A phase II multicentre, open-label, proof-of-concept study of tasquinimod in hepatocellular, ovarian, renal cell, and gastric cancers

Background: Tasquinimod is a small molecule with immunomodulatory, anti-angiogenic, and anti-metastatic properties that targets the tumor microenvironment. This study aimed to obtain a clinical proof of concept that tasquinimod was active and tolerable in patients with advanced solid tumors. Patients and Methods: This early stopping design, open-label, proof-of-concept clinical trial evaluated the clinical activity of tasquinimod in four independent cohorts of patients with advanced hepatocellular (n = 53), ovarian (n = 55), renal cell (n = 38), and gastric (n = 21) cancers. Tasquinimod was given orally every day (0.5 mg/day for at least 2 weeks, with dose increase to 1 mg/day) until radiological progression according to Response Evaluation Criteria in Solid Tumor (RECIST) 1.1 criteria, intolerable toxicity, or patient withdrawal. The primary efficacy endpoint was progression-free survival (PFS) rate according to RECIST 1.1 by central assessment. Results: Interim futility analyses at 8 weeks (6 weeks for the gastric cancer cohort) found adequate clinical activity of tasquinimod only in the hepatocellular cohort and recruitment to the other three cohorts was stopped. PFS rates were 26.9% at 16 weeks, 7.3% at 24 weeks, 13.2% at 16 weeks, and 9.5% at 12 weeks, respectively, in hepatocellular, ovarian, renal cell, and gastric cancer cohorts. The pre-defined PFS threshold was not reached in the hepatocellular cancer cohort at the second stage of the trial. The most common treatment-related adverse events were fatigue (48.5%), nausea (34.1%), decreased appetite (31.7%), and vomiting (24.6%). Conclusions: This study failed to demonstrate clinical activity of tasquinimod in heavily pre-treated patients with advanced hepatocellular, ovarian, renal cell, and gastric cancer. Trial registration: NCT01743469

Aerial Locomotion in Cluttered Environments

Many environments where robots are expected to operate are cluttered with objects, walls, debris, and different horizontal and vertical structures. In this chapter, we present four design features that allow small robots to rapidly and safely move in 3 dimensions through cluttered environments: a perceptual system capable of detecting obstacles in the robot’s surroundings, including the ground, with minimal computation, mass, and energy requirements; a flexible and protective framework capable of withstanding collisions and even using collisions to learn about the properties of the surroundings when light is not available; a mechanism for temporarily perching to vertical structures in order to monitor the environment or communicate with other robots before taking off again; and a self-deployment mechanism for getting in the air and perform repetitive jumps or glided flight. We conclude the chapter by suggesting future avenues for integration of multiple features within the same robotic platform

Influenza Pandemic Vaccines: Spread Them Thin?

Fraser discusses a new study that uses exploratory modeling to tackle the difficult issue of what to do with limited stockpiles of pre-prepared influenza pandemic vaccines

Reducing the Impact of the Next Influenza Pandemic Using Household-Based Public Health Interventions

BACKGROUND: The outbreak of highly pathogenic H5N1 influenza in domestic poultry and wild birds has caused global concern over the possible evolution of a novel human strain [1]. If such a strain emerges, and is not controlled at source [2,3], a pandemic is likely to result. Health policy in most countries will then be focused on reducing morbidity and mortality. METHODS AND FINDINGS: We estimate the expected reduction in primary attack rates for different household-based interventions using a mathematical model of influenza transmission within and between households. We show that, for lower transmissibility strains [2,4], the combination of household-based quarantine, isolation of cases outside the household, and targeted prophylactic use of anti-virals will be highly effective and likely feasible across a range of plausible transmission scenarios. For example, for a basic reproductive number (the average number of people infected by a typically infectious individual in an otherwise susceptible population) of 1.8, assuming only 50% compliance, this combination could reduce the infection (symptomatic) attack rate from 74% (49%) to 40% (27%), requiring peak quarantine and isolation levels of 6.2% and 0.8% of the population, respectively, and an overall anti-viral stockpile of 3.9 doses per member of the population. Although contact tracing may be additionally effective, the resources required make it impractical in most scenarios. CONCLUSIONS: National influenza pandemic preparedness plans currently focus on reducing the impact associated with a constant attack rate, rather than on reducing transmission. Our findings suggest that the additional benefits and resource requirements of household-based interventions in reducing average levels of transmission should also be considered, even when expected levels of compliance are only moderate

