Reperfusion injuries after a period of cardiac ischemia are known to lead to pathological modifications or even death. Among the different therapeutic options proposed, adenosine, a small molecule ...with platelet anti-aggregate and anti-inflammatory properties, has shown encouraging results in clinical trials. However, its clinical use is severely limited because of its very short half-life in the bloodstream. To overcome this limitation, we have proposed a strategy to encapsulate adenosine in squalene-based nanoparticles (NPs), a biocompatible and biodegradable lipid. Thus, the aim of this study was to assess, whether squalene-based nanoparticles loaded with adenosine (SQAd NPs) were cardioprotective in a preclinical cardiac ischemia/reperfusion model. Obtained SQAd NPs were characterized in depth and further evaluated in vitro. The NPs were formulated with a size of about 90 nm and remained stable up to 14 days at both 4 °C and room temperature. Moreover, these NPs did not show any signs of toxicity, neither on HL-1, H9c2 cardiac cell lines, nor on human PBMC and, further retained their inhibitory platelet aggregation properties. In a mouse model with experimental cardiac ischemia-reperfusion, treatment with SQAd NPs showed a reduction of the area at risk, as well as of the infarct area, although not statistically significant. However, we noted a significant reduction of apoptotic cells on cardiac tissue from animals treated with the NPs. Further studies would be interesting to understand how and through which mechanisms these nanoparticles act on cardiac cells.
While Asian Americans and Pacific Islanders (AAPIs) are growing faster than any other racial group in the United States, they are all but invisible in higher education, and generally ignored in the ...research literature, and thus greatly misrepresented and misunderstood.
This book presents disaggregated data to unmask important academic achievement and other disparities within the population, and offers new insights that promote more authentic understandings of the realities masked by the designation of AAPI. In offering new perspectives, conceptual frameworks, and empirical research by seasoned and emerging scholars, this book both makes a significant contribution to the emerging knowledge base on AAPIs, and identifies new directions for future scholarship on this population.
Its overarching purpose is to provide policymakers, practitioners, and researchers in higher education with the information they need to serve an increasingly important segment of their student populations.
This study aims to examine the negative effect of unemployment on mental health among 2,762 veterans and 45,095 civilians aged 18 to 50 years. The data were from the 2012 Behavioral Risk Factor ...Surveillance System (BRFSS) survey. We used ordinary least squares regression to test the interaction association between employment status and veteran/civilian status with mental health status. Findings revealed that long-term unemployed veterans had a significantly greater number of days with poor mental health than long-term unemployed civilians. The study highlights the need for future research concerning the negative effects of long-term unemployment on veterans' mental health as well as the reciprocal relationships between mental health and occupational functioning for veterans. The findings challenge researchers to question the meanings that are associated with employment status for veterans as compared to those of their civilian peers. In addition to this, the study raises the need for further exploration into the topics of identity, self-perception, and the notion often present in the military/veteran culture that there is "dignity in labor."
Radioactive seed localization (RSL) uses a titanium seed labeled with iodine-125 energy for surgery of nonpalpable breast lesions. RSL facilitates radiology–surgery scheduling and allows for improved ...oncoplasty compared with wire localization (WL). The purpose of this work was to compare the 2 techniques.
We performed a retrospective study of all breast lesions operated with RSL between February 2013 and March 2015 at our university institution, and compared with an equivalent number of surgeries performed with a single WL. Imaging and pathology reports were reviewed for information on guidance mode, accuracy of targeting, nature of excised lesion, size and volume of surgical specimen, status of margins, and reinterventions.
A total of 254 lesions (247 women) were excised with RSL and compared with 257 lesions (244 women) whose surgery was guided by WL. Both groups were comparable in lesion pathology, guidance mode for RSL or WL positioning, and accuracy of targeting (98% correct). Mean delay between biopsy and surgery was 84 days for RSL versus 103 after WL (P = .04). No differences were noted after RSL or WL for surgical specimen mean weight, largest diameter, and volume excised. For malignancies, the rate of positive margins was comparable (2.8%-3%), with 5 of 10 women in the RSL group who underwent a second surgery displaying residual malignancy compared with 3 of 9 women in the WL group.
RSL is safe and accurate, and has comparable surgical endpoints to WL. Because RSL offers flexible scheduling and facilitated oncoplasty, RSL may replace WL for resection of nonpalpable single breast lesions.
Le repérage au grain radioactif consiste à utiliser un grain de titane marqué à l'iode 125 dans le cadre d'interventions chirurgicales visant des lésions mammaires non palpables. Le repérage au grain radioactif facilite la coordination des rendez-vous en radiologie et en chirurgie. Il offre aussi de meilleures possibilités d'oncoplastie que le repérage à l'hameçon. Les présents travaux avaient pour objectif de comparer les deux techniques.
