi suhteessa diasporaansa. Diasporiin liittyvät kysymykset ovat ajankohtaisia globaalissa maailmassa, jossa ihmisillä on entistä enemmän mahdollisuuksia pitää siteitä yllä useampaan kuin yhteen valtioon. Diasporien ohella kirjallisuudessa puhutaan myös kin-state -problematiikasta, kun viitataan valtioiden harjoittamaan politiikkaan, joka pyrkii vaikuttamaan toisen valtion alueella asuvien tai oleskelevien ihmisten asemaan. Tutkimuksen teoreettinen viitekehys on englantilaisen koulukunnan ajatus kansainvälisestä yhteisöstä ja sille keskeisistä primaari-instituutioista, kuten valtiosuvereniteetti ja kansainvälinen oikeus. Se, miten valtio politiikassaan suhtautuu instituutioihin, kertoo valtion suhteesta kansainväliseen yhteisöön yleensä. Instituutioita voidaan puolestaan tarkastella tiettyjen kapea-alaisempien normien, sekundaari-instituutioiden, valossa. Edellä mainittuna sekundaari-instituutiona esitellään tutkielmassa se kansainvälinen normisto, joka vaikuttaa diasporien asemaan valtioiden välisessä politiikassa. Normisto perustuu Yhdistyneiden kansakuntien, Euroopan neuvoston ja ETYJ:n sopimuksiin ja suosituksiin. Kansainvälisen oikeuden lähtökohta on, ettei valtio voi puuttua diasporakseen katsomiensa ihmisten asemaan toisessa valtiossa edes ääritapauksessa, jossa asuinvaltio epäonnistuu tehtävässään suojella toisen valtion kansalaisia tai vähemmistöjään. Reagointivastuu on kansainvälisellä yhteisöllä – vaikka interventiota ulkomailla olevien kansalaisten suojelemiseksi onkin suoritettu sekä kylmän sodan aikana että sen jälkeen. Interventiot eivät ole diasporapolitiikan ainoa muoto ja monilla valtioilla onkin niin sanottuja diasporalakeja, joiden puitteissa ne voivat vaikuttaa diasporiensa asemaan. Koulutukseen ja kulttuuriin liittyvä tuki on eurooppalaisissa suosituksissa katsottu hyväksyttäväksi, mutta muiden tukimuotojen ulottamista diasporiin tulee harkita ja soveltaa vain erityistapauksissa, jos politiikalla on valtion toimivallan ulkopuolella vaikuttavia seurauksia. Tutkimus näyttää, että diasporakysymysten sääntely on kansainvälisessä yhteisössä vielä osin määrittelemätöntä sekä altista valtioiden tulkinnoille. Esimerkkinä valtioiden tulkinnoista ja niiden harjoittamasta diasporapolitiikasta tarkastellaan Venäjän federaation politiikkaa, sillä Venäjän ulkopolitiikassa esillä pidetty kiinnostus suojella ulkomailla olevia kansalaisia ja maanmiehiä on herättänyt myös kansainvälistä huomiota. Venäjän politiikan tarkastelu luo kontekstin, jossa tutkielman varsinaista kiinnostuksenkohdetta, Suomen venäläisen diasporan asemaa, on mahdollista tarkastella. Tutkimusaineistoa ovat Venäjän johdon lausunnot liittyen viimeaikaisiin Suomen ja Venäjän välisiin nk. lapsikiistoihin. Teoriaohjaava sisällönanalyysi aineistosta esittää, että vaikka vihjeitä politiikassa yleisesti esiintyvästä nk. suojelupuheesta on havaittavissa myös Suomen venäläisen vähemmistön asemaan liittyen, ei Venäjä lapsikiistoissa kuitenkaan suoraan loukannut Suomen suvereniteettia tai kansainvälistä oikeutta. Tiettyjen puhetapojen ja esimerkiksi lapsiasiamies Astahovin toiminnan voidaan kuitenkin tulkita olevan kansainvälisen normiston vastaisia ja siten myös loukkaavan suvereniteettia ja kansainvälisen oikeuden henkeä. Teoreettisen viitekehyksen tehtävä oli ensisijaisesti antaa näkökulmia aineiston tarkasteluun. Venäjän politiikan suhde suvereniteettiin ja kansainväliseen oikeuteen suhteessa tässä tarkasteltuun politiikkakysymykseen kertoo kuitenkin myös Venäjän asemasta kansainvälisen yhteisön jäsenenä. Diasporanormistoon sitoutuminen osoittaa Venäjän sitoutuneen ainakin periaatteellisella tasolla solidaristiseen, yhteisiä normeja jakavaan kansainväliseen yhteisöön – toisaalta Venäjän viime vuosien politiikka kuitenkin osoittaa Venäjän samalla haastavan myös pluralistisille yhteisöille keskeisiä valtiosuvereniteetin ja kansainvälisen oikeuden noudattamisen periaatteita. Tärkeimmät lähteet: Buzan (2004), Brubakers (1995), Hannikainen (2000), Holsti (2004), Gazzini (2005), Gray (2000), Kántor ym. (2004), Sheffer (2003), Shevel (2010 ja 2011), Turner ja Otsuki (2010) ja Zevelev (2001 ja 2008).