Estimating Individual and Household Reproduction Numbers in an Emerging Epidemic

Reproduction numbers, defined as averages of the number of people infected by a typical case, play a central role in tracking infectious disease outbreaks. The aim of this paper is to develop methods for estimating reproduction numbers which are simple enough that they could be applied with limited data or in real time during an outbreak. I present a new estimator for the individual reproduction number, which describes the state of the epidemic at a point in time rather than tracking individuals over time, and discuss some potential benefits. Then, to capture more of the detail that micro-simulations have shown is important in outbreak dynamics, I analyse a model of transmission within and between households, and develop a method to estimate the household reproduction number, defined as the number of households infected by each infected household. This method is validated by numerical simulations of the spread of influenza and measles using historical data, and estimates are obtained for would-be emerging epidemics of these viruses. I argue that the household reproduction number is useful in assessing the impact of measures that target the household for isolation, quarantine, vaccination or prophylactic treatment, and measures such as social distancing and school or workplace closures which limit between-household transmission, all of which play a key role in current thinking on future infectious disease mitigation

A roadmap for intergenerational leadership in planetary health

Planetary health cannot be achieved without breaking the siloed approach to the most crucial concerns of our time, from the climate emergency, to gender equity, to urbanisation, to the wealth gap—all of which are interconnected and fundamental to human prosperity in the coming decades. Born out of existing structures that are inherently elitist, ageist, and centralised in high-income countries, planetary health often struggles to mitigate the persisting disconnect between various stakeholders and constituents, thus delaying meaningful, lasting impact. It is time to democratise this space, balance the asymmetrical power structures, and leverage fearless voices challenging the status quo

NOF1 Encodes an Arabidopsis Protein Involved in the Control of rRNA Expression

The control of ribosomal RNA biogenesis is essential for the regulation of protein synthesis in eukaryotic cells. Here, we report the characterization of NOF1 that encodes a putative nucleolar protein involved in the control of rRNA expression in Arabidopsis. The gene has been isolated by T-DNA tagging and its function verified by the characterization of a second allele and genetic complementation of the mutants. The nof1 mutants are affected in female gametogenesis and embryo development. This result is consistent with the detection of NOF1 mRNA in all tissues throughout plant life's cycle, and preferentially in differentiating cells. Interestingly, the closely related proteins from zebra fish and yeast are also necessary for cell division and differentiation. We showed that the nof1-1 mutant displays higher rRNA expression and hypomethylation of rRNA promoter. Taken together, the results presented here demonstrated that NOF1 is an Arabidopsis gene involved in the control of rRNA expression, and suggested that it encodes a putative nucleolar protein, the function of which may be conserved in eukaryotes

The “Rougemarine Dilemma”: how much Trust does a State Deserve when it Subsidises Cultural Goods and Services?

This paper focuses on the way welfare states distribute subsidies to cultural industries. It takes the example of the film industry and analyses jurisprudence which addresses socalled “selective state aid” schemes based upon European and Swiss law. States grant selective aid as opposed to “automatic aid” by asking independent experts to decide upon the merits of projects according to criteria that usually refer to subjective elements such as quality or cultural value. Decisions founded on such experts’ opinions normally cannot be challenged in the courts. In fact, these decisions constitute a legal “no man’s land” through which these states preserve a strong decision-making power that allow them to reject projects for “implicit” or “tacit” reasons under the cover of stated conditions and reasons that leave a broad margin of assessment. If states abuse this power, they are able to censor content as well as tolerate and even facilitate forms of clientelism and corruption that can eventually destroy artistic creativity and entrepreneurial innovation. These possible consequences are not only detrimental to the competitiveness of the cultural industries affected by such practices, but also to cultural diversity within and beyond the borders of the states that proceed in this way. The author of this paper therefore advocates protecting cultural industries not only from market economies that suffer from oligopolitic private power, but also from the abuse of the power of the states to correct market failures that damage cultural diversity. He suggests the introduction of the constitutional principle of an effective separation between the state and the culture by analogy of the separation between the church and the state as inspired by the rationale underlying the French “principe the laïcité”. This new principle should promote freedom of opinion and expression by protecting the authors of contemporary cultural expressions from the control of states, their bureaucracies and favouritism in a way that would be legally enforceable