Nilotinib and Imatinib Are Comparably Effective in Reducing Growth of Human Eosinophil Leukemia Cells in a Newly Established Xenograft Model

We developed a xenograft model of human Chronic Eosinophilic Leukemia (CEL) to study disease progression and remission-induction under therapy with tyrosine kinase inhibitors using imatinib and nilotinib as examples. The FIP1L1/PDGFRA+ human CEL cell lineEOL-1 was injected intravenously into scid mice, and MR imaging and FACS analysis of mouse blood samples were performed to monitor disease development and the effects of imatinib and nilotinib. Organ infiltration was analyzed in detail by immunohistochemistry after sacrifice. All animals developed CEL and within one week of therapy, complete remissions were seen with both imatinib and nilotinib, resulting in reduced total tumor volumes by MR-imaging and almost complete disappearance of EOL-1 cells in the peripheral blood and in tissues. The new model system is feasible for the evaluation of new tyrosine kinase inhibitors and our data suggest that nilotinib may be a valuable additional targeted drug active in patients with FIP1L1/PDGFRA+ CEL

Development of total chloroma volume as determined by MR imaging under imatinib treatment.

<p>(A) Total chloroma volume in mm³ for each animal from the therapy group on days 27 (Therapy d0), 30 (Therapy d3) and 34 (Therapy d7). (B) Total chloroma volume in mm³ for each animal from the placebo group on days 27 (Placebo d0), 30 (Placebo d3) and 34 (Placebo d7). (C) Total chloroma volume in mm³ for the therapy and placebo group before (d0) and after (d7) imatinib treatment. n.s.: non-significant, P = 0.1301; ***: highly significant, P<0.0001.</p

Induction of apoptosis and inhibition of proliferation of EOL-1 cells by imatinib and nilotinib <i>in vitro</i>.

<p>(A) EOL-1 cells were cultured in medium supplemented with 1 nM imatinib (middle panel) or 1 nM nilotinib (right panel) for 48 hours. Fractions of active caspase 3 positive cells were quantified by flow cytometry. One typical experiment from three independent experiments is shown. (B) EOL-1 cells were cultured in the absence (0) or presence of various concentrations of imatinib (left panel) or nilotinib (right panel). After incubation, cells were examined for the percentage of apoptotic cells by light microscopy. Results represent the mean±S.D. from three independent experiments. (C) Dose-dependent effects of imatinib (left panel) and nilotinib (right panel) on proliferation of EOL-1 cells. Cells were kept in control medium (0) or various concentrations of imatinib or nilotinib for 48 hours. Thereafter, ³H-thymidine uptake was measured. Results show the percent 3H-thymidine uptake in drug-exposed cells relative to control (100%) and represent the mean±S.D. from 3 independent experiments.</p

Histology.

<p>The presence of human EOL-1 cells was ascertained by labeling for human HLA-DR (seen in red) in tissue-sections. (A) chloroma, placebo group; (B) former chloroma, therapy group with no viable EOL-1 cells detectable; (C) spleen, placebo; (D) spleen, therapy, with no detectable EOL-1 cells; (E) lung, placebo; (E) lung, therapy, with no detectable EOL-1 cells; (F) liver, placebo, massive EOL-1 infiltrates; (G) spine, placebo, with EOL-1 infiltrates in bone marrow.</p

MR imaging.

<p>MR images of one mouse each of the therapy (A, imatinib) and placebo group (B). Coronar (left panels) and sagittal (left panels) T2 images of EOL-1 bearing scid mice on days 27 (d0 of treatment), 30 (d3 of treatment) and 34 (d7 of treatment). In the selected plane, remission (therapy) or growth (placebo) of a large abdominal chloroma can be observed (arrows). Chloroma is in complete remission on day 34 under imatinib treatment (A, d7).</p

Flow Cytometry of blood samples.

<p>(A) EOL-1 cells grown in cell culture express HLA-DR: Histogram for anti-HLA-DR staining (filled curve) versus isotype control (open curve). (B) EOL-1 cells could also be detected in mouse blood after xenotransplantation of EOL-1 cells. Staining of EOL-1 cells with anti HLA-DR from the blood of mouse pB4 on day 35 after erythrolysis is shown. Human EOL-1 cells can clearly be distinguished from murine leukocytes by size (forward scatter, FSC) and HLA-DR positivity (FL2-H). EOL-1 cells (upper right quadrant) constitute 22.2% of non-erythrocyte cells in mouse blood. (C, D) Percentage of EOL-1 cells in mouse leukocytes (part B of the experiment) under imatinib treatment for the placebo group (C) and the therapy group (D). Values are shown for day 28 (d28, black square), day 31 (d31, grey triangle) and day 35 (d35, black triangle). Missing value for a mouse on a given day indicates that the mouse was no longer alive at this point of time.</p

