Loss of PTEN expression and AKT activation in HER2-positive breast carcinomas

PURPOSE: To examine the expression of AKT and PTEN in a series of HER2-positive primary invasive breast tumors using immunohistochemistry, and to associate these expression profiles with classic pathologic features such as tumor grade, hormone receptor expression, lymphatic vascular invasion, and proliferation.METHODS: A total of 104 HER2-positive breast carcinoma specimens were prepared in tissue microarrays blocks for immunohistochemical detection of PTEN and phosphorylated AKT (pAKT). Original histologic sections were reviewed to assess pathological features, including HER2 status and Ki-67 index values. The associations between categorical and numeric variables were identified using Pearson's chi-square test and the Mann-Whitney, respectively.RESULTS: Co-expression of pAKT and PTEN was presented in 59 (56.7%) cases. Reduced levels of PTEN expression were detected in 20 (19.2%) cases, and these 20 tumors had a lower Ki-67 index value. In contrast, tumors positive for pAKT expression [71 (68.3%)] were associated with a higher Ki-67 index value.CONCLUSION: A role for AKT in the proliferation of HER2-positive breast cancers was confirmed. However, immunohistochemical detection of PTEN expression did not correlate with an inhibition of cellular proliferation or control of AKT phosphorylation, suggesting other pathways in these mechanisms of control.

Pursuing substantive participation in Russia : a perspective from international legal obligations and comparative law

Så som är fallet för många andra stater, kan vissa delar av den ryska förvaltningen ännu utvecklas för att till fullo uppfylla internationella standarder. Internationella fördragsorgan som övervakar förverkligandet i Ryssland av fördrag om mänskliga rättigheter framför ibland kritiska anmärkningar om den demokratiska utvecklingen i Ryssland. Enskilda fall där politiska rättigheter möjligen kränkts av ryska myndigheter har utan tvivel placerat Ryssland i fokus för internationell media. Exempel på sådana fall är mordet på journalisten Anna Politkovskaya, Sergei Magnitskys död i fängelse och fängslandet av medlemmarna i "Pussy Riot”. Likväl anser författaren av denna studie att politiska rättigheter i Ryssland förverkligas inom rimliga gränser och i enlighet med internationell människorättslagstiftning. Denna studie fokuserar på förverkligandet av den individuella rättigheten att delta i det politiska beslutsfattandet i Ryssland genom andra mekanismer för deltagande än val och folkomröstningar. Studien utgörs av en sammanställning av forskningsartiklar som har publicerats i olika internationella tidskrifter. Sammanställningen föregås av ett fristående inledande kapitel. Författaren koncentrerar sig på frågan om Rysslands invånare ges effektiva möjligheter att delta i handhavandet av allmänna angelägenheter och om det finns användbara rättsmedel till hands för skydd av de politiska rättigheterna. Författaren tar sig an en juridisk analys av rysk lagstiftning gällande olika sätt för direkt deltagande i beslutsfattande samt analyserar rättsfall angående direkt deltagande från domstolarna i Moskva, Perm Krai och Sverdlovsk Oblast. Denna studie använder sig även av en rättshistorisk infallsvinkel för att visa på den positiva dynamiken hos den historiska utvecklingen beträffande d e väsentligaste plattformarna för offentligt deltagande. Det bevisas att rysk lagstiftning som garanterar rätten att delta i beslutsfattande är väl utvecklad i enlighet med internationella människorättsfördrag, och att åtminstone domstolarna i de utvalda ryska områdena fattar beslut som stöder deltaganderättigheter som eventuellt kränkts av myndigheter inom den verkställande makten. Författaren kommer till den slutsatsen att de i denna studie inkluderade enskilda dokumenterade händelserna gällande administrativ felbehandling inte nödvändigtvis tillåter den direkta slutsatsen att det begås systematiska och grova kränkningar av medborgares deltaganderättigheter i Ryssland.

