Development of Novel Models to Study Ovarian Cancer Stem Cells.

Cancer stem cells (CSC) are rare cells within a tumor reported to be resistant to standard chemotherapy, which can serve to populate the bulk of a tumor with more differentiated daughter cells and potentially contribute to recurrent disease and metastasis. A better understanding of ovarian CSC could lead to novel therapeutic approaches to specifically target CSC. We developed two in vivo models for the study of ovarian CSC. We first generated a human embryonic stem cell derived teratoma (hESCT) tumor model, creating a human tumor microenvironment for CSC growth. We demonstrate that unlike other tumor models, this model has human tumor vessels, a critical part of the CSC niche. These vessels express tumor vascular specific markers (TVMs). We showed the ability of the hESCT model, with human tumor vascular niche, to enhance the engraftment rate of primary human ovarian cancer stem-like cells. Furthermore, this model can be used to test anti-human specific TVM immunotherapeutics. Unfortunately, the study of human CSC can be hampered by heterogeneity of primary tumor samples, long requirements for tumor growth in vivo, and the need for tumor growth in immune-deficient mice. We therefore evaluated CSC in a transgenic murine model of ovarian cancer. Using flow cytometry to characterize a cell line derived from this tumor model we identified that CD24+ cells have a enhanced ability to form tumor spheres, to passage, and to initiate tumors in vivo; hallmarks of CSC. CD24+ cells preferentially express stem cell markers Nanog and c-myc and demonstrate preferential phosphorylation of STAT3. Suggesting an important role for STAT3 in CD24+ CSC, CD24+ cells were preferentially sensitive to inhibition of STAT3 phosphorylation with the JAK2 inhibitor TG101209. Finally, in vivo therapy with TG101209 appeared to decrease tumor metastasis and combined with chemotherapy, prolonged overall survival. Furthermore, preliminary data suggests a role of CD24+ cells in tumor migration. Combined we have characterized two distinct models for the characterization of ovarian CSC targeted therapeutics.PHDCellular & Molecular BiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/107182/1/danivane_1.pd

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Thinking with Sloterdijk. Anthropotechnics, exercise, and education

El presente libro aborda los textos de Peter Sloterdijk en busca de nociones teórico-metodológicas para pensar los problemas de la educación, de la pedagogía y de la filosofía misma desde otras perspectivas. Al asumir la filosofía como una labor de problematización, emergen nociones como antropotécnica y ejercicio para dar forma a nuevas preguntas y a nuevasmaneras de preguntar en el ámbito de la filosofía de la educación. La lectura de los textos de Sloterdijk lleva a escritos que indagan sobre las formas ejercitantes que rodean la enseñanza, el ser maestro, el aprendiz, el aprender y los cuerpos esculpidos por prácticas deportivas, la escritura y la lectura. Mediante estas técnicas, espacios y mecanismos, los seres humanos se hacen lo que son: humanos. Operar con problemas bajo esta perspectiva teórico-metodológica significa explorar las potencialidades de las herramientas para hacer uso de ellas e, incluso, para forjar otras aplicaciones, formas y posibilidades. Sin embargo, este uso debe sustentarse en la revisión, el conocimiento y la preparación de las herramientas, lo cual es el propósito de este libro, a partir de la aproximación al pensamiento de Sloterdijk.This book addresses the texts of Peter Sloterdijk searching for theoreticalmethodological notions to reflect on the problems of education, pedagogy, and philosophy itself from other perspectives. By assuming philosophy as a matter of problematization, notions such as anthropotechnics and exercise emerge to shape new questions and new ways of asking in the field of philosophy of education. Reading Sloterdijk’s texts leads to pieces of writing that inquire into the exercising forms involved in teaching, being a teacher, the learner, the learning, and the bodies sculpted by sports practices, writing, and reading. Through these techniques, spaces and mechanisms, human beings become what they are: human. Working on problems under this theoretical-methodological perspective means exploring the potential of the tools to use them and even to develop otherapplications, forms, and possibilities. However, this use must be supported by the review, the knowledge, and the preparation of tools, which is the purpose of this book, based on the approach to Sloterdijk’s though

I simposio Internacional sobre Investigación en la enseñanza de las ciencias

Edición 202