Reversal of oncogene transformation and suppression of tumor growth by the novel IGF1R kinase inhibitor A-928605

BACKGROUND: The insulin-like growth factor (IGF) axis is an important signaling pathway in the growth and survival of many cell and tissue types. This pathway has also been implicated in many aspects of cancer progression from tumorigenesis to metastasis. The multiple roles of IGF signaling in cancer suggest that inhibition of the pathway might yield clinically effective therapeutics. METHODS: We describe A-928605, a novel pyrazolo [3,4-d]pyrimidine small molecule inhibitor of the receptor tyrosine kinases (IGF1R and IR) responsible for IGF signal transduction. This compound was first tested for its activity and selectivity via conventional in vitro kinome profiling and cellular IGF1R autophosphorylation. Additionally, cellular selectivity and efficacy of A-928605 were analyzed in an IGF1R oncogene-addicted cell line by proliferation, signaling and microarray studies. Finally, in vivo efficacy of A-928605 was assessed in the oncogene-addicted cell line and in a neuroblastoma model as a single agent as well as in combination with clinically approved therapeutics targeting EGFR in models of pancreatic and non-small cell lung cancers. RESULTS: A-928605 is a selective IGF1R inhibitor that is able to abrogate activation of the pathway both in vitro and in vivo. This novel compound dosed as a single agent is able to produce significant growth inhibition of neuroblastoma xenografts in vivo. A-928605 is also able to provide additive effects when used in combination with clinically approved agents directed against EGFR in non-small cell lung and human pancreatic tumor models. CONCLUSION: These results suggest that a selective IGF1R inhibitor such as A-928605 may provide a useful clinical therapeutic for IGF pathway affected tumors and warrants further investigation

Identification of Interleukin-27 (IL-27)/IL-27 Receptor Subunit Alpha as a Critical Immune Axis for In Vivo HIV Control

Intact and broad immune cell effector functions and specific individual cytokines have been linked to HIV disease outcome, but their relative contribution to HIV control remains unclear. We asked whether the proteome of secreted cytokines and signaling factors in peripheral blood can be used to discover specific pathways critical for host viral control. A custom glass-based microarray, able to measure >600 plasma proteins involved in cell-to-cell communication, was used to measure plasma protein profiles in 96 HIV-infected, treatment-naive individuals with high (>50,000) or low (600 soluble proteins, our data highlight the importance of Th17 cells and Wnt/β-catenin signaling in HIV control and especially identify the IL-27/IL-27 receptor subunit alpha (IL-27RA) axis as a predictor of plasma viral load and proviral copy number in the peripheral blood. These data may provide important guidance to therapeutic approaches in the HIV cure agenda

Changes in capital allocation practices – ERM and organisational change

This paper aims to study changes in capital allocation routines following the introduction of a new risk management system, enterprise risk management (ERM). Based on an institutional framework and empirical evidence from multiple sources in a large UK insurance company, we evaluated the extent and nature of organisational change. ERM was seen as an external driver to the change in the existing routines, which in turn led to internal changes in new capital allocation routines. The change was extreme, which signifies that existing capital allocation routines were not strong enough to deal with ERM as a key driver of change

Identification of interleukin-27 (IL-27)/IL-27 receptor subunit alpha as a critical immune axis for in vivo hiv control

Intact and broad immune cell effector functions and specific individual cytokines have been linked to HIV disease outcome, but their relative contribution to HIV control remains unclear. We asked whether the proteome of secreted cytokines and signaling factors in peripheral blood can be used to discover specific pathways critical for host viral control. A custom glass-based microarray, able to measure >600 plasma proteins involved in cell-to-cell communication, was used to measure plasma protein profiles in 96 HIV-infected, treatment-naive individuals with high (> 50,000) or low (<10,000 HIV RNA copies/ml) viral loads. Univariate and regression model analysis demonstrate that plasma levels of soluble interleukin-27 (IL-27) are significantly elevated in individuals with high plasma viremia (P < 0.0001) and are positively correlated with proviral HIV-DNA copy numbers in peripheral blood mononuclear cells (PBMC) (Rho = 0.4011; P = 0.0027). Moreover, soluble IL-27 plasma levels are negatively associated with the breadth and magnitude of the total virus-specific T-cell responses and directly with plasma levels of molecules involved in Wnt/beta-catenin signaling. In addition to IL-27, gene expression levels of the specific IL-27 receptor (IL27RA) in PBMC correlated directly with both plasma viral load (Rho = 0.3531; P = 0.0218) and the proviral copy number in the peripheral blood as an indirect measure of partial viral reservoir (Rho = 0.4580; P = 0.0030). These results were validated in unrelated cohorts of early infected subjects as well as subjects before and after initiation of antiretroviral treatment, and they identify IL-27 and its specific receptor as a critical immune axis for the antiviral immune response and as robust correlates of viral load and proviral reservoir size in PBMC. IMPORTANCE The detailed knowledge of immune mechanisms that contribute to HIV control is a prerequisite for the design of effective treatment strategies to achieve HIV cure. Cells communicate with each other by secreting signaling proteins, and the blood is a key conduit for transporting such factors. Investigating the communication factors promoting effective immune responses and having potentially antiviral functions against HIV using a novel focused omics approach (Peer ReviewedPostprint (published version

