The Open Road: How To Build a Sustainable Open Infrastructure System

The open infrastructure ecosystem spans open source software and standards, and is a shifting constellation of individuals, organisations and private and public bodies. Working with Omidyar Networks, this report sets out how governments, civil society and philanthropic organisations can build sustainability in the open infrastructure ecosystem.Over the past decades, open source and open standards have emerged as the de facto way digital technologies are created. From individual developers building a profile and skills to interoperability between multi-billion dollar companies, open source software and open standards are universal technological forces.Despite this economic and industrial reliance on open infrastructure, the ecosystem as a whole faces a sustainability crisis. There is a major gap in funding, a gap felt most acutely at the foundations and by open source communities outside the digital limelight. For some developers, upskilling, economic security and a love for coding covers the costs of participation, but for many potential participants the barriers remain high. This includes non-code participants in an ecosystem where legal, management, governance and communications skills are in short supply. Where funding is available there remain gaps in tooling, governance and skills for OS communities to manage the money they receive and the responsibilities that come with it.But money isn't everything. We need to defend the open infrastructure ecosystem from state and corporate capture, inadvertent or otherwise. We need to support its maintenance. We need to incentivise participation from a diverse group of participants. And we need to talk about why this all matters to a non-technical audience, be they corporate budget holders or government decision makers. These priorities should inform philanthropic decision-making

A randomised trial comparing combination chemotherapy using mitomycin C, mitozantrone and methotrexate (3M) with vincristine, anthracycline and cyclophosphamide (VAC) in advanced breast cancer.

This paper describes a randomised clinical trial in patients with advanced breast cancer, comparing the regimen 3M, mitomycin C 7-8 mg m-2 (day 1), mitozantrone 7-8 mg m-2 (day 1 and 21), methotrexate 35 mg m-2 (day 1 and 21) given on a 42 day cycle with a standard anthracycline containing regimen, VAC, vincristine 1.4 mg m-2 (day 1), anthracycline (adriamycin or epirubicin) 30 mg m-2 (day 1), cyclophosphamide 400 mg m-2 (day 1) given on a 21 day cycle. Of a total of 217 patients, 107 were randomised to 3M and 110 to VAC and a mean of 5.5 courses was given per patient. The overall response rate (complete and partial) was 53% (95% Confidence Limits (CL): 43-62%) for 3M and 49% (CL; 39-58%) for VAC. The response according to sites of metastases was the same for both treatment groups. Symptomatic toxicity including alopecia, neuropathy, vomiting (P less than 0.001) and nausea (P less than 0.01) were significantly less for 3M. Myelosuppression including leucopenia (P less than 0.001) and thrombocytopenia (P less than 0.001) was significantly greater with 3M at day 21, although there was no difference in nadir counts in patients at special risk of myelosuppression and there was no evidence of an increase in infective or bleeding complications. There was no significant difference in the duration of response to 3M (10 months, CL 6-15) and VAC (11 months, CL 7-12), nor in survival (3M, 8 months, CL 6-12; VAC, 10 months, CL 8-12). These results indicate that 3M is as effective as, but has significantly less symptomatic toxicity than, an anthracycline containing regimen for the treatment of advanced breast cancer

Targeting the Insulin-Like Growth Factor 1 Receptor in Ewing's Sarcoma: Reality and Expectations

Ewing's sarcoma family of tumours comprises a group of very aggressive diseases that are potentially curable with multimodality treatment. Despite the undoubted success of current treatment, approximately 30% of patients will relapse and ultimately die of disease. The insulin-like growth factor 1 receptor (IGF-1R) has been implicated in the genesis, growth, proliferation, and the development of metastatic disease in Ewing's sarcoma. In addition, IGF1-R has been validated, both in vitro and in vivo, as a potential therapeutic target in Ewing's sarcoma. Phase I studies of IGF-1R monoclonal antibodies reported several radiological and clinical responses in Ewing's sarcoma patients, and initial reports of several Phase II studies suggest that about a fourth of the patients would benefit from IGF-1R monoclonal antibodies as single therapy, with approximately 10% of patients achieving objective responses. Furthermore, these therapies are well tolerated, and thus far severe toxicity has been rare. Other studies assessing IGF-1R monoclonal antibodies in combination with traditional cytotoxics or other targeted therapies are expected. Despite, the initial promising results, not all patients benefit from IGF-1R inhibition, and consequently, there is an urgent need for the identification of predictive markers of response

