Clusterin inhibition using OGX-011 synergistically enhances zoledronic acid activity in osteosarcoma

Purpose: Despite recent improvements in therapeutic management of osteosarcoma, ongoing challenges in improving the response to chemotherapy warrants new strategies still needed to improve overall patient survival. Among new therapeutic approaches, zoledronic acid (ZOL) represents a promising adjuvant molecule to chemotherapy to limit the osteolytic component of bone tumors. However, ZOL triggers the elevation of heat shock proteins (Hsp), including Hsp27 and clusterin (CLU), which could enhance tumor cell survival and treatment resistance. We hypothesized that targeting CLU using siRNA or the antisense drug, OGX-011, will suppress treatment-induced CLU induction and enhance ZOL-induced cell death in osteosarcoma (OS) cells. Methods: The combined effects of OGX-011 and ZOL were investigated in vitro on cell growth, viability, apoptosis and cell cycle repartition of ZOL-sensitive or -resistant human OS cell lines (SaOS2, U2OS, MG63 and MNNG/HOS). Results: In OS cell lines, ZOL increased levels of HSPs, especially CLU, in a dose- and time-dependent manner by mechanism including increased HSF1 transcription activity. The OS resistant cells to ZOL exhibited higher CLU expression level than the sensitive cells. Moreover, CLU overexpression protects OS sensitive cells to ZOL-induced cell death by modulating the MDR1 and farnesyl diphosphate synthase expression. OGX-011 suppressed treatment-induced increases in CLU and synergistically enhanced the activity of ZOL on cell growth and apoptosis. These biologic events were accompanied by decreased expression of HSPs, MDR1 and HSF1 transcriptional activity. In vivo, OGX-011, administered 3 times a week (IP, 20mg/kg), potentiated the effect of ZOL (s.c; 50µg/kg), significantly inhibiting tumor growth by 50% and prolonging survival in MNNG/HOS xenograft model compared to ZOL alone. Conclusion: These results indicate that ZOL-mediated induction of CLU can be attenuated by OGX-011, with synergistic effects on delaying progression of osteosarcoma

Muhammad Taqi al-Majlisi and Safavid Shi‘Ism: Akhbarism and Anti-sunni Polemic During the Reigns of Shah ‘Abbas the Great and Shah Safi

This is the author accepted manuscript. The final version is available from Taylor & Francis via the DOI in this record.The rise of the Akhbari school in the Safavid period has been portrayed as a challenge to both the clerical power of the ʿulamaʾ and sometimes even as in opposition to the Safavid state. As a counter example to these characterisations of Akhbarism, one might consider the example Muhammad Taqi al-Majlisi (d.1070/1659), known as “The First Majlisi”, and father of the famous Safavid scholar Muhammad Baqir al-Majlisi (“The Second Majlisi”, d.1110/1699 or 1111/1700). He had close relations with the Safavid court, dedicating a work to Shah Abbas II, and generally accepting royal patronage when it was offered. His system of legal interpretation and the analysis of hadith in particular, is thoroughly Akhbari. In this article I analyse Taqi al-Majlisi’s ideas as found in the introductory sections to his Lawamiʿ-i Sahibqirani, a Persian language commentary on an early collection of Twelver Shiʿi reports from the Imams. As an appendix, I translate one section which demonstrates not only his thoroughly Akhbari methodology, but also his originality within the Akhbari school. He should, I argue, be particularly remembered for promoting the authority of the ʿulamaʾ from an Akhbari perspective, and here he links the rejection of ijtihad (a hallmark of the Akhbari school) to the Shiʿi rejection of the selection of Abu Bakr as caliph. In doing this, he establishes and exploits a link between the support of ijtihad (that is, the Usuli position), the heresy of Sunnism and the betrayal of fundamental Shi‘i beliefs

Patent Licensing and Price Discrimination

We extend the Kamien and Tauman model of patent licensing by introducing heterogeneous licensees that differ in their marginal costs using the licensed technology. We show that price discrimination does not necessarily ensure an efficient allocation of licenses. Moreover, it is possible that more licenses are sold without rather than with price discrimination.Endogenous valuation

Active Inverse Reward Design

Designers of AI agents often iterate on the reward function in a trial-and-error process until they get the desired behavior, but this only guarantees good behavior in the training environment. We propose structuring this process as a series of queries asking the user to compare between different reward functions. Thus we can actively select queries for maximum informativeness about the true reward. In contrast to approaches asking the designer for optimal behavior, this allows us to gather additional information by eliciting preferences between suboptimal behaviors. After each query, we need to update the posterior over the true reward function from observing the proxy reward function chosen by the designer. The recently proposed Inverse Reward Design (IRD) enables this. Our approach substantially outperforms IRD in test environments. In particular, it can query the designer about interpretable, linear reward functions and still infer non-linear ones