Essays on auditor independence

Auditor independence is a cornerstone of the auditing profession and the basic principle that underpins the reputation of the auditing profession in the public eye. Indeed, it is the attribute most demanded from auditors by the public. Therefore, the sustainability of the auditing profession depends on how auditors can protect this principle. This dissertation consists of four interrelated essays concerned with auditor independence. Specifically, it examines situations that can threaten and impair auditor independence. In addition, this dissertation also examines several variables that may enhance and protect auditor independence. The first essay aims to examine the impact of social pressures occurring within audit firms on auditors’ judgment in the setting of a society with “high power distance” and “low individualism” cultural dimensions. The social pressures consisted of obedience pressure exerted by an auditor’s superior and conformity pressure exerted by an auditor’s colleague. Moreover, two moderating variables—a multi-dimensional professional commitment and locus of control—were included as moderator variables in the relationship between the social pressures faced by auditors and their judgment. The findings show that obedience and conformity pressures influence auditor judgment. Auditors who face the social pressures will make a judgment that may be even diametrically opposite to the independence principle. The findings also indicate that a multi-dimensional professional commitment and locus of control may potentially influence auditor judgment in a situation with social pressures. The second essay aims to investigate the association of advocacy and familiarity threats caused by auditor fee dependence and auditor tenure on auditor independence based on Finnish data, law, and auditing environment. This essay was motivated by the Green Paper on Audit Policy, published by the European Commission in 2010 that questions whether the maximum fee collected from a client should be regulated and whether consecutive assignments should be limited, among others. Contrary to popular belief, this essay does not find evidence that audit fees and long auditor tenure will jeopardise auditor independence. Therefore, the findings do not support policies to regulate auditor fees or limit auditor tenure in Finland. The third essay aims to examine the effect of client intimidation on auditor independence in an audit-client conflict situation. Intimidation threat is one of five independence threats that are explicitly referenced in the IFAC’s independence framework. Client intimidation was manifested in the client threatening to replace the auditor if the auditor did not adopt the client’s position. In addition, this essay examines the role of auditor’s perceived pressure and multi-dimensions of professional commitment as moderator variables. The findings suggest that auditors who experience client intimidation in an audit conflict situation are more likely to have their independence impaired than those who are in a similar situation but without client intimidation. Moreover, auditors who experience client intimidation perceive higher pressure than those who do not experience intimidation. Finally, auditors’ affective and continuance professional commitment dimensions moderate the relationship between auditors’ perceived pressures and auditor independence. The aim of the fourth essay is twofold. First, it aims to develop a scale for measuring auditors’ reputation awareness. Second, it aims to examine the correlation between the levels of auditor reputation awareness and auditor independence. A seven-item scale was developed as the reputation awareness scale. The findings indicate that the scale consists of one dimension. It also has a level of satisfactory reliability and a high level of validity. The findings show that there is a positive correlation between the level of auditors’ reputation awareness and auditor independence.

Opportunistisen sopimusrikkomuksen ongelmasta, erityisesti Suomen vahingonkorvaus- ja rikoslainsäädännön näkökulmasta tarkasteltuna. Law and Economics -näkökulma.