Nous avons effectué une analyse rétrospective de toutes les lésions mammaires ayant fait l'objet d'une intervention chirurgicale avec repérage au grain radioactif entre février 2013 et mars 2015 au sein de notre établissement universitaire. Nous les avons ensuite comparées à un nombre égal de lésions ayant fait l'objet d'une intervention chirurgicale avec repérage à un seul hameçon. Les rapports d'imagerie et de pathologie ont été examinés afin de recueillir des renseignements sur le mode de guidage, la précision du repérage, la nature des lésions excisées, la taille et le volume des prélèvements chirurgicaux, l'état des marges chirurgicales et les reprises chirurgicales.
Au total, 254 lésions (247 femmes) excisées à l'aide d'un repérage au grain radioactif ont été comparées à 257 lésions (244 femmes) excisées à l'aide d'un repérage à l'hameçon. Les deux groupes affichaient des caractéristiques semblables sur le plan de l'analyse pathologique des lésions, du mode de guidage pour le positionnement du grain radioactif ou de l'hameçon, et de la précision du repérage (exactitude à 98 %). Le délai moyen entre la biopsie et l'intervention chirurgicale se chiffrait à 84 jours pour le repérage au grain radioactif, contre 103 jours après le repérage à l'hameçon (P = 0,04). Aucune différence n'a été relevée après repérage au grain radioactif ou à l'hameçon au chapitre du poids moyen, du diamètre le plus grand et du volume excisé des prélèvements chirurgicaux. En ce qui concerne les lésions malignes, les taux de marges chirurgicales positives étaient comparables (de 2,8 à 3 %). Cinq des 10 femmes du groupe de repérage au grain radioactif ayant subi une deuxième intervention ont affiché des lésions malignes résiduelles, contre 3 chez les 9 femmes du groupe de repérage à l'hameçon.
Le repérage au grain radioactif est sécuritaire et précis, et ses indicateurs de résultats chirurgicaux sont comparables à ceux du repérage à l'hameçon. Le repérage au grain radioactif pourrait remplacer le repérage à l'hameçon pour la résection de lésions non palpables à un sein puisqu'il offre plus de souplesse pour la planification des rendez-vous et facilite l'oncoplastie.
Objective
To develop and test the validity of an objective structured assessment of technical skill (OSATS) tool for vertex presentation delivery simulations.
Materials and methods
Monocentric ...prospective study conducted in the Department of Gynecology, Obstetrics, Fetal Medicine and Reproductive Biology at the University Hospital of Nice. The study consisted of two parts, the development of the scoring system and then its validation. Experts in obstetrics from several academic institutions and private French hospitals were invited to participate in the development phase of the scoring system. For the validation phase, we formed a group of 20 novices and a group of 20 experts, who performed a childbirth simulation according to a standard scenario. Each participant was filmed and then two experts evaluated their performance with the OSATS score by viewing anonymized videos.
Results
The scores obtained by the expert group were significantly higher than those of the novice group, whether we compared the total score or each part of the score (task-specific or global) independently. We obtained a
p
value of 0.03 for the total score,
p
= 0.036 for the task-specific score, and
p
< 0.001 for the overall score.
Conclusion
The OSATS score developed in this study for vertex presentation delivery is a reliable mean to assess the medical students’ competence in procedural skills using a simulator.
The outcome of children with Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukaemia significantly improved with the combination of imatinib and intensive chemotherapy. We aimed ...to investigate the efficacy of dasatinib, a second-generation ABL-class inhibitor, with intensive chemotherapy in children with newly diagnosed Ph-positive acute lymphoblastic leukaemia.
CA180-372/COG AALL1122 was a joint Children's Oncology Group (COG) and European intergroup study of post-induction treatment of Ph-positive acute lymphoblastic leukaemia (EsPhALL) open-label, single-arm, phase 2 study. Eligible patients (aged >1 year to <18 years) with newly diagnosed Ph-positive acute lymphoblastic leukaemia and performance status of at least 60% received EsPhALL chemotherapy plus dasatinib 60 mg/m
orally once daily from day 15 of induction. Patients with minimal residual disease of at least 0·05% after induction 1B or who were positive for minimal residual disease after the three consolidation blocks were classified as high risk and allocated to receive haematopoietic stem-cell transplantation (HSCT) in first complete remission. The remaining patients were considered standard risk and received chemotherapy plus dasatinib for 2 years. The primary endpoint was the 3-year event-free survival of dasatinib plus chemotherapy compared with external historical controls. The trial was considered positive if one of the following conditions was met: superiority over chemotherapy alone in the AIEOP-BFM 2000 high-risk group; or non-inferiority (with a margin of -5%) or superiority to imatinib plus chemotherapy in the EsPhALL 2010 cohort. All participants who received at least one dose of dasatinib were included in the safety and efficacy analyses. This trial was registered with ClinicalTrials.gov, NCT01460160, and recruitment is closed.
