Characterization of nanosensitive multifractality in submicron scale tissue morphology and its alteration in tumor progression.

SIGNIFICANCE: Assessment of disease using optical coherence tomography is an actively investigated problem, owing to many unresolved challenges in early disease detection, diagnosis, and treatment response monitoring. The early manifestation of disease or precancer is typically associated with subtle alterations in the tissue dielectric and ultrastructural morphology. In addition, biological tissue is known to have ultrastructural multifractality. AIM: Detection and characterization of nanosensitive structural morphology and multifractality in the tissue submicron structure. Quantification of nanosensitive multifractality and its alteration in progression of tumor. APPROACH: We have developed a label free nanosensitive multifractal detrended fluctuation analysis(nsMFDFA) technique in combination with multifractal analysis and nanosensitive optical coherence tomography (nsOCT). The proposed method deployed for extraction and quantification of nanosensitive multifractal parameters in mammary fat pad (MFP). RESULTS: Initially, the nsOCT approach is numerically validated on synthetic submicron axial structures. The nsOCT technique was applied to pathologically characterized MFP of murine breast tissue to extract depth-resolved nanosensitive submicron structures. Subsequently, two-dimensional MFDFA were deployed on submicron structural en face images to extract nanosensitive tissue multifractality. We found that nanosensitive multifractality increases in transition from healthy to tumor. CONCLUSIONS: This method for extraction of nanosensitive tissue multifractality promises to provide a noninvasive diagnostic tool for early disease detection and monitoring treatment response. The novel ability to delineate the dominant submicron scale nanosensitive multifractal properties may also prove useful for characterizing a wide variety of complex scattering media of non-biological origin.

Characterization of nanosensitive multifractality in submicron scale tissue morphology and its alteration in tumor progression (Erratum).

An error in the 2nd author's name is corrected.

Extracellular Vesicles for Cancer Therapy: Impact of Host Immune Response.

In recent times, extracellular vesicles (EVs) have come under the spotlight as potential therapeutics for cancer, due to the relative ease of manipulation of contents and potential for tumor targeting. The use of EVs as delivery vehicles may bypass some of the negative effects associated with cell-based carriers, and there has been a major focus on defining EV subtypes, establishing transparent nomenclature, and isolation and characterization techniques. EVs are believed to be a fingerprint of the secreting cell and so researchers harness the positive aspects of a particular cell of origin, and can then further modify EV contents to improve therapeutic efficacy. In this review, we highlight studies employing EVs as cancer therapeutics that have reported on immune response. As we rapidly advance towards potential application in the clinical setting, the question of immune response to EV administration in the cancer setting has become critically important.

Investigating the Potential and Pitfalls of EV-Encapsulated MicroRNAs as Circulating Biomarkers of Breast Cancer.

Extracellular vesicles (EVs) shuttle microRNA (miRNA) throughout the circulation and are believed to represent a fingerprint of the releasing cell. We isolated and characterized serum EVs of breast tumour-bearing animals, breast cancer (BC) patients, and healthy controls. EVs were characterized using transmission electron microscopy (TEM), protein quantification, western blotting, and nanoparticle tracking analysis (NTA). Absolute quantitative (AQ)-PCR was employed to analyse EV-miR-451a expression. Isolated EVs had the appropriate morphology and size. Patient sera contained significantly more EVs than did healthy controls. In tumour-bearing animals, a correlation between serum EV number and tumour burden was observed. There was no significant relationship between EV protein yield and EV quantity determined by NTA, highlighting the requirement for direct quantification. Using AQ-PCR to relate miRNA copy number to EV yield, a significant increase in miRNA-451a copies/EV was detected in BC patient sera, suggesting potential as a novel biomarker of breast cancer.

First demonstration of effective spatial training for near transfer to spatial performance and far transfer to a range of mathematics skills at 8 years.