Tämä pro gradu -tutkielma käsittelee opportunistisen sopimusrikkomuksen ongelmaa erityisesti Suomen vahingonkorvaus- ja rikoslainsäädännön näkökulmasta tarkasteltuna. Tutkielman lähestymistapa on oikeustaloustieteellinen (engl. Law and Economics). Opportunistisella sopimusrikkomuksella tarkoitetaan toimintaa, jossa sopimusosapuoli rikkoo sopimuksen tarkoituksellisesti, pyrkimyksenään tällä toiminnalla saavuttaa enemmän hyötyä kuin sopimuksessa pysymällä. Opportunistinen sopimusrikkomus on mahdollista toteuttaa tilanteessa, jossa sopimusasetelma itsessään antaa mahdollisuuden enemmän hyödyn saavuttamiseen rikkomus toteuttamalla kuin sopimus asianmukaisesti täyttämällä. Suomalaisessa vahingonkorvausjärjestelmässä sovelletaan sopimusrikkomusten osalla positiivisen sopimusedun mukaista vahingonkorvausta, joka hyvittää rikotulle osapuolelle sopimussuhteeseen ryhtymisestä syntyneet kustannukset sekä sopimusrikkomuksen johdosta saamatta jääneen tuoton. Positiivisen sopimusedun soveltaminen ei kuitenkaan ole opportunistisen sopimusrikkomuksen ehkäisemiseksi riittävää, sillä opportunistisesti toimiva sopimusosapuoli voi jäädä rikkomuksensa johdosta voitolle vielä sen jälkeenkin, kun kärsineelle osapuolelle on jo positiivista sopimusetua noudattaen korvattu sopimussuhteessa syntyneet kustannukset sekä rikkomuksen johdosta saamatta jäänyt tuotto. Keskeinen ongelma koskien opportunististen sopimusrikkomustilanteiden syntyä onkin juuri vallitsevan sääntelyn liiallinen keskittyminen rikotun osapuolen kärsimän vahingon kompensoimiseen, ei rikkomustilanteiden synnyn ennaltaehkäisemiseen. Suomen vahingonkorvausjärjestelmää tulisi kehittää suuntaan, jossa järjestelmä paremmin ennaltaehkäisisi opportunististen sopimusrikkomustilanteiden syntyä. Common law -oikeusjärjestelmässä käytössä olevan disgorgement principle -suuntaisen ajattelun, jossa korvauksen perustana toimisi rikkomuksella saatu hyöty kärsityn vahingon sijaan, omaksuminen olisi yksi mahdollinen kehityskulku. Olennaista olisi kuitenkin se, että järjestelmää kehitettäisiin suuntaan, jossa rikkomus ei enää voisi tulla rikkojalle kannattavaksi. Opportunistisen toiminnan kannustimet tulisi lainsäädäntöä tarkistamalla poistaa. Tällä olisi sekä sopimusinstituutiota turvaavaa että vaihdantaa edistävää vaikutusta.

Coping with international atrocities through criminal law : a study into the typical features of international criminality and the reflection of these traits in international criminal law

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A law of the wall formulation for recirculating flows

This work presents a new law of the wall formulation for recirculating turbulent flows. An alternative expression for the internal length which can be applied in the separated region is also presented. The formulation is implemented in a numerical code which solves the k-epsilon model through a finite volume method. The theoretical results are compared with the experimental data of Vogel and Eaton (J. of Heat Transfer, Transactions of ASME, vol.107, pp. 922-929, 1985). The paper shows that the present formulation furnishes better results than the standard k-epsilon formulation.

Rocket tracking and decoupling eigenstructure control law

A control law was designed for a satellite launcher ( rocket ) vehicle using eigenstructure assignment in order that the vehicle tracks a reference attitude and also to decouple the yaw response from roll and pitch manoeuvres and to decouple the pitch response from roll and yaw manoeuvres. The design was based on a complete linear coupled model obtained from the complete vehicle non linear model by linearization at each trajectory point. After all, the design was assessed with the vehicle time varying non-linear model showing a good performance and robustness. The used design method is explained and a case study for the Brazilian satellite launcher ( VLS Rocket ) is reported.

Pulse response based control for positive definite systems

Pulse Response Based Control (PRBC) is a recently developed minimum time control method for flexible structures. The flexible behavior of the structure is represented through a set of discrete time sequences, which are the responses of the structure due to rectangular force pulses. The rectangular force pulses are given by the actuators that control the structure. The set of pulse responses, desired outputs, and force bounds form a numerical optimization problem. The solution of the optimization problem is a minimum time piecewise constant control sequence for driving the system to a desired final state. The method was developed for driving positive semi-definite systems. In case the system is positive definite, some final states of the system may not be reachable. Necessary conditions for reachability of the final states are derived for systems with a finite number of degrees of freedom. Numerical results are presented that confirm the derived analytical conditions. Numerical simulations of maneuvers of distributed parameter systems have shown a relationship between the error in the estimated minimum control time and sampling interval