Between March 13, 2012, and May 27, 2014, 109 patients were enrolled at 69 sites (including 51 COG sites in the USA, Canada, and Australia, and 18 EsPhALL sites in Italy and the UK). Three patients were ineligible and did not receive dasatinib. 106 patients were treated and included in analyses (49 46% female and 57 54% male; 85 80% White, 13 12% Black or African American, five 5% Asian, and three 3% other races; 24 23% Hispanic or Latino ethnicity). All 106 treated patients reached complete remission; 87 (82%) were classified as standard risk and 19 (18%) met HSCT criteria and were classified as high risk, but only 15 (14%) received HSCT in first complete remission. The 3-year event-free survival of dasatinib plus chemotherapy was superior to chemotherapy alone (65·5% 90% Clopper-Pearson CI 57·7 to 73·7 vs 49·2% 38·0 to 60·4; p=0·032), and was non-inferior to imatinib plus chemotherapy (59·1% 51·8 to 66·2, 90% CI of the treatment difference: -3·3 to 17·2), but not superior to imatinib plus chemotherapy (65·5% vs 59·1%; p=0·27). The most frequent grade 3-5 adverse events were febrile neutropenia (n=93) and bacteraemia (n=21). Nine remission deaths occurred, which were due to infections (n=5), transplantation-related (n=2), due to cardiac arrest (n=1), or had an unknown cause (n=1). No dasatinib-related deaths occurred.
Dasatinib plus EsPhALL chemotherapy is safe and active in paediatric Ph-positive acute lymphoblastic leukaemia. 3-year event-free survival was similar to that of previous Ph-positive acute lymphoblastic leukaemia trials despite the limited use of HSCT in first complete remission.
Bristol Myers Squibb.
Abstract
Drug discovery and toxicity studies require access to methods and technologies that can provide comprehensive evaluation of the types of cellular impacts caused by anti-cancer compounds. In ...particular, there is growing emphasis on the study of mitochondrial toxicity at an early phase of compound evaluation and its relations to multiple cell death processes that include apoptotic cell death, caspase-independent death and autophagic processes. The study of oxidative stress and its relation to cell death pathways also provides insights into mechanism of cellular stress. In this study we have used multiparametric assays that correlate changes in mitochondria with different cell health parameters using plate-based microcapillary cytometry on guava easyCyte platforms. Compound screening studies were performed on Jurkats (suspension) and HeLa adherent cell lines using an array of over 80 compounds to study inter-relationships between mitochondrial perturbations and different cell health parameters. Compounds were evaluated for mitochondrial depolarization and relationship to apoptosis and cell death; mitochondrial perturbations with regard to caspase levels were also evaluated; and the parallel connection between mitochondrial superoxide stress and apoptosis was also studied. Our studies identified several hit compounds, examples of which included compounds like gambogic acid, thimerosal, camtothecin, antimycin A, staurosporine, celastrol and juglone which caused significant mitochondrial perturbation and apoptosis. In addition, compounds such as antimycin A and staurosporine caused significant oxidative stress. Simplified and rapid screening assays that provide information on multiple parameters of cellular stress and apoptosis can greatly benefit the identification of hit compounds and provide a more comprehensive understanding of the mechanism of compound toxicity.
Citation Format: Katherine Gillis, Julie Clor, Kimvan Tran, Asima Khan, Kamala Tyagarajan. Multiparametric approaches to evaluate mitochondrial toxicity, oxidative stress and apoptosis in drug discovery studies. abstract. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1738. doi:10.1158/1538-7445.AM2013-1738
Cerebral malaria (CM) is a major cause of death in severe Plasmodium falciparum malaria. We present quantitative electron microscopic findings of the neuropathologic features in a prospective ...clinicopathologic study of 65 patients who died of severe malaria in Thailand and Vietnam. Sequestration of parasitized red blood cells (PRBCs) in cerebral microvessels was significantly higher in the brains of patients with CM compared with those with non-cerebral malaria (NCM) in all parts of the brain (cerebrum, cerebellum, and medulla oblongata). There was a hierarchy of sequestration with more in the cerebrum and cerebellum than the brain stem. When cerebral sequestration was compared with the peripheral parasitemia pre mortem, there were 26.6 times more PRBCs in the brain microvasculature than in the peripheral blood. The sequestration index was significantly higher in CM patients (median = 50.7) than in NCM patients (median = 6.9) (P = 0.042). The degree of sequestration of P. falciparum-infected erythrocytes in cerebral microvessels is quantitatively associated with pre-mortem coma.
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