La pensée épistémologique de John Locke

Le travail qui suit, intitulé La pensée épistémologique de John Locke, a comme but de contribuer d'une façon positive à une meilleure compréhension de l'épistémologie lockienne. Nous sommes conscients de ce que nous devons à tous ceux qui ont écrit précédemment sur Locke. A cet égard, nous incluons dans notre bibliographie des livres et des articles que nous avons trouvés utiles dans l'élaboration de ce mémoire. Cependant nous aimerions mentionner ici les quatre livres principaux qui constituent la base de notre documentation. Il s'agit des ouvrages de M. Cranston, John Locke, a Biography; de K. Dewhurst, John Locke, 1632-1704, Physician and Philosopher, A Medi-cal Biography; de J.W. Yolton, Locke and The Compass of Human Understanding;et de F. Duchesneau, L'empirisme de de Locke. Les deux premiers nous ont aidé particulièrement en tant que sources biographiques excellentes et complètes. Les deux autres contiennent une nouvelle approche de la théorie lockienne de la connaissance. Cette approche est fort semblable à la nôtre, qui consiste à tenir compte de la formation scientifique et médicale de Locke ainsi que de ses relations avec la "Royal Society", lorsqu'on analyse sa pensée. Notre travail est divisé en deux parties. La première contient une analyse du climat intellectuel du XVIIe siècle (Chapitre I) et de la formation intellectuelle de John Locke (Chapitre II). Dans la seconde partie, nous faisons une analyse sélective de tous les textes de l'Essay portant sur la connaissance, en essayant de les interpréter à la lumière des données fournies dans la première partie. Nous examinerons, dans des chapitres successifs, l'Épitre au lecteur placée au début de l'Essay, puis la critique que fait Locke de l'innéisme, et enfin ses théories sur l'origine des idées, sur l'usage correct du langage, sur la nature et les limites du savoir. Nous espérons que cette nouvelle enquête, qui met en lumière la formation scientifique de Locke ainsi que sa pensée médicale, suscitera de l'intérêt et pourra aboutir à de nouveaux résultats en ce qui concerne la théorie épistémologique de Locke. Ces résultats, ajoutés à d'autres déjà établis, nous permettront de mieux rendre justice à la pensée de Locke ainsi que de mesurer avec plus d'objectivité l'importance de son apport original

La pensée épistémologique de John Locke

Le travail qui suit, intitulé La pensée épistémologique de John Locke, a comme but de contribuer d'une façon positive à une meilleure compréhension de l'épistémologie lockienne. Nous sommes conscients de ce que nous devons à tous ceux qui ont écrit précédemment sur Locke. A cet égard, nous incluons dans notre bibliographie des livres et des articles que nous avons trouvés utiles dans l'élaboration de ce mémoire. Cependant nous aimerions mentionner ici les quatre livres principaux qui constituent la base de notre documentation. Il s'agit des ouvrages de M. Cranston, John Locke, a Biography; de K. Dewhurst, John Locke, 1632-1704, Physician and Philosopher, A Medi-cal Biography; de J.W. Yolton, Locke and The Compass of Human Understanding;et de F. Duchesneau, L'empirisme de de Locke. Les deux premiers nous ont aidé particulièrement en tant que sources biographiques excellentes et complètes. Les deux autres contiennent une nouvelle approche de la théorie lockienne de la connaissance. Cette approche est fort semblable à la nôtre, qui consiste à tenir compte de la formation scientifique et médicale de Locke ainsi que de ses relations avec la "Royal Society", lorsqu'on analyse sa pensée. Notre travail est divisé en deux parties. La première contient une analyse du climat intellectuel du XVIIe siècle (Chapitre I) et de la formation intellectuelle de John Locke (Chapitre II). Dans la seconde partie, nous faisons une analyse sélective de tous les textes de l'Essay portant sur la connaissance, en essayant de les interpréter à la lumière des données fournies dans la première partie. Nous examinerons, dans des chapitres successifs, l'Épitre au lecteur placée au début de l'Essay, puis la critique que fait Locke de l'innéisme, et enfin ses théories sur l'origine des idées, sur l'usage correct du langage, sur la nature et les limites du savoir. Nous espérons que cette nouvelle enquête, qui met en lumière la formation scientifique de Locke ainsi que sa pensée médicale, suscitera de l'intérêt et pourra aboutir à de nouveaux résultats en ce qui concerne la théorie épistémologique de Locke. Ces résultats, ajoutés à d'autres déjà établis, nous permettront de mieux rendre justice à la pensée de Locke ainsi que de mesurer avec plus d'objectivité l'importance de son apport original

