Normative explanation unchained

Normative theories aim to explain why things have the normative features they have. This paper argues that, contrary to some plausible existing views, one important kind of normative explanations which first‐order normative theories aim to formulate and defend can fail to transmit downward along chains of metaphysical determination of normative facts by non‐normative facts. Normative explanation is plausibly subject to a kind of a justification condition whose satisfaction may fail to transmit along the relevant kind of metaphysical hierarchy. A broader aim of the paper is to contribute to systematic theorizing about normative explanation: whereas there has been a great deal of work on scientific explanation, there has been little by way of systematic exploration of what sort of explanations normative theories aim to formulate and defend

Reasons why in normative explanation

Normative explanations, which specify why things have the normative features they do, are ubiquitous in normative theory and ordinary thought. But there is much less work on normative explanation than on scientific or metaphysical explanation. Skow [2016. Reasons Why. Oxford: Oxford University Press] argues that a complete answer to the question why some fact Q occurs consists in all of the reasons why Q occurs. This paper explores this theory as a case study of a general theory that promises to offer us a grip on normative explanation which is independent of particular normative theories. I first argue that the theory doesn't give an adequate account of certain enablers of reasons which are important in normative explanation. I then formulate and reject three responses on behalf of the theory. But I suggest that since theories of this general sort have the right kind of resources to illuminate how normative explanation might be similar to and different from explanations in other domains, they nonetheless merit further exploration by normative theorists

Immune cell profiles of metastatic HER2-positive breast cancer patients according to the sites of metastasis

Purpose Recent works have characterized that metastatic site can affect the tumour immune profiles and efficiency of cancer immunotherapies. The prognosis of HER2-positive breast cancer is associated with the characteristics of the tumour immune microenvironment, with immunological cells playing a central role in efficiency of HER2-targeted antibodies. Here we investigated the prognostic significance of different metastatic sites and their correlation to tumour immune profiles in HER2-positive breast cancer treated with trastuzumab. Methods We collected all (n = 54) HER2-positive metastatic breast cancer patients treated with trastuzumab containing regimens at Oulu University Hospital 2009-2014. Pathological and clinical data were collected from electronic patient records. The tumour immune profiles were analysed from pre-treatment primary tumours using well-characterized immunological markers with computer-assisted immune cell counting. Results Of the metastatic sites, only liver metastases were associated with poor prognosis (hazard ratio 1.809, 95% confidence interval 1.004-3.262), especially when presented as the primary site of metastases. Of the other sites, pulmonary metastases characterized a patient profile with trend to improved survival. Of the studied tumour immunological markers, patients with liver metastases had low densities of CD3(+) T cells (p = 0.030) and M1-like macrophages in their primary tumours (p = 0.025). Of the other studied markers and sites, patients with pulmonary metastases had low STAB1(+)-immunosuppressive macrophage density in their primary tumours. Conclusion Our results suggest that the site of metastasis is associated with prognosis in HER2-positive breast cancer, highlighted by the poor prognosis of liver metastases. Furthermore, liver metastases were associated with adverse tumour immune cell profiles.Peer reviewe

Immune cell profiles of metastatic HER2-positive breast cancer patients according to the sites of metastasis

Purpose Recent works have characterized that metastatic site can affect the tumour immune profiles and efficiency of cancer immunotherapies. The prognosis of HER2-positive breast cancer is associated with the characteristics of the tumour immune microenvironment, with immunological cells playing a central role in efficiency of HER2-targeted antibodies. Here we investigated the prognostic significance of different metastatic sites and their correlation to tumour immune profiles in HER2-positive breast cancer treated with trastuzumab. Methods We collected all (n = 54) HER2-positive metastatic breast cancer patients treated with trastuzumab containing regimens at Oulu University Hospital 2009-2014. Pathological and clinical data were collected from electronic patient records. The tumour immune profiles were analysed from pre-treatment primary tumours using well-characterized immunological markers with computer-assisted immune cell counting. Results Of the metastatic sites, only liver metastases were associated with poor prognosis (hazard ratio 1.809, 95% confidence interval 1.004-3.262), especially when presented as the primary site of metastases. Of the other sites, pulmonary metastases characterized a patient profile with trend to improved survival. Of the studied tumour immunological markers, patients with liver metastases had low densities of CD3(+) T cells (p = 0.030) and M1-like macrophages in their primary tumours (p = 0.025). Of the other studied markers and sites, patients with pulmonary metastases had low STAB1(+)-immunosuppressive macrophage density in their primary tumours. Conclusion Our results suggest that the site of metastasis is associated with prognosis in HER2-positive breast cancer, highlighted by the poor prognosis of liver metastases. Furthermore, liver metastases were associated with adverse tumour immune cell profiles.Peer reviewe

Incidence and management of patients with colorectal cancer and synchronous and metachronous colorectal metastases : a population-based study

