The complexity of human tissue fluid precludes timely identification of cancer biomarkers by immunoassay or mass spectrometry. An increasingly attractive strategy is to primarily enrich extracellular ...vesicles (EVs) released from cancer cells in an accelerated manner compared to normal cells. The Vn96 peptide was herein employed to recover a subset of EVs released into the media from cellular models of breast cancer. Vn96 has affinity for heat shock proteins (HSPs) decorating the surface of EVs. Reflecting their cells of origin, cancer EVs displayed discrete differences from those of normal phenotype. GELFrEE LC/MS identified an extensive proteome from all three sources of EVs, the vast majority having been previously reported in the ExoCarta database. Pathway analysis of the Vn96-affinity proteome unequivocally distinguished EVs from tumorigenic cell lines (SKBR3 and MCF-7) relative to a non-tumorigenic source (MCF-10a), particularly with regard to altered metabolic enzymes, signaling, and chaperone proteins. The protein data sets provide valuable information from material shed by cultured cells. It is probable that a vast amount of biomarker identities may be collected from established and primary cell cultures using the approaches described here.
Triathletes represent a growing and unique population of individuals willing to endure significant mental and physical stress to practice the sport they love. However, little is known about the pain ...experienced while training for and competing in a triathlon and how psychological factors influence this experience. This study will assess pain experienced by triathletes in training and competition, and investigate the association between pain catastrophizing and pain expectations with triathlon pain intensity and pain unpleasantness.
In this observational study, a sample of 261 triathletes completed two online surveys before and after participating in a triathlon.
Moderate levels of pain intensity and pain unpleasantness were reported during training and competition. Pain catastrophizing was positively associated with expected and actual triathlon pain unpleasantness, but not with pain intensity. Expected pain intensity was also significantly associated with pain intensity experienced while competing, whereas expected pain unpleasantness was significantly related to both triathlon pain intensity and unpleasantness. Finally, regression analysis revealed pain catastrophizing and pain expectations to be unique predictors of triathlon pain intensity and pain unpleasantness.
This study highlights the important role of psychological factors in triathletes' experience of pain and could eventually help tailor interventions aimed at improving the practice of triathlon.
•Moderate levels of pain intensity and pain unpleasantness are reported by triathletes, both during training and competition.•Pain catastrophizing and pain expectations are unique predictors of triathlon pain intensity and pain unpleasantness.•Age, gender, distance, and pain at the starting line also predict triathlon pain unpleasantness.•Whereas gender and pain at the starting line also contribute to the prediction of triathlon pain intensity.•Psychological factors must be considered to improve our understanding of pain experienced by triathletes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Here we report the isolation of a murine model for heritable T cell lymphoblastic leukemia/lymphoma (T-ALL) called Spontaneous dominant leukemia (Sdl). Sdl heterozygous mice develop disease with a ...short latency and high penetrance, while mice homozygous for the mutation die early during embryonic development. Sdl mice exhibit an increase in the frequency of micronucleated reticulocytes, and T-ALLs from Sdl mice harbor small amplifications and deletions, including activating deletions at the Notch1 locus. Using exome sequencing it was determined that Sdl mice harbor a spontaneously acquired mutation in Mcm4 (Mcm4(D573H)). MCM4 is part of the heterohexameric complex of MCM2-7 that is important for licensing of DNA origins prior to S phase and also serves as the core of the replicative helicase that unwinds DNA at replication forks. Previous studies in murine models have discovered that genetic reductions of MCM complex levels promote tumor formation by causing genomic instability. However, Sdl mice possess normal levels of Mcms, and there is no evidence for loss-of-heterozygosity at the Mcm4 locus in Sdl leukemias. Studies in Saccharomyces cerevisiae indicate that the Sdl mutation produces a biologically inactive helicase. Together, these data support a model in which chromosomal abnormalities in Sdl mice result from the ability of MCM4(D573H) to incorporate into MCM complexes and render them inactive. Our studies indicate that dominantly acting alleles of MCMs can be compatible with viability but have dramatic oncogenic consequences by causing chromosomal abnormalities.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Better knowledge on why some individuals succeed in maintaining participation in physical activity throughout adolescence is needed to guide the development of effective interventions to increase and ...then maintain physical activity levels. Despite allowing an in-depth understanding, qualitative designs have infrequently been used to study physical activity maintenance. We explored factors contributing to the maintenance and the decline of physical activity during adolescence.
