A Phase I Study of Abiraterone Acetate Combined with BEZ235, a Dual PI3K/mTOR Inhibitor, in Metastatic Castration Resistant Prostate Cancer.

Lessons learnedThe combination of standard dose abiraterone acetate and BEZ235, a pan-class I PI3K and mTORC1/2 inhibitor, was poorly tolerated in men with progressive mCRPC.Although the clinical development of BEZ235 has been discontinued in prostate cancer, agents that more selectively target PI3K-AKT-mTOR signaling may have a more favorable therapeutic index and should continue to be explored.BackgroundAndrogen receptor (AR) and phosphatidylinositol-3 kinase (PI3K) signaling are two commonly perturbed pathways in prostate cancer. Preclinical data have shown that the two pathways compensate for each other when one is inhibited, and combined inhibition of AR and PI3K signaling may be a viable strategy to prevent or overcome castration resistance.MethodsThis phase I study evaluated the safety and tolerability of abiraterone acetate and prednisone combined with BEZ235, a dual PI3K and mTORC1/2 inhibitor, in men with progressive metastatic castration resistant prostate cancer (mCRPC) who have not received prior chemotherapy.ResultsSix patients (n = 6) were treated at the starting dose level of abiraterone acetate 1,000 mg with prednisone 5 mg twice daily and BEZ235 200 mg twice daily in a 3 + 3 dose escalation design. The study was terminated early because three of the six patients (50%) experienced dose-limiting toxicities: grade 3 mucositis, grade 3 hypotension, and grade 4 dyspnea and pneumonitis. All six patients had previously progressed on abiraterone/prednisone. The median treatment duration was 27 days (range: 3-130 days). No prostate-specific antigen (PSA) decline or objective response were observed.ConclusionThe combination of standard-dose abiraterone/prednisone with BEZ235 200 mg twice daily was poorly tolerated in patients with mCRPC. The on-target and off-target effects of dual PI3K and mTORC inhibition likely contributed to the unacceptable toxicity profile. The Oncologist 2017;22:503-e43

Open Access, Public Access: Policies, Implementation, Developments, and the Future of U.S.-Published Research

In February, the White House Office of Science and Technology Policy (OSTP) released a memo directing each US funding agency with over $100 million in annual research expenditure to develop a plan to support public access to the results of research funded by the federal government, including results published in scholarly journals. How has the OSTP memo impacted scholarly publishing so far? What exactly has been achieved so far, and what will it mean for the future of U.S.-published research? This interactive session features a panel of speakers who will be discussing the recent developments and emerging issues from the librarian, funder, researcher, and publisher perspectives. Among the questions to be addressed are: What is the US position on implementing open access? What steps have been taken to implement OSTP objectives? What role do institutional repositories play in open access? How will funder’s open access policies impact universities and researchers? What role are publishers playing in the implementation of open access? How will open access content be linked and measured? Will it affect usage

Commercialization of the Internet: The Interaction of Public Policy and Private Actions,” in

