A phase Ib/II study of cabozantinib (XL184) with or without erlotinib in patients with non-small cell lung cancer.

PurposeCabozantinib is a multi-kinase inhibitor that targets MET, AXL, and VEGFR2, and may synergize with EGFR inhibition in NSCLC. Cabozantinib was assessed alone or in combination with erlotinib in patients with progressive NSCLC and EGFR mutations who had previously received erlotinib.MethodsThis was a phase Ib/II study (NCT00596648). The primary objectives of phase I were to assess the safety, pharmacokinetics, and pharmacodynamics and to determine maximum tolerated dose (MTD) of cabozantinib plus erlotinib in patients who failed prior erlotinib treatment. In phase II, patients with prior response or stable disease with erlotinib who progressed were randomized to single-agent cabozantinib 100 mg qd vs cabozantinib 100 mg qd and erlotinib 50 mg qd (phase I MTD), with a primary objective of estimating objective response rate (ORR).ResultsSixty-four patients were treated in phase I. Doses of 100 mg cabozantinib plus 50 mg erlotinib, or 40 mg cabozantinib plus 150 mg erlotinib were determined to be MTDs. Diarrhea was the most frequent dose-limiting toxicity and the most frequent AE (87.5% of patients). The ORR for phase I was 8.2% (90% CI 3.3-16.5). In phase II, one patient in the cabozantinib arm (N = 15) experienced a partial response, for an ORR of 6.7% (90% CI 0.3-27.9), with no responses for cabozantinib plus erlotinib (N = 13). There was no evidence that co-administration of cabozantinib markedly altered erlotinib pharmacokinetics or vice versa.ConclusionsDespite responses with cabozantinib/erlotinib in phase I, there were no responses in the combination arm of phase II in patients with acquired resistance to erlotinib. Cabozantinib did not appear to re-sensitize these patients to erlotinib

The politics of petroleum pricing in Ghana: Institutions, power dynamics, and social networks

The study, drawing on the political settlement approach, examines how powers, institutions, networks, and interests influence the pricing of petroleum products in Ghana. Qualitative research approach was for the study, and purposive sampling was used to interview 24 respondents. The findings suggest the existence of power struggles among the key actors in the pricing of fuel. The findings revealed that the National Petroleum Authority, bulk distribution oil companies, oil marketing companies, International Monetary Fund, and energy policy think tanks influence result into policy. Actors influence fuel prices through taxes, policy guidelines, exchange rate, and legal actions. The study recommends that capacity of the key players should be built by the Government of Ghana so as to ensure healthy competition and stability in the pricing of petroleum products in Ghana. Political interference in the pricing of fuel should be limited so that the key players can operate successfully in the petroleum downstream

Timing of immune escape linked to success or failure of vaccination

Successful vaccination against HIV should limit viral replication sufficiently to prevent the emergence of viral immune escape mutations. Broadly directed immunity is likely to be required to limit opportunities for immune escape variants to flourish. We studied the emergence of an SIV Gag cytotoxic T cell immune escape variant in pigtail macaques expressing the Mane-A*10 MHC I allele using a quantitative RT-PCR to measure viral loads of escape and wild type variants. Animals receiving whole Gag expressing vaccines completely controlled an SIVmac251 challenge, had broader CTL responses and exhibited minimal CTL escape. In contrast, animals vaccinated with only a single CTL epitope and challenged with the same SIVmac251 stock had high levels of viral replication and rapid CTL escape. Unvaccinated na&iuml;ve animals exhibited a slower emergence of immune escape variants. Thus narrowly directed vaccination against a single epitope resulted in rapid immune escape and viral levels equivalent to that of na&iuml;ve unvaccinated animals. These results emphasize the importance of inducing broadly directed HIV-specific immunity that effectively quashes early viral replication and limits the generation of immune escape variants. This has important implications for the selection of HIV vaccines for expanded human trials.<br /

Organizing degrowth: The ontological politics of enacting degrowth in OMS

As degrowth notions begin to gain traction within business schools and organization and management studies (OMS), this paper draws on Science and Technology Studies to interrogate the ontological politics of enacting degrowth in this relatively new context. We argue that the ‘degrowth multiple’ is a boundary object which takes on different forms as it circulates among different epistemic communities and within their respective boundaries, institutional arrangements, practices, and agendas. We investigate this empirically to elucidate how degrowth is being enacted within the OMS epistemic apparatus, revealing three set of practices characterizing extant OMS-degrowth engagements: stabilizations, reconfigurations, and projections. These motivate a subsequent discussion of the ontological politics unfolding through degrowth performances in OMS, its transformations (t)herein, and degrowth’s wider enrollment within the OMS epistemic apparatus. We thus contribute a reflexive intervention to organizing degrowth such that it remains a politically actionable concept across multiple contexts, and avoids becoming uncritically black-boxed, fetishized, and/or diluted by diverging cross-boundary enactments

Complexity of the Inoculum Determines the Rate of Reversion of SIV Gag CD8 T Cell Mutant Virus and Outcome of Infection

Escape mutant (EM) virus that evades CD8+ T cell recognition is frequently observed following infection with HIV-1 or SIV. This EM virus is often less replicatively “fit” compared to wild-type (WT) virus, as demonstrated by reversion to WT upon transmission of HIV to a naïve host and the association of EM virus with lower viral load in vivo in HIV-1 infection. The rate and timing of reversion is, however, highly variable. We quantified reversion to WT of a series of SIV and SHIV viruses containing minor amounts of WT virus in pigtail macaques using a sensitive PCR assay. Infection with mixes of EM and WT virus containing ≥10% WT virus results in immediate and rapid outgrowth of WT virus at SIV Gag CD8 T cell epitopes within 7 days of infection of pigtail macaques with SHIV or SIV. In contrast, infection with biologically passaged SHIVmn229 viruses with much smaller proportions of WT sequence, or a molecular clone of pure EM SIVmac239, demonstrated a delayed or slow pattern of reversion. WT virus was not detectable until ≥8 days after inoculation and took ≥8 weeks to become the dominant quasispecies. A delayed pattern of reversion was associated with significantly lower viral loads. The diversity of the infecting inoculum determines the timing of reversion to WT virus, which in turn predicts the outcome of infection. The delay in reversion of fitness-reducing CD8 T cell escape mutations in some scenarios suggests opportunities to reduce the pathogenicity of HIV during very early infection

A strategic approach to mitigating operational failure across transitions

It is recognized that projects continue to deliver operational assets that are partially defective. This article proposes this because the causes of operational failures have not been extensively analyzed. This study explores how an infrastructure client made quality a strategic and project delivery necessity by undertaking research to analyze operational failure. A mixed-method approach consisting of three phases was used: (1) to understand the operational failure elements; (2) to explore the causes of operational failure; and (3) to develop a new strategic framework to address failure mitigation. The study showed the need for transferring, applying, and recognizing capabilities across strategic business, project delivery, and operational use transitions