Neutropenia Prediction Based on First-Cycle Blood Counts Using a FOS-3NN Classifier

Background. Delivery of full doses of adjuvant chemotherapy on schedule is key to optimal breast cancer outcomes. Neutropenia is a serious complication of chemotherapy and a common barrier to this goal, leading to dose reductions or delays in treatment. While past research has observed correlations between complete blood count data and neutropenic events, a reliable method of classifying breast cancer patients into low- and high-risk groups remains elusive. Patients and Methods. Thirty-five patients receiving adjuvant chemotherapy for early-stage breast cancer under the care of a single oncologist are examined in this study. FOS-3NN stratifies patient risk based on complete blood count data after the first cycle of treatment. All classifications are independent of breast cancer subtype and clinical markers, with risk level determined by the kinetics of patient blood count response to the first cycle of treatment. Results. In an independent test set of patients unseen by FOS-3NN, 19 out of 21 patients were correctly classified (Fisher’s exact test probability P<0.00023 [2 tailed], Matthews’ correlation coefficient +0.83). Conclusions. We have developed a model that accurately predicts neutropenic events in a population treated with adjuvant chemotherapy in the first cycle of a 6-cycle treatment

A novel role for ezrin in breast cancer angio/lymphangiogenesis

Abstract Introduction Recent evidence suggests that tumour lymphangiogenesis promotes lymph node metastasis, a major prognostic factor for survival of breast cancer patients. However, signaling mechanisms involved in tumour-induced lymphangiogenesis remain poorly understood. The expression of ezrin, a membrane cytoskeletal crosslinker and Src substrate, correlates with poor outcome in a diversity of cancers including breast. Furthermore, ezrin is essential in experimental invasion and metastasis models of breast cancer. Ezrin acts cooperatively with Src in the regulation of the Src-induced malignant phenotype and metastasis. However, it remains unclear if ezrin plays a role in Src-induced tumour angio/lymphangiogenesis. Methods The effects of ezrin knockdown and mutation on angio/lymphangiogenic potential of human MDA-MB-231 and mouse AC2M2 mammary carcinoma cell lines were examined in the presence of constitutively active or wild-type (WT) Src. In vitro assays using primary human lymphatic endothelial cells (hLEC), an ex vivo aortic ring assay, and in vivo tumour engraftment were utilized to assess angio/lymphangiogenic activity of cancer cells. Results Ezrin-deficient cells expressing activated Src displayed significant reduction in endothelial cell branching in the aortic ring assay in addition to reduced hLEC migration, tube formation, and permeability compared to the controls. Intravital imaging and microvessel density (MVD) analysis of tumour xenografts revealed significant reductions in tumour-induced angio/lymphangiogenesis in ezrin-deficient cells when compared to the WT or activated Src-expressing cells. Moreover, syngeneic tumours derived from ezrin-deficient or Y477F ezrin-expressing (non-phosphorylatable by Src) AC2M2 cells further confirmed the xenograft results. Immunoblotting analysis provided a link between ezrin expression and a key angio/lymphangiogenesis signaling pathway by revealing that ezrin regulates Stat3 activation, VEGF-A/-C and IL-6 expression in breast cancer cell lines. Furthermore, high expression of ezrin in human breast tumours significantly correlated with elevated Src expression and the presence of lymphovascular invasion. Conclusions The results describe a novel function for ezrin in the regulation of tumour-induced angio/lymphangiogenesis promoted by Src in breast cancer. The combination of Src/ezrin might prove to be a beneficial prognostic/predictive biomarker for early-stage metastatic breast cancer

Neurocognitive outcomes following fetal exposure to chemotherapy for gestational breast cancer: A Canadian multi-center cohort study