The National Student Survey: validation in Portuguese medical students

The UK National Student Survey (NSS) is a sound and widely used instrument for assessing students’ academic experiences. We aimed to translate the NSS for Portuguese students and to validate the instrument in a sample of medical undergraduates. The research team translated and adapted the NSS for Portuguese students (NSS-P). The survey was administered on an online platform to 1,256 final-year students at eight Portuguese medical schools. A total of 329 medical students (69.9% female) replied to the NSS-P, a response rate of 26.2%. Confirmatory factor analysis showed that the original six-factor structure had an adequate fit to the data. Adequate internal consistency was observed for all the subscales. Medium to large correlations were found among all the subscale scores and between the subscale scores and the students’ overall satisfaction. Multiple regression showed that the scores on the Teaching, Organization and Management and Personal Development subscales significantly predicted the students’ overall satisfaction. Approximately 64% of the students reported being satisfied with the quality of their courses. Significant differences among the medical schools in their NSS-P scores were found. The NSS-P is a valid and reliable measure for assessing medical students’ perceptions of academic quality

Anthropology in Portugal

Portuguese anthropology had its beginnings with the work of late nineteenth‐century folklorists, ethnographers, linguists, archaeologists, and physical anthropologists, in tune with international debates and in parallel with their European counterparts. In the twentieth century, physical anthropology had modest yet uninterrupted development whereas the social and cultural components of the discipline had a fragmented history, mostly for political reasons. There were ethnographic works conducted in Portugal and its colonies but researchers could not expand the analysis into some of the social issues and political contexts directly related to the subject of study. After the end of the authoritarian regime in 1974, social and cultural anthropology made up for lost time and dozens of works on Portugal were conducted in the 1980s and beyond. By the end of the twentieth century, the field was vibrant, diverse, and international, with hundreds of graduates and a large number of research projects, books, and journals.info:eu-repo/semantics/publishedVersio

Characterisation of microbial attack on archaeological bone

As part of an EU funded project to investigate the factors influencing bone preservation in the archaeological record, more than 250 bones from 41 archaeological sites in five countries spanning four climatic regions were studied for diagenetic alteration. Sites were selected to cover a range of environmental conditions and archaeological contexts. Microscopic and physical (mercury intrusion porosimetry) analyses of these bones revealed that the majority (68%) had suffered microbial attack. Furthermore, significant differences were found between animal and human bone in both the state of preservation and the type of microbial attack present. These differences in preservation might result from differences in early taphonomy of the bones. © 2003 Elsevier Science Ltd. All rights reserved

Paediatric COVID-19 mortality: a database analysis of the impact of health resource disparity

Background The impact of the COVID-19 pandemic on paediatric populations varied between high-income countries (HICs) versus low-income to middle-income countries (LMICs). We sought to investigate differences in paediatric clinical outcomes and identify factors contributing to disparity between countries.Methods The International Severe Acute Respiratory and Emerging Infections Consortium (ISARIC) COVID-19 database was queried to include children under 19 years of age admitted to hospital from January 2020 to April 2021 with suspected or confirmed COVID-19 diagnosis. Univariate and multivariable analysis of contributing factors for mortality were assessed by country group (HICs vs LMICs) as defined by the World Bank criteria.Results A total of 12 860 children (3819 from 21 HICs and 9041 from 15 LMICs) participated in this study. Of these, 8961 were laboratory-confirmed and 3899 suspected COVID-19 cases. About 52% of LMICs children were black, and more than 40% were infants and adolescent. Overall in-hospital mortality rate (95% CI) was 3.3% [=(3.0% to 3.6%), higher in LMICs than HICs (4.0% (3.6% to 4.4%) and 1.7% (1.3% to 2.1%), respectively). There were significant differences between country income groups in intervention profile, with higher use of antibiotics, antivirals, corticosteroids, prone positioning, high flow nasal cannula, non-invasive and invasive mechanical ventilation in HICs. Out of the 439 mechanically ventilated children, mortality occurred in 106 (24.1%) subjects, which was higher in LMICs than HICs (89 (43.6%) vs 17 (7.2%) respectively). Pre-existing infectious comorbidities (tuberculosis and HIV) and some complications (bacterial pneumonia, acute respiratory distress syndrome and myocarditis) were significantly higher in LMICs compared with HICs. On multivariable analysis, LMIC as country income group was associated with increased risk of mortality (adjusted HR 4.73 (3.16 to 7.10)).Conclusion Mortality and morbidities were higher in LMICs than HICs, and it may be attributable to differences in patient demographics, complications and access to supportive and treatment modalities