Questionnaires were administered to 515 grade 10-12 students. The Physical Activity Questionnaire for Adolescents was used to determine physical activity level at the end of adolescence. An adapted version of this questionnaire was used to estimate physical activity in early adolescence. Among both genders, we identified participants who maintained a high level of physical activity since grade 7 and some whose activity level declined. For each category, groups of 10 students were randomly selected to take part in focus group discussions.
Seven focus groups with 5 to 8 participants in each were held. Both maintainers and decliners associated physical activity with positive health outcomes. Maintenance of physical activity was associated with supportive social environments and heightened feelings of competence and attractiveness. A decline in physical activity was associated with negative social validation, poor social support and barriers related to access.
Although maintainers and decliners associate physical activity with similar themes, the experiences of both groups differ substantially with regards to those themes. Taking both perspectives in consideration could help improve interventions to increase and maintain physical activity levels of adolescents.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
We aimed to characterize the spatial proximity of plaque destabilizing features local endothelial shear stress (ESS), minimal luminal area (MLA), plaque burden (PB), and near-infrared spectroscopy ...(NIRS) lipid signal in high- vs. low-risk plaques.
Coronary arteries imaged with angiography and NIRS-intravascular ultrasound (IVUS) underwent 3D reconstruction and computational fluid dynamics calculations of local ESS. ESS, PB, MLA, and lipid core burden index (LCBI), for each 3-mm arterial segment were obtained in arteries with large lipid-rich plaque (LRP) vs. arteries with smaller LRP. The locations of the MLA, minimum ESS (minESS), maximum ESS (maxESS), maximum PB (maxPB), and maximum LCBI in a 4-mm segment (maxLCBI4mm) were determined along the length of each plaque.
The spatial distributions of minESS, maxESS, maxPB, and maxLCBI4mm, in reference to the MLA, were significantly heterogeneous within and between each variable. The location of maxLCBI4mm was spatially discordant from sites of the MLA (p<0.0001), minESS (p = 0.003), and maxESS (p = 0.003) in arteries with large LRP (maxLCBI4mm ≥ 400) and non-large LRP. Large LRP arteries had higher maxESS (9.31 ± 4.78 vs. 6.32 ± 5.54 Pa; p = 0.023), lower minESS (0.41 ± 0.16 vs. 0.61 ± 0.26 Pa; p = 0.007), smaller MLA (3.54 ± 1.22 vs. 5.14 ± 2.65 mm2; p = 0.002), and larger maxPB (70.64 ± 9.95% vs. 56.70 ± 13.34%, p<0.001) compared with non-large LRP arteries.
There is significant spatial heterogeneity of destabilizing plaque features along the course of both large and non-large LRPs. Large LRPs exhibit significantly more abnormal destabilizing plaque features than non-large LRPs. Prospective, longitudinal studies are required to determine which patterns of heterogeneous destabilizing features act synergistically to cause plaque destabilization.
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•The spatial relationship between plaque features of local endothelial shear stress (ESS), minimal luminal area (MLA), plaque burden (PB), and near-infrared spectroscopy (NIRS) lipid signal is unknown.•Coronary arteries imaged with angiography and NIRS-intravascular ultrasound (IVUS) underwent 3D reconstruction and computational fluid dynamics calculations of local flow patterns.•The spatial distributions of minESS, maxESS, maxPB, and maxLCBI4mm, in reference to the MLA, were significantly heterogeneous within and between each variable.•The location of maxLCBI4mm was spatially discordant from sites of MLA, minESS, and maxESS in most arteries, but not discordant with the site of maxPB.•There is significant heterogeneity between hemodynamic, anatomic, and biochemical coronary plaque features.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, SAZU, SBCE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) is a promising treatment for metastatic melanoma unresponsive to conventional therapies. We report here on the ...results of an ongoing phase II clinical trial testing the efficacy of ACT using TIL in patients with metastatic melanoma and the association of specific patient clinical characteristics and the phenotypic attributes of the infused TIL with clinical response.