There is evidence that spatial thinking is malleable, and that spatial and mathematical skills are associated (Mix et al. [2016] Journal of Experimental Psychology: General, 145, 1206; Mix et al. [2017] Journal of Cognition and Development, 18, 465; Uttal et al. [2013] Psychological Bulletin, 139, 352). However, few studies have investigated transfer of spatial training gains to mathematics outcomes in children, and no known studies have compared different modes of spatial instruction (explicit vs. implicit instruction). Based on a sample of 250 participants, this study compared the effectiveness of explicit and implicit spatial instruction in eliciting near transfer (to the specific spatial skills trained), intermediate transfer (to untrained spatial skills) and far transfer (to mathematics domains) at age 8. Spatial scaling and mental rotation skills were chosen as training targets as previous studies have found, and proposed explanations for, associations between these skills and mathematics in children of this age (Journal of Experimental Psychology: General, 145, 2016 and 1206). In this study, spatial training led to near, intermediate and far transfer of gains. Mental visualization and proportional reasoning were proposed to explain far transfer from mental rotation and spatial scaling skills respectively. For most outcomes, except for geometry, there was no difference in the effectiveness of implicit (practice with feedback) compared to explicit instruction (instructional videos). From a theoretical perspective, the study identified a specific causal effect of spatial skills on mathematics skills in children. Practically, the results also highlight the potential of instructional videos as a method of introducing spatial thinking into the classroom.

Oncological Risk in Autologous Stem Cell Donation for Novel Tissue-Engineering Approaches to Postmastectomy Breast Regeneration.

Adipose tissue engineering using adipose-derived stem cells (ADSCs) has emerged as an opportunity to develop novel approaches to postmastectomy breast reconstruction with the potential for an autologous tissue source with a natural appearance and texture. As of yet, the role of ADSCs in breast cancer development and metastasis is not completely understood; therefore, we must consider the oncological safety of employing an autologous source of ADSCs for use in breast regeneration. This study investigated the regenerative properties of ADSCs isolated from breast cancer patients, including those who had received neoadjuvant chemotherapy, and noncancer controls. The ADSCs were characterised for several parameters central to tissue regeneration, including cell viability, proliferation, differentiation potential, and cytokine secretion. A stem cell population was isolated and confirmed by flow cytometry and multilineage differentiation. There was no difference in cell phenotype or surface antigen expression between ADSCs from different sources. Adipose-derived stem cells isolated from the breast of cancer patients exhibited reduced adipogenic differentiation potential compared with ADSCs from other sources. The greatest degree of adipogenic differentiation was observed in ADSCs isolated from the subcutaneous abdominal fat of noncancer controls. The proliferation rate of ADSCs isolated from the breast of cancer patients was increased compared with other sources; however, it was decreased in ADSCs isolated from breast cancer patients who had recently been treated with neoadjuvant chemotherapy. A number of cytokines were detected in the cell conditioned media of ADSCs from different sources, including matrix metalloproteinase-2 (MMP-2), which was detected at higher levels in the secretome of ADSCs from breast cancer patients compared with noncancer controls. This study provides important information relating to the suitability of ADSCs as an autologous cell source for adipose tissue engineering in postcancer reconstruction. Results indicate that while the surface phenotype does not differ, the differentiation capacity, proliferative rate, and secreted cytokine profile are affected by the presence or treatment of breast cancer. These findings support further investigation into the regenerative potential of these ADSCs, if they are to be considered in clinical reconstructive strategies.

Role of Extracellular Vesicles (EVs) in Cell Stress Response and Resistance to Cancer Therapy.

Extracellular vesicles (EVs) are nanosized particles released by all cells that have been heralded as novel regulators of cell-to-cell communication. It is becoming increasingly clear that in response to a variety of stress conditions, cells employ EV-mediated intercellular communication to transmit a pro-survival message in the tumor microenvironment and beyond, supporting evasion of cell death and transmitting resistance to therapy. Understanding changes in EV cargo and secretion pattern during cell stress may uncover novel, targetable mechanisms underlying disease progression, metastasis and resistance to therapy. Further, the profile of EVs released into the circulation may provide a circulating biomarker predictive of response to therapy and indicative of microenvironmental conditions linked to disease progression, such as hypoxia. Continued progress in this exciting and rapidly expanding field of research will be dependent upon widespread adoption of transparent reporting standards and implementation of guidelines to establish a consensus on methods of EV isolation, characterisation and nomenclature employed.

The developmental relations between spatial cognition and mathematics in primary school children.

Spatial thinking is an important predictor of mathematics. However, existing data do not determine whether all spatial sub-domains are equally important for mathematics outcomes nor whether mathematics-spatial associations vary through development. This study addresses these questions by exploring the developmental relations between mathematics and spatial skills in children aged 6-10 years (N = 155). We extend previous findings by assessing and comparing performance across Uttal et al.'s (2013), four spatial sub-domains. Overall spatial skills explained 5%-14% of the variation across three mathematics performance measures (standardized mathematics skills, approximate number sense and number line estimation skills), beyond other known predictors of mathematics including vocabulary and gender. Spatial scaling (extrinsic-static sub-domain) was a significant predictor of all mathematics outcomes, across all ages, highlighting its importance for mathematics in middle childhood. Other spatial sub-domains were differentially associated with mathematics in a task- and age-dependent manner. Mental rotation (intrinsic-dynamic skills) was a significant predictor of mathematics at 6 and 7 years only which suggests that at approximately 8 years of age there is a transition period regarding the spatial skills that are important for mathematics. Taken together, the results support the investigation of spatial training, particularly targeting spatial scaling, as a means of improving both spatial and mathematical thinking.