The European Union and Assembling Biofuel Development – topological investigations concerning the associations between law, policy and space

Biofuels for transport are a renewable source of energy that were once heralded as a solution to multiple problems associated with poor urban air quality, the overproduction of agricultural commodities, the energy security of the European Union (EU) and climate change. It was only after the Union had implemented an incentivizing framework of legal and political instruments for the production, trade and consumption of biofuels that the problems of weakening food security, environmental degradation and increasing greenhouse gases through land-use changes began to unfold. In other words, the difference between political aims for why biofuels are promoted and their consequences has grown – which is also recognized by the EU policy-makers. Therefore, the global networks of producing, trading and consuming biofuels may face a complete restructure if the European Commission accomplishes its pursuit to sideline crop-based biofuels after 2020. My aim with this dissertation is not only to trace the manifold evolutions of the instruments used by the Union to govern biofuels but also to reveal how this evolution has influenced the dynamics of biofuel development. Therefore, I study the ways the EU’s legal and political instruments of steering biofuels are coconstitutive with the globalized spaces of biofuel development. My analytical strategy can be outlined through three concepts. I use the term ‘assemblage’ to approach the operations of the loose entity of actors and non-human elements that are the constituents of multi-scalar and -sectorial biofuel development. ‘Topology’ refers to the spatiality of this European biofuel assemblage and its parts whose evolving relations are treated as the active constituents of space, instead of simply being located in space. I apply the concept of ‘nomosphere’ to characterize the framework of policies, laws and other instruments that the EU applies and construes while attempting to govern biofuels. Even though both the materials and methods vary in the independent articles, these three concepts characterize my analytical strategy that allows me to study law, policy and space associated with each other. The results of my examinations underscore the importance of the instruments of governance of the EU constituting and stabilizing the spaces of producing and, on the other hand, how topological ruptures in biofuel development have enforced the need to reform policies. This analysis maps the vast scope of actors that are influenced by the mechanism of EU biofuel governance and, what is more, shows how they are actively engaging in the Union’s institutional policy formulation. By examining the consequences of fast biofuel development that are spatially dislocated from the established spaces of producing, trading and consuming biofuels such as indirect land use changes, I unfold the processes not tackled by the instruments of the EU. Indeed, it is these spatially dislocated processes that have pushed the Commission construing a new type of governing biofuels: transferring the instruments of climate change mitigation to land-use policies. Although efficient in mitigating these dislocated consequences, these instruments have also created peculiar ontological scaffolding for governing biofuels. According to this mode of governance, the spatiality of biofuel development appears to be already determined and the agency that could dampen the negative consequences originating from land-use practices is treated as irrelevant.

The effects of positive end-expiratory pressure on respiratory system mechanics and hemodynamics in postoperative cardiac surgery patients