Estimating the Cost of Executive Stock Options: Evidence from Switzerland

It is often argued that Black-Scholes (1973) values overstate the subjective NEWLINE value of stock options granted to risk-averse and under-diversified executives. NEWLINE We construct a “representative” Swiss executive and extend the certainty- NEWLINE equivalence approach presented by Hall and Murphy (2002) to assess NEWLINE the value-cost wedge of executive stock options. Even with low coefficients NEWLINE of relative risk aversion, the discount can be above 50% compared to the NEWLINE Black-Scholes values. Regression analysis reveals that the equilibrium level NEWLINE of executive compensation is explained by economic determinant variables NEWLINE such as firm size and growth opportunities, whereas the managers’ pay-forperformance NEWLINE sensitivity remains largely unexplained. Firms with larger NEWLINE boards of directors pay higher wages, indicating potentially unresolved NEWLINE agency conflicts. We reject the hypothesis that cross-sectional differences in NEWLINE the amount of executive pay vanish when risk-adjusted values are used as NEWLINE the dependent variable

HIV-related stigma within communities of gay men: A literature review

While stigma associated with HIV infection is well recognised, there is limited information on the impact of HIV-related stigma between men who have sex with men and within communities of gay men. The consequences of HIV-related stigma can be personal and community-wide, including impacts on mood and emotional well-being, prevention, testing behaviour, and mental and general health. This review of the literature reports a growing division between HIV-positive and HIV-negative gay men, and a fragmentation of gay communities based along lines of perceived or actual HIV status. The literature includes multiple references to HIV stigma and discrimination between gay men, men who have sex with men, and among and between many gay communities. This HIV stigma takes diverse forms and can incorporate aspects of social exclusion, ageism, discrimination based on physical appearance and health status, rejection and violence. By compiling the available information on this understudied form of HIV-related discrimination, we hope to better understand and target research and countermeasures aimed at reducing its impact at multiple levels

HIVconsv Vaccines and Romidepsin in Early-Treated HIV-1-Infected Individuals: Safety, Immunogenicity and Effect on the Viral Reservoir (Study BCN02)

Kick&kill strategies combining drugs aiming to reactivate the viral reservoir with therapeutic vaccines to induce effective cytotoxic immune responses hold potential to achieve a functional cure for HIV-1 infection. Here, we report on an open-label, single-arm, phase I clinical trial, enrolling 15 early-treated HIV-1-infected individuals, testing the combination of the histone deacetylase inhibitor romidepsin as a latency-reversing agent and the MVA.HIVconsv vaccine. Romidepsin treatment resulted in increased histone acetylation, cell-associated HIV-1 RNA, and T-cell activation, which were associated with a marginally significant reduction of the viral reservoir. Vaccinations boosted robust and broad HIVconsv-specific T cells, which were strongly refocused toward conserved regions of the HIV-1 proteome. During a monitored ART interruption phase using plasma viral load over 2,000 copies/ml as a criterium for ART resumption, 23% of individuals showed sustained suppression of viremia up to 32 weeks without evidence for reseeding the viral reservoir. Results from this pilot study show that the combined kick&kill intervention was safe and suggest a role for this strategy in achieving an immune-driven durable viremic control

Therapeutic Vaccination Refocuses T-cell Responses Towards Conserved Regions of HIV-1 in Early Treated Individuals (BCN 01 study)

Background Strong and broad antiviral T-cell responses targeting vulnerable sites of HIV-1 will likely be a critical component for any effective cure strategy. Methods BCN01 trial was a phase I, open-label, non-randomized, multicenter study in HIV-1-positive individuals diagnosed and treated during early HIV-1 infection to evaluate two vaccination regimen arms, which differed in the time (8 versus 24 week) between the ChAdV63.HIVconsv prime and MVA.HIVconsv boost vaccinations. The primary outcome was safety. Secondary endpoints included frequencies of vaccine-induced IFN-γ+ CD8+ T cells, in vitro virus-inhibitory capacity, plasma HIV-1 RNA and total CD4+ T-cells associated HIV-1 DNA. (NCT01712425). Findings No differences in safety, peak magnitude or durability of vaccine-induced responses were observed between long and short interval vaccination arms. Grade 1/2 local and systemic post-vaccination events occurred in 22/24 individuals and resolved within 3 days. Weak responses to conserved HIV-1 regions were detected in 50% of the individuals before cART initiation, representing median of less than 10% of their total HIV-1-specific T cells. All participants significantly elevated these subdominant T-cell responses, which after MVA.HIVconsv peaked at median (range) of 938 (73-6,805) IFN-γ SFU/106 PBMC, representing on average 58% of their total anti-HIV-1 T cells. The decay in the size of the HIV-1 reservoir was consistent with the first year of early cART initiation in both arms