Background: Limited knowledge exists on outcomes of children exposed prenatally to chemotherapy for breast cancer (BC). The purpose of this study was to compare long-term neurocognitive, behavioral, developmental, growth, and health outcomes of children exposed in-utero to chemotherapy for BC. Methods: This is a multi-center matched cross-sectional cohort study involving seven cancer centers across the region of Southern Ontario (Canada), and the Hospital for Sick Children (Toronto, Ontario). Using standardized psychological and behavioral tests, we compared cognitive and behavioral outcomes in children exposed to chemotherapy during pregnancy for BC to age-matched pairs exposed to known non-teratogens. Results: We recruited 17 parent-child pairs and their matched controls. There were more preterm deliveries in the chemotherapy-exposed group compared to controls (p < 0.05). Full Scale IQ of children in the chemotherapy group was significantly confounded by maternal IQ and prematurity. Exposed children born at term were not different in cognitive outcomes. Children from both groups were similar in their developmental milestones, pediatric anthropometric measurements and health problems. There were no cases of autoimmune cytopenia. Conclusions: This is the first Canadian prospective comparative study designed to assess pediatric cognition following prenatal exposure to chemotherapy for BC. Chemotherapy was not found to be neurotoxic in this cohort and did not affect pediatric health. The decision to plan a preterm birth for initiating or continuing chemotherapy treatment must be taken into consideration in context of pediatric implications. While these results may assist in such decision making, replication with a larger sample is needed for more conclusive findings

Intravital imaging reveals systemic ezrin inhibition impedes cancer cell migration and lymph node metastasis in breast cancer

Abstract Background Limited understanding of the cancer biology of metastatic sites is a major factor contributing to poor outcomes in cancer patients. The regional lymph nodes are the most common site of metastasis in most solid cancers and their involvement is a strong predictor of relapse in breast cancer (BC). We have previously shown that ezrin, a cytoskeletal–membrane linker protein, is associated with lymphovascular invasion and promotes metastatic progression in BC. However, the efficacy of pharmacological inhibition of ezrin in blocking cancer cell migration and metastasis remains unexplored in BC. Methods We quantified ezrin expression in a BC tissue microarray (n = 347) to assess its correlation with risk of relapse. Next, we developed a quantitative intravital microscopy (qIVM) approach, using a syngeneic lymphatic reporter mouse tumor model, to investigate the effect of systemic ezrin inhibition on cancer cell migration and metastasis. Results We show that ezrin is expressed at significantly higher levels in lymph node metastases compared to matched primary tumors, and that a high tumor ezrin level is associated with increased risk of relapse in BC patients with regional disease. Using qIVM, we observe a subset of cancer cells that retain their invasive and migratory phenotype at the tumor-draining lymph node. We further show that systemic inhibition of ezrin, using a small molecule compound (NSC668394), impedes the migration of cancer cells in vivo. Furthermore, systemic ezrin inhibition leads to reductions in metastatic burden at the distal axillary lymph node and lungs. Conclusions Our findings demonstrate that the tumor ezrin level act as an independent biomarker in predicting relapse and provide a rationale for therapeutic targeting of ezrin to reduce the metastatic capacity of cancer cells in high-risk BC patients with elevated ezrin expression

Immunohistochemical Assessment of Expression of Centromere Protein—A (CENPA) in Human Invasive Breast Cancer

Abnormal cell division leading to the gain or loss of entire chromosomes and consequent genetic instability is a hallmark of cancer. Centromere protein –A (CENPA) is a centromere-specific histone-H3-like variant gene involved in regulating chromosome segregation during cell division. CENPA is one of the genes included in some of the commercially available RNA based prognostic assays for breast cancer (BCa)—the 70 gene signature MammaPrint® and the five gene Molecular Grade Index (MGISM). Our aim was to assess the immunohistochemical (IHC) expression of CENPA in normal and malignant breast tissue. Clinically annotated triplicate core tissue microarrays of 63 invasive BCa and 20 normal breast samples were stained with a monoclonal antibody against CENPA and scored for percentage of visibly stained nuclei. Survival analyses with Kaplan–Meier (KM) estimate and Cox proportional hazards regression models were applied to assess the associations between CENPA expression and disease free survival (DFS). Average percentage of nuclei visibly stained with CENPA antibody was significantly higher (p = 0.02) in BCa than normal tissue. The 3-year DFS in tumors over-expressing CENPA (>50% stained nuclei) was 79% compared to 85% in low expression tumors ( 60.07; p = 0.06) within our small cohort. To the best of our knowledge, this is the first published report evaluating the implications of increased IHC expression of CENPA in paraffin embedded breast tissue samples. Our finding that increased CENPA expression may be associated with shorter DFS in BCa supports its exploration as a potential prognostic biomarker