Suggested Improvements in the Law of Evidence

The Washington Committee on Judicial Administration assigned a section of its membership to study the law of evidence in the state of Washington in the light of the Reports of the Section of Judicial Administration of the American Bar Association, published in July, 1938. The observations and recommendations of the Washington Section on the Law of Evidence appear in the following report

The Macro Content of the PRSPs: Assessing the Need for a more Flexible Macroeconomic Policy Framework

This paper analyses the macroeconomic content of 15 PRSPs from a growth and poverty reduction perspective. It finds that, in the main and contrary to new trends in developed and middle income countries, their macroeconomic policy frameworks lack the necessary flexibility to deal with external shocks and to appropriately address macroeconomic volatility. To ilustrate the point, their fiscal andmonetary policies are too narrowly focused on fiscal balance and price stability, and as a consequence pay too little attention to sharp economic fluctuations arising from external shocks. The paper argues that this is problematic, as sharp macro volatility have major effects on poverty and long-term growth. PRSP countries are particularly vulnerable to external shocks such as a fall in the terms of trade due to their narrow economic structures and heavy reliance on a few primary commodities as export earnings and as sources of fiscal revenues. To reduce macroeconomic volatility, the paper proposes a set of policy measures including: avoidance of excessively tight inflation and fiscal targets (with provisions for fluctuations in their commodity prices), more room for counter-cyclical policy and the adoption of safety nets

A Phase I/II Clinical Trial of Belinostat (PXD101) in Combination with Doxorubicin in Patients with Soft Tissue Sarcomas

Background. Belinostat is a novel histone deacetylase inhibitor. Primary Objectives. Maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) of belinostat (Bel) in combination with doxorubicin (Dox) in solid tumours (phase I) and response rate (RR) in soft tissue sarcomas (phase II). Methods. Bel was administered as a 30-minute IV infusion on days 1–5 and on day 5 with Dox. The dose escalation schedule was as follows: cohort 1: Bel 600 mg/m2 and 50 mg/m2 Dox, cohort 2: Bel 600 mg/m2 and 75 mg/m2 Dox, cohort 3: Bel 800 mg/m2 and 75 mg/m2 Dox, and cohort 4: Bel 1000 mg/m2 and 75 mg/m2 Dox. Results. 41 patients were included (25 in phase I, 16 in phase II). Adverse events were fatigue (95%), nausea (76%), and alopecia (63%). There was one DLT, grade 3 rash/hand and foot syndrome. MTD was Bel 1000 mg/m2/d and Dox 75 mg/m2. Four responses were seen: 2 PR in phase I, RR of 8%; in phase II, 1 PR/1 CR, RR of 13%, and 9 patients (56%) with SD. Conclusion. The combination was well tolerated. Response rate was moderate but median time to progression was 6.0 months (95% CI, 1.6–9.7 months) which is superior to some reports of single-agent Dox

Optimally shaped terahertz pulses for phase retrieval in a Rydberg atom data register

We employ Optimal Control Theory to discover an efficient information retrieval algorithm that can be performed on a Rydberg atom data register using a shaped terahertz pulse. The register is a Rydberg wave packet with one consituent orbital phase-reversed from the others (the ``marked bit''). The terahertz pulse that performs the decoding algorithm does so by by driving electron probability density into the marked orbital. Its shape is calculated by modifying the target of an optimal control problem so that it represents the direct product of all correct solutions to the algorithm.Comment: 6 pages, 3 figure

The landscape of tyrosine kinase inhibitors in sarcomas: looking beyond pazopanib.

Introduction: Tyrosine kinases are key mediators of intracellular signaling cascades and aberrations in these proteins have been implicated in driving oncogenesis through the dysregulation of fundamental cellular processes including proliferation, migration, and apoptosis. As such, targeting these proteins with small molecule tyrosine kinase inhibitors (TKI) has led to significant advances in the treatment of a number of cancer types.Areas covered: Soft tissue sarcomas (STS) are a heterogeneous and challenging group of rare cancers to treat, but the approval of the TKI pazopanib for the treatment of advanced STS demonstrates that this class of drugs may have broad utility against a range of different sarcoma histological subtypes. Since the approval of pazopanib, a number of other TKIs have entered clinical trials to evaluate whether their activity in STS matches the promising results seen in other solid tumors. In this article, we review the emerging role of TKIs in the evolving landscape of sarcoma treatment.Expert opinion: As our biological understanding of response and resistance of STS to TKIs advances, we anticipate that patient management will move away from a 'one size fits all' paradigm toward personalized, multi-line, and patient-specific treatment regimens where patients are treated according to the underlying biology and genetics of their specific disease