Dynamic Models of the Interaction between Migration and the Differential Growth of Cities

The general area of interest of this paper is the dynamic relationship between regional imbalances, migration, and the differential growth of cities. In particular, the paper considers the feasibility of building dynamic models of the economic and demographic interactions between a set of linked cities, which could be used to explore the effects and repercussions of national settlement policies addressed at the alleviation of imbalances. Inter-regional economic growth models are well known, and, recently several papers have focused on inter-regional demographic models. There has been less research on the dynamics of the interdependent interaction between economic and demographic growth. This paper focuses on this economic-demographic adjustment for a system of linked city regions and considers research results which point to several difficulties in building theoretically well structured dynamic models of differential city growth. Part of the paper considers the inadequacies of current theories of inter-regional population migration and a new approach based on job-search theory is outlined

Cold Induction of EARLI1, a Putative Arabidopsis Lipid Transfer Protein, Is Light and Calcium Dependent

As sessile organisms, plants must adapt to their environment. One approach toward understanding this adaptation is to investigate environmental regulation of gene expression. Our focus is on the environmental regulation of EARLI1, which is activated by cold and long-day photoperiods. Cold activation of EARLI1 in short-day photoperiods is slow, requiring several hours at 4ºC to detect an increase in mRNA abundance. EARLI1 is not efficiently cold-activated in etiolated seedlings, suggesting that photomorphogenesis is necessary for its cold activation. Cold activation of EARLI1 is inhibited in the presence of the calcium channel blocker lanthanum chloride or the calcium chelator EGTA. Addition of the calcium ionophore Bay K8644 results in cold-independent activation of EARLI1. These data suggest that EARLI1 is not an immediate target of the cold response, and that calcium flux affects its expression. EARLI1 is a putative secreted protein and has motifs found in lipid transfer proteins. Over-expression of EARLI1 in transgenic plants results in reduced electrolyte leakage during freezing damage, suggesting that EARLI1 may affect membrane or cell wall stability in response to low temperature stress

Bad expression influences time to androgen escape in prostate cancer

<b>OBJECTIVE</b>: To assess the role of selected downstream Bcl-2 family members (Bad, Bax, Bcl-2 and Bcl-xL) in the development of androgen-independent prostate cancer (AIPC), as androgen-deprivation therapy is the treatment of choice in advanced prostate cancer, yet patients generally relapse and progress to an AI state within 18–24 months. <b>PATIENTS, MATERIALS AND METHODS</b>: The patient cohort was established by retrospectively selecting patients with prostate cancer who had an initial response to androgen-deprivation therapy, but subsequently relapsed with AIPC. In all, 58 patients with prostate cancer were included with matched androgen-dependent (AD) and AI prostate tumours available for immunohistochemical analysis; two independent observers using a weighted-histoscore method scored the staining. Changes in Bad, Bax, Bcl-2 and Bcl-xL expression during transition to AIPC were evaluated and then correlated to known clinical variables. <b>RESULTS</b>: High Bad expression in AD tumours was associated with an increased time to biochemical relapse (<i>P</i> = 0.007) and a trend towards improved overall survival (<i>P</i> = 0.053). There were also trends towards a decrease in Bad (<i>P</i> = 0.068) and Bax (<i>P</i> = 0.055) expression with progression to AIPC. There were no significant results for Bcl-2 or Bcl-xL. <b>CONCLUSION</b>: There is evidence to suggest that Bad expression levels at diagnosis influence time to biochemical relapse and overall survival, and that levels of pro-apoptotic proteins Bad and Bax fall during AIPC development. Bad might therefore represent a possible positive prognostic marker and potential therapeutic target for AIPC in the future

Filarial infection influences mosquito behaviour and fecundity

Understanding vector-parasite interactions is increasingly important as we move towards the endpoint goals set by the Global Programme for the Elimination of Lymphatic Filariasis (GPELF), as interaction dynamics may change with reduced transmission pressure. Elimination models used to predict programmatic endpoints include parameters for vector-specific transmission dynamics, despite the fact that our knowledge of the host-seeking behaviour of filariasis infected mosquitoes is lacking. We observed a dynamic, stage-specific and density dependent change in Aedes aegypti behaviour towards host cues when exposed to Brugia malayi filarial parasites. Infected mosquitoes exhibited reduced activation and flight towards a host during the period of larval development (L1/L2), transitioning to a 5 fold increase in activation and flight towards a host when infective stage larvae (L3) were present (p < 0.001). In uninfected control mosquitoes, we observed a reduction in convergence towards a host during the same period. Furthermore, this behaviour was density dependent with non-activated mosquitoes harbouring a greater burden of L1 and L2 larvae while activated mosquitoes harboured a greater number of L3 (p < 0.001). Reductions in fecundity were also density-dependent, and extended to mosquitoes that were exposed to microfilariae but did not support larval development