Background This population-based study aimed to examine the incidence, patterns and results of multimodal management of metastatic colorectal cancer. Methods A retrospective population-based study was conducted on patients with metastatic colorectal cancer in Central Finland in 2000-2015. Clinical and histopathological data were retrieved and descriptive analysis was conducted to determine the pattern of metastatic disease, defined as synchronous, early metachronous (within 12 months of diagnosis of primary disease) and late metachronous (more than 12 months after diagnosis). Subgroups were compared for resection and overall survival (OS) rates. Results Of 1671 patients, 296 (17.7 per cent) had synchronous metastases, and 255 (19.6 per cent) of 1302 patients with resected stage I-III tumours developed metachronous metastases (94 early and 161 late metastases). Liver, pulmonary and intraperitoneal metastases were the most common sites. The commonest metastatic patterns were a combination of liver and lung metastases. The overall metastasectomy rate for patients with synchronous metastases was 16.2 per cent; in this subgroup, 3- and 5-year OS rates after any resection were 63 and 44 per cent respectively, compared with 7.1 and 3.3 per cent following no resection (P <0.001). The resection rate was higher for late than for early metachronous disease (28.0versus17 per cent respectively;P = 0.048). Three- and 5-year OS rates after any resection of metachronous metastases were 78 and 62 per cent respectivelyversus42.1 and 18.2 per cent with no metastasectomy (P <0.001). Similarly, 3- and 5-year OS rates after any metastasectomy for early metachronous metastases were 57 and 50 per centversus84 and 66 per cent for late metachronous metastases (P = 0.293). Conclusion The proportion of patients with metastatic colorectal cancer was consistent with that in earlier population-based studies, as were resection rates for liver and lung metastases and survival after resection. Differentiation between synchronous, early and late metachronous metastases can improve assessment of resectability and survival.Peer reviewe

Prognostic significance of spatial and density analysis of T lymphocytes in colorectal cancer

Background Although high T cell density is a strong favourable prognostic factor in colorectal cancer, the significance of the spatial distribution of T cells is incompletely understood. We aimed to evaluate the prognostic significance of tumour cell-T cell co-localisation and T cell densities. Methods We analysed CD3 and CD8 immunohistochemistry in a study cohort of 983 colorectal cancer patients and a validation cohort (N = 246). Individual immune and tumour cells were identified to calculate T cell densities (to derive T cell density score) and G-cross function values, estimating the likelihood of tumour cells being co-located with T cells within 20 mu m radius (to derive T cell proximity score). Results High T cell proximity score associated with longer cancer-specific survival in both the study cohort [adjusted HR for high (vs. low) 0.33, 95% CI 0.20-0.52, P-trend < 0.0001] and the validation cohort [adjusted HR for high (vs. low) 0.15, 95% CI 0.05-0.45, P-trend < 0.0001] and its prognostic value was independent of T cell density score. Conclusions The spatial point pattern analysis of tumour cell-T cell co-localisation could provide detailed information on colorectal cancer prognosis, supporting the value of spatial measurement of T cell infiltrates as a novel, robust tumour-immune biomarker.Peer reviewe

Influence of disorder on antidot vortex Majorana states in 3D topological insulators

Topological insulator/superconductor two-dimensional heterostructures are promising candidates for realizing topological superconductivity and Majorana modes. In these systems, a vortex pinned by a pre-fabricated antidot in the superconductor can host Majorana zero-energy modes (MZMs), which are exotic quasiparticles that may enable quantum information processing. However, a major challenge is to design devices that can manipulate the information encoded in these MZMs. One of the key factors is to create small and clean antidots, so that the MZMs, localized in the vortex core, have a large gap to other excitations. If the antidot is too large or too disordered, the level spacing for the subgap vortex states may become smaller than temperature. In this paper, we numerically investigate the effects of disorder, chemical potential, and antidot size on the subgap vortex spectrum, using a two-dimensional effective model of the topological insulator surface. Our model allows us to simulate large system sizes with vortices up to 1.8 $\mu$m in diameter. We also compare our disorder model with the transport data from existing experiments. We find that the spectral gap can exhibit a non-monotonic behavior as a function of disorder strength, and that it can be tuned by applying a gate voltage.Comment: 10 pages, 6 figure

Human pluripotent stem cell-derived cells endogenously expressing follicle-stimulating hormone receptors : modeling the function of an inactivating receptor mutation

Follicle-stimulating hormone (FSH) is crucial in the development and regulation of reproductive functions. The actions of human FSH and its receptor (FSHR) and mutations therein have mainly been studied using in vivo models, primary cells, cancer cells and cell lines ectopically expressing the FSHR. To allow studies of endogenous FSHR function in vitro, we differentiated FSHR-expressing cells from human pluripotent stem cells. FSH stimulation of the wild-type (WT), but not the inactivating Finnish founder mutant (A189V) receptor, activated the canonical cyclic adenosine monophosphate (cAMP)-dependent signaling pathway and downstream mediators. To investigate protein-protein interaction partners of FSHR at resting state and upon FSH stimulation, we expressed FSHR in HEK293 cells followed by affinity purification mass spectrometry analyses. We found 19 specific high-confidence interacting proteins for WT FSHR and 14 for A189V FSHR, several of which have been linked to infertility. Interestingly, while only WT FSHR interacted with FSH, insulin-like growth factor 1 receptor (IGF1R), for example, interacted with both WT and A189V FSHR upon FSH stimulation. In conclusion, our protocol allows detailed studies of FSH action and disease modeling in human cells endogenously expressing FSHR.Peer reviewe