Stability, Breadth and Guidance

Much recent work on explanation in the interventionist tradition emphasizes the explanatory value of stable causal generalizations – i.e., causal generalizations that remain true in a wide range of background circumstances. We argue that two separate explanatory virtues are lumped together under the heading of `stability’. We call these two virtues breadth and guidance respectively. In our view, these two virtues are importantly distinct, but this fact is neglected or at least under-appreciated in the literature on stability. We argue that an adequate theory of explanatory goodness should recognize breadth and guidance as distinct virtues, as breadth and guidance track different ideals of explanation, satisfy different cognitive and pragmatic ends, and play different theoretical roles in (for example) helping us understand the explanatory value of mechanisms. Thus keeping track of the distinction between these two forms of stability yields a more accurate and perspicuous picture of the role that stability considerations play in explanation

Multi-epoch VLBI of a double maser super burst

In a rare and spectacular display, two well-known massive star forming regions, W49N and G25.65+1.05, recently underwent maser 'super burst' - their fluxes suddenly increasing above 30,000 and 18,000 Jy, respectively, reaching several orders of magnitude above their usual values. In quick-response, ToO observations with the EVN, VLBA and KaVA were obtained constituting a 4 week campaign - producing a high-cadence multi-epoch VLBI investigation of the maser emission. The combination of high-resolution, polarisation and flux monitoring during the burst provides one of the best accounts, to date, of the maser super burst phenomenon, aiding their use as astrophysical tools. These proceedings contain the preliminary results of our campaign

Circulating tumor DNA tracking through driver mutations as a liquid biopsy-based biomarker for uveal melanoma

© The Author(s). 2021 Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background: Uveal melanoma (UM) is the most common intraocular tumor in adults. Despite good primary tumor control, up to 50% of patients develop metastasis, which is lethal. UM often presents asymptomatically and is usually diagnosed by clinical examination and imaging, making it one of the few cancer types diagnosed without a biopsy. Hence, alternative diagnostic tools are needed. Circulating tumor DNA (ctDNA) has shown potential as a liquid biopsy target for cancer screening and monitoring. The aim of this study was to evaluate the feasibility and clinical utility of ctDNA detection in UM using specific UM gene mutations. Methods: We used the highly sensitive digital droplet PCR (ddPCR) assay to quantify UM driver mutations (GNAQ, GNA11, PLCβ4 and CYSTLR2) in cell-free DNA (cfDNA). cfDNA was analyzed in six well established human UM cell lines with known mutational status. cfDNA was analyzed in the blood and aqueous humor of an UM rabbit model and in the blood of patients. Rabbits were inoculated with human UM cells into the suprachoroidal space, and mutated ctDNA was quantified from longitudinal peripheral blood and aqueous humor draws. Blood clinical specimens were obtained from primary UM patients (n = 14), patients presenting with choroidal nevi (n = 16) and healthy individuals (n = 15). Results: The in vitro model validated the specificity and accuracy of ddPCR to detect mutated cfDNA from UM cell supernatant. In the rabbit model, plasma and aqueous humor levels of ctDNA correlated with tumor growth. Notably, the detection of ctDNA preceded clinical detection of the intraocular tumor. In human specimens, while we did not detect any trace of ctDNA in healthy controls, we detected ctDNA in all UM patients. We observed that UM patients had significantly higher levels of ctDNA than patients with nevi, with a strong correlation between ctDNA levels and malignancy. Noteworthy, in patients with nevi, the levels of ctDNA highly correlated with the presence of clinical risk factors. Conclusions: We report, for the first time, compelling evidence from in vitro assays, and in vivo animal model and clinical specimens for the potential of mutated ctDNA as a biomarker of UM progression. These findings pave the way towards the implementation of a liquid biopsy to detect and monitor UM tumors.info:eu-repo/semantics/publishedVersio