Imaging biomarkers (IBs) are integral to the routine management of patients with cancer. IBs used daily in oncology include clinical TNM stage, objective response and left ventricular ejection fraction. Other CT, MRI, PET and ultrasonography biomarkers are used extensively in cancer research and drug development. New IBs need to be established either as useful tools for testing research hypotheses in clinical trials and research studies, or as clinical decision-making tools for use in healthcare, by crossing ‘translational gaps’ through validation and qualification. Important differences exist between IBs and biospecimen-derived biomarkers and, therefore, the development of IBs requires a tailored ‘roadmap’. Recognizing this need, Cancer Research UK (CRUK) and the European Organisation for Research and Treatment of Cancer (EORTC) assembled experts to review, debate and summarize the challenges of IB validation and qualification. This consensus group has produced 14 key recommendations for accelerating the clinical translation of IBs, which highlight the role of parallel (rather than sequential) tracks of technical (assay) validation, biological/clinical validation and assessment of cost-effectiveness; the need for IB standardization and accreditation systems; the need to continually revisit IB precision; an alternative framework for biological/clinical validation of IBs; and the essential requirements for multicentre studies to qualify IBs for clinical use.
Tumours require a vascular supply to grow and can achieve this via the expression of pro-angiogenic growth factors, including members of the vascular endothelial growth factor (VEGF) family of ligands. Since one or more of the VEGF ligand family is overexpressed in most solid cancers, there was great optimism that inhibition of the VEGF pathway would represent an effective anti-angiogenic therapy for most tumour types. Encouragingly, VEGF pathway targeted drugs such as bevacizumab, sunitinib and aflibercept have shown activity in certain settings. However, inhibition of VEGF signalling is not effective in all cancers, prompting the need to further understand how the vasculature can be effectively targeted in tumours. Here we present a succinct review of the progress with VEGF-targeted therapy and the unresolved questions that exist in the field: including its use in different disease stages (metastatic, adjuvant, neoadjuvant), interactions with chemotherapy, duration and scheduling of therapy, potential predictive biomarkers and proposed mechanisms of resistance, including paradoxical effects such as enhanced tumour aggressiveness. In terms of future directions, we discuss the need to delineate further the complexities of tumour vascularisation if we are to develop more effective and personalised anti-angiogenic therapies.
Carbohydrate quality and human health: a series of systematic reviews and meta-analyses. Lancet, 393(10170), 434-445. and the Otago Southland Diabetes Research Trust. 94 the light of current evidence, dietary glycaemic index or glycaemic load may be less useful as overall measures 95 of carbohydrate quality than dietary fibre and wholegrain content.
The efficacy of angiogenesis inhibitors in cancer is limited by resistance mechanisms that are poorly understood. Notably, instead of inducing angiogenesis, some cancers vascularize by the non-angiogenic mechanism of vessel co-option. Here we show that vessel co-option is associated with a poor response to the anti-angiogenic agent bevacizumab in patients with colorectal cancer liver metastases. Moreover, we find that vessel co-option prevails in human breast cancer liver metastases, a setting where results with anti-angiogenic therapy have been disappointing. In our preclinical mechanistic studies, we show that cancer cell motility mediated by the Arp2/3 complex is required for vessel co-option in liver metastases in vivo and that combined inhibition of angiogenesis and vessel co-option is more effective than inhibiting angiogenesis alone in this setting. Vessel co-option is therefore a clinically relevant mechanism of resistance to anti-angiogenic therapy and combined inhibition of angiogenesis and vessel co-option may be a warranted therapeutic strategy.
This article reports the results of a survey of women in legislatures and executives around the world as they were constituted in 1998 (N = 180). The chief hypotheses regarding the factors hindering or facilitating women's access to political representation were tested by multivariate regression models. The regression models juxtaposed a cocktail of institutional, political, cultural, and socioeconomic variables with the following dependent variables: (1) the percentage of MPs who are women and (2) the percentage of cabinet ministers who are women.A number, although not all, of the cited hypotheses were statistically confirmed and more finely quantified. The socioeconomic development of women in society has an effect on the number of women in parliament but not in the cabinet. A country's length of experience with multipartyism and women's enfranchisement correlates with both the legislative and the executive percentage. Certain electoral systems are more women friendly than others. The ideological nature of the party system affects the number of women elected and chosen for cabinet posts. And last, the state's dominant religion, taken as a proxy for culture, also statistically relates to the number of women who will make it to high political office. However, other long-held hypotheses were not proved. The degree of democracy is not a good indicator of the percentage of women who will make it into the legislature or the cabinet, nor is the dichotomy between a presidential or parliamentary system.
Inhibitors of alpha(v)beta(3) and alpha(v)beta(5) integrin have entered clinical trials as antiangiogenic agents for cancer treatment but generally have been unsuccessful. Here we present in vivo evidence that low (nanomolar) concentrations of RGD-mimetic alpha(v)beta(3) and alpha(v)beta(5) inhibitors can paradoxically stimulate tumor growth and tumor angiogenesis. We show that low concentrations of these inhibitors promote VEGF-mediated angiogenesis by altering alpha(v)beta(3) integrin and vascular endothelial growth factor receptor-2 trafficking, thereby promoting endothelial cell migration to VEGF. The proangiogenic effects of low concentrations of RGD-mimetic integrin inhibitors could compromise their efficacy as anticancer agents and have major implications for the use of RGD-mimetic compounds in humans.
For organisms that fly or swim, movement results from the combined effects of the moving medium - air or water - and the organism's own locomotion. For larger organisms, propulsion contributes significantly to progress but the flow usually still provides significant opposition or assistance, or produces lateral displacement ('drift'). Animals show a range of responses to flows, depending on the direction of the flow relative to their preferred direction, the speed of the flow relative to their own self-propelled speed, the incidence of flows in different directions and the proportion of the journey remaining. We here present a classification of responses based on the direction of the resulting movement relative to flow and preferred direction, which is applicable to a range of taxa and environments. The responses adopted in particular circumstances are related to the organisms' locomotory and sensory capacities and the environmental cues available. Advances in biologging technologies and particle tracking models are now providing a wealth of data, which often demonstrate a striking level of convergence in the strategies that very different animals living in very different environments employ when moving in a flow.
CVC4 is the latest version of the Cooperating Validity Checker. A joint project of NYU and U Iowa, CVC4 aims to support the useful feature set of CVC3 and SMT-LIBv2 while optimizing the design of the core system architecture and decision procedures to take advantage of recent engineering and algorithmic advances. CVC4 represents a completely new code base; it is a from-scratch rewrite of CVC3, and many subsystems have been completely redesigned. Additional decision procedures for CVC4 are currently under development, but for what it currently achieves, it is a lighter-weight and higher-performing tool than CVC3. We describe the system architecture, subsystems of note, and discuss some applications and continuing work.
scite is a Brooklyn-based startup that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.