Altogether, 31 transiently lymphodepleted patients were treated with their expanded TIL, followed by two cycles of high-dose interleukin (IL)-2 therapy. The effects of patient clinical features and the phenotypes of the T cells infused on the clinical response were determined.
Overall, 15 of 31 (48.4%) patients had an objective clinical response using immune-related response criteria (irRC) with 2 patients (6.5%) having a complete response. Progression-free survival of more than 12 months was observed for 9 of 15 (60%) of the responding patients. Factors significantly associated with the objective tumor regression included a higher number of TIL infused, a higher proportion of CD8(+) T cells in the infusion product, a more differentiated effector phenotype of the CD8(+) population, and a higher frequency of CD8(+) T cells coexpressing the negative costimulation molecule "B- and T-lymphocyte attenuator" (BTLA). No significant difference in the telomere lengths of TIL between responders and nonresponders was identified.
These results indicate that the immunotherapy with expanded autologous TIL is capable of achieving durable clinical responses in patients with metastatic melanoma and that CD8(+) T cells in the infused TIL, particularly differentiated effectors cells and cells expressing BTLA, are associated with tumor regression.
To make a diagnosis, clinicians rely on both diagnostic criteria and clinical reasoning. In the case of learning disabilities (LDs), reliance on the latter (clinical reasoning) is likely to be ...heightened, given the current absence of a consistent LD diagnostic approach or definition. This study investigated the agreement between diagnostic decisions of reading LD (RLD) made by clinicians and those produced from strict adherence to 3 commonly employed diagnostic models (i.e., low achievement, ability-achievement discrepancy, processing strengths and weakness). Using a clinical sample of 313 elementary-aged children, the level of agreement between clinician and models was determined using kappa. The Wechsler Intelligence Scale for Children (4th ed.: Canadian; WISC-IVCDN; Wechsler, 2003) and the Wechsler Individual Achievement Test (3rd ed.: Canadian; WIAT-IIICDN; Wechsler, 2010) were used in the comparisons. Overall, the results indicate varying levels of agreement between: (a) clinician and model identification of reading disabilities, and (b) model-model agreement. The strongest agreement was between the clinician and low achievement model (LAM)-the model with the broadest LD definition. Clinicians should carefully consider the rationale for their diagnostic approach and be mindful of additional factors influencing their clinical judgment.
Pour établir un diagnostic, les cliniciens se fondent sur des critères diagnostics et sur le raisonnement clinique. Dans le cas des troubles d'apprentissage, il est probable que l'on se fonde davantage sur le raisonnement clinique pour poser un diagnostic, en raison de l'absence actuelle d'une approche ou d'une définition homogène de ces troubles. Cette étude s'est penchée sur la concordance entre l'établissement de diagnostics de trouble d'apprentissage de lecture par des cliniciens et les diagnostics établis grâce au recours à trois modèles couramment utilisés, à savoir : le modèle de performance sous le seuil de réussite (low achievement model), le modèle des différences entre aptitudes et réussite (ability achievement discrepancy) et les points forts et les points faibles des processus cognitifs (processing strengths and weakness). Se fondant sur un échantillon clinique de 313 enfants de l'âge du primaire, le niveau de concordance entre le diagnostic clinique et les modèles a été évalué selon le test de concordance Kappa. L'échelle d'intelligence de Wechsler destinée aux enfants (Wechsler Intelligence Scale for Children; 4th ed.: Canadian; WISC-IVCDN; Wechsler, 2003) et le test de rendement individuel de Wechsler (Wechsler Individual Achievement Test; 3rd ed.: Canadian; WIAT-IIICDN; Wechsler, 2010) ont été utilisés pour établir les comparaisons. Dans l'ensemble, les résultats montrent des niveaux variés de concordance entre : (a) l'identification clinique et à l'aide de modèles des difficultés de lecture, ainsi qu'entre (b) les divers modèles. La meilleure concordance s'observe entre le diagnostic clinique et l'identification à l'aide du modèle de faible réussite, soit celui qui propose la définition la plus vaste des troubles d'apprentissage. Les cliniciens devraient évaluer soigneusement la justification de leur approche diagnostique et tenir compte des autres facteurs pouvant influer sur leur jugement clinique.
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CEKLJ, FFLJ, NUK, ODKLJ, PEFLJ, UPUK, VSZLJ
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