seminar participants for comments. I am particularly grateful to Zvi Griliches who encouraged this research when it was at a formative stage. All remaining errors are mine alone. Abstract Why did commercialization of the Internet go so well? This paper examines events in the Internet access market as a window on this broad question. The study emphasizes four themes. First, commercializing Internet access did not give rise to many of the anticipated technical and operational challenges. Entrepreneurs quickly learned that the Internet access business was commercially feasible. Second, Internet access was malleable as a technology and as an economic unit. Third, privatization fostered attempts to adapt the technology in new uses, new locations, new market settings, new applications and in conjunction with other lines of business. These went beyond what anyone would have forecast by examining the uses for the technology prior to 1992. Fourth, and not trivially, the NSF was lucky in one specific sense. The Internet access industry commercialized at a propitious moment, at the same time as the growth of an enormous new technological opportunity, the World Wide Web. As it turned out, the Web thrived under market-oriented, decentralized and independent decision making. The paper draws lessons for policies governing the commercialization of other government managed technologies and for the Internet access market moving forward. 1 Motivation The "commercialization of the Internet" is shorthand for three nearly simultaneous events: the removal of restrictions by the National Science Foundation (NSF) over use of the Internet for commercial purposes, the browser wars initiated by the founding of Netscape, and the rapid entry of tens of thousands of firms into commercial ventures using technologies which employ the suite of TCP/IP standards. These events culminated years of work at NSF to transfer the Internet into commercial hands from its exclusive use for research activity in government funded laboratories and universities. Sufficient time has passed to begin to evaluate how the market performed after commercialization. Such an evaluation is worth doing. Actual events have surpassed the forecasts of the most optimistic managers at NSF. Was this due to mere good fortune or something systematic whose lessons illuminate the market today? Other government managed technologies usually face vexing technical and commercial challenges that prevent the technology from diffusing quickly, if at all. Can we draw lessons from this episode for the commercialization of other government managed technologies? In that spirit, this paper examines the Internet access market and one set of actors, Internet Service Provides (ISPs). ISPs provide Internet access for most of the households and business users in the country (NTIA, 1999), usually for a fee or, more recently, in exchange for advertising. Depending on the user facilities, whether it is a business or personal residence, access can involve dial-up to a local number or 1-800 number at different speeds, or direct access to the user's server employing one of several high-speed access technologies. The largest ISP in the United States today is America-On-Line, to which approximately half the households in the US subscribe. There also are many national ISPs with recognizable names, such as AT&T Worldnet, MCI WorldCom/UUNet, Mindspring/Earthlink, and PSINet, as well as thousands of smaller regional ISPs. The Internet access market is a good case to examine. Facilities for similar activity existed prior to commercialization, but there was reason to expect a problematic migration into commercial use. This activity 2 appeared to possess idiosyncratic technical features and uneconomic operational procedures which made it unsuitable in other settings. The Internet's exclusive use by academics and researchers fostered cautious predictions that unanticipated problems would abound and commercial demand might not materialize. In sharp contrast to cautious expectations, however, the ISP market displayed three extraordinary features. For one, this market grew rapidly, attracting thousands of entrants and many users, quickly achieving mass-market status. Second, firms offering this service became nearly geographically pervasive, a diffusion pattern rarely found in new infrastructure markets. And third, firms did not settle on a standard menu of services to offer, indicative of new commercial opportunities and also a lack of consensus about the optimal business model for this opportunity. Aside from defying expectations, all three traits --rapid growth, geographic pervasiveness and the absence of settlement --do not inherently go together in most markets. The presence of restructuring should have interfered with rapid growth and geographic expansion. So explaining this market experience is also interesting in its own right. What happened to make commercialization go so well? This paper's examination reveals four themes. First, commercialization did not give rise to many of the anticipated technical and operational challenges. Entrepreneurs quickly learned that the Internet access business was commercially feasible. This happened for a variety of economic reasons. ISPs began offering commercial service after making only incremental changes to familiar operating procedures borrowed from the academic setting. It was technically easy to collect revenue at what used to be the gateway functions of academic modem pools. Moreover, the academic model of Internet access migrated into commercial operation without any additional new equipment suppliers. Second, Internet access was malleable as a technology and as an economic unit. This is because the foundation for Internet inter-connectivity, TCP/IP, is not a single invention, diffusing across time and space without changing form. Instead, it is embedded in equipment which uses a suite of communication technologies, protocols and standards for networking between computers. This technology obtains economic value in combination with complementary invention, investment and equipment. While commercialization did 3 give rise to restructuring of Internet access to suit commercial users, the restructuring did not stand in the way of diffusion, nor interfere with the initial growth of demand. Third, privatizing Internet access fostered customizing Internet access technology to a wide variety of locations, circumstances and users. As it turned out, the predominant business model was feasible at small scale and, thus, at low levels of demand. This meant that the technology was commercially viable at low densities of population, whether or not it was part of a national branded service or a local geographically Fourth, and not trivially, the NSF was lucky in a particular sense of the word. It enabled the commercialization of the Internet access industry at a propitious moment, at the same time as the growth of an enormous new technological opportunity, the World Wide Web. This invention motivated further experimentation to take advantage of the new opportunity, which, as it turned out, thrived under marketoriented and decentralized decision making. The paper first develop