We prospectively evaluated the effects of positive end-expiratory pressure (PEEP) on the respiratory mechanical properties and hemodynamics of 10 postoperative adult cardiac patients undergoing mechanical ventilation while still anesthetized and paralyzed. The respiratory mechanics was evaluated by the inflation inspiratory occlusion method and hemodynamics by conventional methods. Each patient was randomized to a different level of PEEP (5, 10 and 15 cmH2O), while zero end-expiratory pressure (ZEEP) was established as control. PEEP of 15-min duration was applied at 20-min intervals. The frequency dependence of resistance and the viscoelastic properties and elastance of the respiratory system were evaluated together with hemodynamic and respiratory indexes. We observed a significant decrease in total airway resistance (13.12 ± 0.79 cmH2O l-1 s-1 at ZEEP, 11.94 ± 0.55 cmH2O l-1 s-1 (P<0.0197) at 5 cmH2O of PEEP, 11.42 ± 0.71 cmH2O l-1 s-1 (P<0.0255) at 10 cmH2O of PEEP, and 10.32 ± 0.57 cmH2O l-1 s-1 (P<0.0002) at 15 cmH2O of PEEP). The elastance (Ers; cmH2O/l) was not significantly modified by PEEP from zero (23.49 ± 1.21) to 5 cmH2O (21.89 ± 0.70). However, a significant decrease (P<0.0003) at 10 cmH2O PEEP (18.86 ± 1.13), as well as (P<0.0001) at 15 cmH2O (18.41 ± 0.82) was observed after PEEP application. Volume dependence of viscoelastic properties showed a slight but not significant tendency to increase with PEEP. The significant decreases in cardiac index (l min-1 m-2) due to PEEP increments (3.90 ± 0.22 at ZEEP, 3.43 ± 0.17 (P<0.0260) at 5 cmH2O of PEEP, 3.31 ± 0.22 (P<0.0260) at 10 cmH2O of PEEP, and 3.10 ± 0.22 (P<0.0113) at 15 cmH2O of PEEP) were compensated for by an increase in arterial oxygen content owing to shunt fraction reduction (%) from 22.26 ± 2.28 at ZEEP to 11.66 ± 1.24 at PEEP of 15 cmH2O (P<0.0007). We conclude that increments in PEEP resulted in a reduction of both airway resistance and respiratory elastance. These results could reflect improvement in respiratory mechanics. However, due to possible hemodynamic instability, PEEP should be carefully applied to postoperative cardiac patients.

Induction of interleukin-10 by HIV antigens in peripheral mononuclear cells of health care workers after occupational exposure to HIV-1-positive blood

Evaluation of HIV-induced IL-2 production by peripheral blood mononuclear cells (PBMC) and HIV-specific T helper and cytotoxic T lymphocyte (CTL) responses in health care workers (HCW) occupationally exposed to HIV reveals a high rate of response to HIV among non-seroconverters. IL-10 is also known to interfere with HIV infection in vitro. To evaluate the induction of IL-10 by HIV antigens in HCW occupationally exposed to HIV, 18 HCW with percutaneous injury were enrolled in this study, 9 of them exposed to HIV-contaminated blood, and 9 exposed to HIV-negative blood. PBMC were incubated on plates coated with HIV-1 antigens, and IL-10 was measured in supernatants by ELISA. Five of nine HCW exposed to HIV-contaminated blood presented HIV-induced IL-10. Two of nine HCW exposed to HIV-negative source patients also had detectable levels of HIV-induced IL-10, one of them in the sample obtained on the day of accidental exposure. There was a relationship between the type of device involved in injury and IL-10 production. Individuals exposed to hollow needles or scalpels presented HIV-induced IL-10, whereas those exposed to solid needles and to digital puncture did not, suggesting a relationship between infectious load and IL-10. Although occupational exposure to HIV leads to a low rate of seroconversion, these individuals can develop an antigen-specific immune response characterized in our study by induction of IL-10 in PBMC in vitro.

Vertical growth phase and positive sentinel node in thin melanoma

Sentinel node (SN) status is the most important prognostic factor for localized melanoma. Usually, patients with Breslow thickness of less than 1.0 mm are not included in SN protocols. However, the literature presents a rate ranging from 3 to 7% of nodal recurrence in thin melanoma. Ulceration, regression and high mitotic rate have been considered to be indications for an SN biopsy. The metastatic potential of the vertical growth phase is uncertain. To correlate pathological features in thin melanoma with SN metastasis, we reviewed 358 patients submitted to SN biopsy. Seventy-seven patients with lesions of 1 mm or smaller were included in the study group. Histological evaluation of the primary tumor included thickness, Clark level, mitotic rate, ulceration, regression, and growth phase. Lymphoscintigraphy was performed on all patients. Lymphatic mapping and gamma probe detection were both used for SN biopsy. Histological examination of SN consisted of hematoxylin-eosin and immunohistochemical staining. Median follow-up was 37 months. Six patients had micrometastases. Statistical analysis by the Fisher test showed that ulceration (P = 0.019), high mitotic rate (P = 0.008) and vertical growth phase (P = 0.002) were positively correlated with micrometastases. If other studies confirm these results, more melanoma patients must be submitted to SN biopsy.