Spatial cognition and science achievement: The contribution of intrinsic and extrinsic spatial skills from 7 to 11 years.

BACKGROUND: Prior longitudinal and correlational research with adults and adolescents indicates that spatial ability is a predictor of science learning and achievement. However, there is little research to date with primary-school aged children that addresses this relationship. Understanding this association has the potential to inform curriculum design and support the development of early interventions. AIMS: This study examined the relationship between primary-school children's spatial skills and their science achievement. METHOD: Children aged 7-11 years (N = 123) completed a battery of five spatial tasks, based on a model of spatial ability in which skills fall along two dimensions: intrinsic-extrinsic; static-dynamic. Participants also completed a curriculum-based science assessment. RESULTS: Controlling for verbal ability and age, mental folding (intrinsic-dynamic spatial ability), and spatial scaling (extrinsic-static spatial ability) each emerged as unique predictors of overall science scores, with mental folding a stronger predictor than spatial scaling. These spatial skills combined accounted for 8% of the variance in science scores. When considered by scientific discipline, mental folding uniquely predicted both physics and biology scores, and spatial scaling accounted for additional variance in biology and variance in chemistry scores. The children's embedded figures task (intrinsic-static spatial ability) only accounted for variance in chemistry scores. The patterns of association were consistent across the age range. CONCLUSION: Spatial skills, particularly mental folding, spatial scaling, and disembedding, are predictive of 7- to 11-year-olds' science achievement. These skills make a similar contribution to performance for each age group.

The contribution of spatial ability to mathematics achievement in middle childhood.

Strong spatial skills are associated with success in science, technology, engineering, and mathematics (STEM) domains. Although there is convincing evidence that spatial skills are a reliable predictor of mathematical achievement in preschool children and in university students, there is a lack of research exploring associations between spatial and mathematics achievement during the primary school years. To address this question, this study explored associations between mathematics and spatial skills in children aged 5 and 7years. The study sample included 12,099 children who participated in both Wave 3 (mean age=5; 02 [years; months]) and Wave 4 (mean age=7; 03) of the Millennium Cohort Study. Measures included a standardised assessment of mathematics and the Pattern Construction subscale of the British Ability Scales II to assess intrinsic-dynamic spatial skills. Spatial skills at 5 and 7years of age explained a significant 8.8% of the variation in mathematics achievement at 7years, above that explained by other predictors of mathematics, including gender, socioeconomic status, ethnicity, and language skills. This percentage increased to 22.6% without adjustment for language skills. This study expands previous findings by using a large-scale longitudinal sample of primary school children, a population that has been largely omitted from previous research exploring associations between spatial ability and mathematics achievement. The finding that early and concurrent spatial skills contribute to mathematics achievement at 7years of age highlights the potential of spatial skills as a novel target in the design of mathematics interventions for children in this age range.

Engineering Exosomes for Cancer Therapy.

There remains an urgent need for novel therapeutic strategies to treat metastatic cancer, which results in over 8 million deaths annually worldwide. Following secretion, exosomes are naturally taken up by cells, and capable of the stable transfer of drugs, therapeutic microRNAs and proteins. As knowledge of the biogenesis, release and uptake of exosomes continues to evolve, and thus also has interest in these extracellular vesicles as potential tumor-targeted vehicles for cancer therapy. The ability to engineer exosome content and migratory itinerary holds tremendous promise. Studies to date have employed viral and non-viral methods to engineer the parent cells to secrete modified exosomes, or alternatively, to directly manipulate exosome content following secretion. The majority of studies have demonstrated promising results, with decreased tumor cell invasion, migration and proliferation, along with enhanced immune response, cell death, and sensitivity to chemotherapy observed. The studies outlined in this review highlight the exciting potential for exosomes as therapeutic vehicles for cancer treatment. Successful implementation in the clinical setting will be dependent upon establishment of rigorous standards for exosome manipulation, isolation, and characterisation.