these themes. Then it describes recent experience. It ends by discussing how these themes continue to resonate today. Challenges during technology transfer: an overview Conventional approaches to technological development led most observers in 1992 to be cautious about the commercialization of the Internet. To understand how this prediction went awry, it is important to understand its foundations. For example, military users frequently require electronic components to meet specifications that suit 6 the component to battle conditions. Extensive technical progress is needed to tailor a product design to meet these requirements. Yet, and this is difficult to anticipate prior to commercialization, an additional amount of invention is often needed to bring such a product design and to bring its manufacturing to a price/point with features that meet more cost-conscious or less technically stringent commercial requirements. Commercial challenges arise when commercial markets require substantial adaptation of operation and business processes in order to put technologies into use. In other words, government users or users in a research environment often tolerate operational processes that do not translate profitably to commercial environments. After a technology transfers out of government sponsorship, it may not be clear how to balance costs and revenues for technologies that had developed under settings with substantial subsidies underwriting losses, and research goals justifying expenditures. Hence, many government managed technologies require considerable experimentation with business models before they begin to grow, if they grow at all. For example, the supersonic transport actually met its engineering targets, but still failed to satisfy basic operational economics in most settings. Being technically sleek was insufficient to attract enough interest to generate the revenue which covered operating costs on any but a small set of routes. No amount of operational innovations and marketing campaigns were able to overcome these commercial problems. New technologies are also vulnerable to structural challenges that impede pathways to commercialization. Commercial and structural challenges are not necessarily distinct, though the latter are typically more complex. Structural challenges are those which require change to the bundle of services offered, change to the boundary of the firms offering or using the new technology, or dramatic change to the operational structure of the service organization. These challenges arise because technologies developed under government auspices may presume implementation at a particular scale or with a set of technical standards, but require a different set of organizational arrangements to support commercial applications. For example, while many organizations provided the technical advances necessary for scientific 7 computing in academic settings during the 1950s, very few of these same firms migrated into supporting large customer bases among business users. As it turned out, the required changes were too dramatic for many companies to make. The structure of the support and sales organization were very different, and so too were the product designs. Of course, the few who successfully made the transition to commercial users, such as IBM, did quite well, but doing so required overcoming considerable obstacles. In summary, conventional analysis forecasts that migrating Internet access into commercial use would engender technical, commercial and structural challenges. Why did the migration proceed so different than expected? The absence of challenge in the Internet Access industry An ISP is a commercial firm who provides access, maintains it for a fee and develop related applications as users require. While sometimes this is all they do, with business users they often do much more. Sometimes ISPs do simple things such as filtering. Sometimes it involves managing and designing email accounts, data-bases and web pages. Some ISPs label this activity consulting and charge for it separately; others do not consider it distinct from the normal operation of the Internet access services. On the surface the record of achievement for ISPs is quite remarkable. Most recent surveys show that no more than 10 percent of US households get their Internet access from university-sponsored Internet access providers, the predominant provider of such access prior to commercialization. Today almost all users go to a commercial providers By the end of the century the ISP market had obtained a remarkable structure. One firm, America On-line, provided access to close to half the households in the US market, while several score of other ISPs provided access to millions of households and businesses on a nationwide basis. Thousands of ISPs also 8 provided access for limited geographic areas, such as one city or region. Such small ISPs accounted for roughly a quarter of household use and another fraction of business use. Technical challenges did not get in the way The Internet access market did suffer from some technical challenges, but not enough to prevent rapid diffusion. Commercialization induced considerable technical innovation in complementary inventive activities. Much of this innovative activity became associated with developing new applications for existing users and new users. It is often forgotten that when the electronic commerce first developed based on TCP/IP standards, it was relatively mature in some applications, such as e-mail and file transfers, which were the most popular applications (these programs continue to be the most popular today, NTIA [1999]). To be sure, TCP/IP based programs were weak in others areas, such as commercial data base and software applications for business use, but those uses did not necessarily have to come immediately. The invention of the World Wide Web in the early 1990s further stretched the possibilities for potential applications and highlighted these weaknesses. More important for the initial diffusion, little technical invention was required for commercial vendors to put this technology into initial mainstream use. Academic modem pools and computing centers tended to use technologies similar to their civilian counterparts --such as bulletin board operators --while buying most equipment from commercial suppliers. Moving this activity into the mainstream commercial sector did not necessitate building a whole new Internet equipment industry; it was already there, supplying goods and services to the universities and to home PC users. Similarly, much of the software continued to be usefuli.e., Unix systems, the gate-keeping software, and the basic communication protocols. Indeed, every version of Unix software had been TPC/IP compatible for many years due to Department of Defense requirements. A simple commercial operation only needed to add a billing component to the gate-keeping software to turn an academic modem pool into a rudimentary commercial operation. 9 Technical information about these operations was easy to obtain if one had sufficient technical background; a BA in basic electrical engineering or computer science was far more than adequate. Many IS

Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity.

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels

Chromosomal-level assembly of the Asian Seabass genome using long sequence reads and multi-layered scaffolding

We report here the ~670 Mb genome assembly of the Asian seabass (Lates calcarifer), a tropical marine teleost. We used long-read sequencing augmented by transcriptomics, optical and genetic mapping along with shared synteny from closely related fish species to derive a chromosome-level assembly with a contig N50 size over 1 Mb and scaffold N50 size over 25 Mb that span ~90% of the genome. The population structure of L. calcarifer species complex was analyzed by re-sequencing 61 individuals representing various regions across the species' native range. SNP analyses identified high levels of genetic diversity and confirmed earlier indications of a population stratification comprising three clades with signs of admixture apparent in the South-East Asian population. The quality of the Asian seabass genome assembly far exceeds that of any other fish species, and will serve as a new standard for fish genomics

Women Have Higher Protein Content of β-Oxidation Enzymes in Skeletal Muscle than Men

It is well recognized that compared with men, women have better ultra-endurance capacity, oxidize more fat during endurance exercise, and are more resistant to fat oxidation defects i.e. diet-induced insulin resistance. Several groups have shown that the mRNA and protein transcribed and translated from genes related to transport of fatty acids into the muscle are greater in women than men; however, the mechanism(s) for the observed sex differences in fat oxidation remains to be determined. Muscle biopsies from the vastus lateralis were obtained from moderately active men (N = 12) and women (N = 11) at rest to examine mRNA and protein content of genes involved in lipid oxidation. Our results show that women have significantly higher protein content for tri-functional protein alpha (TFPα), very long chain acyl-CoA dehydrogenase (VLCAD), and medium chain acyl-CoA dehydrogenase (MCAD) (P<0.05). There was no significant sex difference in the expression of short-chain hydroxyacyl-CoA dehydrogenase (SCHAD), or peroxisome proliferator activated receptor alpha (PPARα), or PPARγ, genes potentially involved in the transcriptional regulation of lipid metabolism. In conclusion, women have more protein content of the major enzymes involved in long and medium chain fatty acid oxidation which could account for the observed differences in fat oxidation during exercise

Cross-cutting principles for planetary health education

Since the 2015 launch of the Rockefeller Foundation Lancet Commission on planetary health,1 an enormous groundswell of interest in planetary health education has emerged across many disciplines, institutions, and geographical regions. Advancing these global efforts in planetary health education will equip the next generation of scholars to address crucial questions in this emerging field and support the development of a community of practice. To provide a foundation for the growing interest and efforts in this field, the Planetary Health Alliance has facilitated the first attempt to create a set of principles for planetary health education that intersect education at all levels, across all scales, and in all regions of the world—ie, a set of cross-cutting principles

Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci

Introduction: Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes. Methods: A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: “Some College” (yes/no, for any education beyond high school) and “Graduated College” (yes/no, for completing a 4-year college degree). Genome-wide significant (p &lt; 5 × 10−8) and suggestive (p &lt; 1 × 10−6) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals). Results: In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (FOXP1, MBOAT4, SKP2, STIM1, STX4), brain (BRI3, FILIP1, FOXP1, LINC00290, LMTK2, MBOAT4, MYO6, SENP6, SRGAP3, STIM1, TMEM167A, TMEM30A), and liver (BRI3, FOXP1) biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue. Discussion: Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.</p

Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity.

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels