Relative Importance of Well-Being Determinants in Atlantic Canadian Families During the Pandemic.

Framed by the socio-ecological model of well-being, we examined the relative importance of factors contributing to three dimensions of well-being (child, parent, and family) during the COVID-19 pandemic. A sample of 536 participants from the Atlantic provinces of Canada answered a cross-sectional survey in 2021, covering experiences during the pandemic (eg, changes in family life and well-being). Well-being was assessed with 3 single-item measures on positive change in the life of children, parents, and families during the pandemic. This study involved 21 predictor variables (eg, change in time spent on various family activities). Using multiple regression and measures of relative importance based on the Lindeman, Merenda and Gold (lmg) method, we identified the variables most important to predicting well-being. Twenty-one predictors accounted for 21% of the variance in child well-being, 25% in parent well-being, and 36% in family well-being. Well-being at all 3 levels (child, parent, and family) shared the same top predictor (family closeness). The top 6 predictors of well-being at each level were related to leisure (eg, play) and time-use (eg, to prepare meals, engage in self-care, and rest). The effect sizes were smaller for child well-being than at the parent or family level, suggesting there may be important predictors of child well-being not accounted for in these analyses. This study may inform family-level programing and policy that seeks to promote well-being for children and their families.

Responsive Feeding Environments in Childcare Settings: A Scoping Review of the Factors Influencing Implementation and Sustainability.

Children benefit from responsive feeding environments, where their internal signals of hunger and satiety are recognized and met with prompt, emotionally supportive and developmentally appropriate responses. Although there is existing research on responsive feeding environments in childcare, there is little synthesized literature on the implementation practices using a behavior change framework. This scoping review sought to explore the factors influencing the implementation and sustainability of responsive feeding interventions in the childcare environment, using the behavior change wheel (BCW). A total of 3197 articles were independently reviewed and 39 met the inclusion criteria. A thematic analysis identified the factors influencing the implementation and sustainability of responsive feeding, including the following: (1) pre-existing nutrition policies, (2) education and training, (3) provider beliefs and confidence, (4) partnership development and stakeholder engagement and (5) resource availability. The most common BCW intervention functions were education (n = 39), training (n = 38), environmental restructuring (n = 38) and enablement (n = 36). The most common policy categories included guidelines (n = 39), service provision (n = 38) and environmental/social planning (n = 38). The current literature suggests that broader policies are important for responsive feeding, along with local partnerships, training and resources, to increase confidence and efficacy among educators. Future research should consider how the use of a BCW framework may help to address the barriers to implementation and sustainability.

Comparison of Responsive Feeding Practices in Child Care and Home Environments in Nova Scotia.

Purpose: The values, beliefs and practices between the family home and child care environment can play a role in shaping a responsive food environment for young children, but few studies have explored the differences across these settings. The purpose of this study was to compare responsive feeding practices in child care and home environments through the framework of the 2019 Canada Food Guide healthy eating recommendations.Methods: Nova Scotia families and child care providers completed an online survey on responsive feeding. Independent-samples t-tests explored the differences between family and child care respondents on variables related to the 2019 Canada's Food Guide, including: food variety, mindfulness, eating with others, cooking more often, and enjoyment of food. A directed content analysis was used to code the open-ended qualitative questions.Results: Family respondents (n = 603) were more likely to report offering a variety of foods, repeated exposures to new foods, and asking children about fullness. Child care respondents (n = 253) were more likely to sit with children during meals and less likely to encourage children to finish their food.Conclusions: The results identify potential points of intervention, including the importance of increasing communication to ensure mutually supportive messages and environments for healthy eating.

Early pandemic impacts on family environments that shape childhood development and health: A Canadian study.

OBJECTIVES: Changes to income and employment are key social determinants of health that have impacted many families during the COVID-19 pandemic. This research aimed to understand how changes to employment and income influenced family environments that contribute to early childhood development and health. METHODS: A concurrent triangulation mixed method design was used through a cross-sectional survey on early impacts of the COVID-19 pandemic involving families with young children in the Canadian Maritime provinces (n = 2158). Analyses included multivariate regression models to examine whether changes to employment and income predicted changes to Family access to resources and social support, parenting Abilities and self-care at home, and home Routines and Environments (FARE Change Scale). Content analysis was used to identify themes from the open-ended questions. RESULTS: Changes to employment and income early in the pandemic like no longer working but continued to receive salary, working fewer hours for the same salary earned before the pandemic, no longer working nor receiving salary, working fewer hours resulting in salary reduction, essential worker status and household income were significant predictors of FARE Change Scale when ethnicity/cultural background and province of residence are controlled (P < .05). Themes provided a description of family impacts, including shifting employment and income, finding time and capacity, feelings of guilt and the creation of new routines. CONCLUSION: Our study provides insight on the implications of public health restrictions, such as the importance of increased time for parents (through reduced work hours) and access to resources and social support to support child development and health.

Expression of Myoglobin in Normal and Cancer Brain Tissues: Correlation With Hypoxia Markers.

BACKGROUND: Myoglobin (MB) is increasingly recognized as a key player in cancer growth and metastasis. Low oxygen tensions, commonly associated with highly aggressive and recurrent cancers, have been shown to regulate its expression in several cancers such as lung, neck, prostate and breast cancer. However, it is not yet known whether it contributes to the growth and spread of brain cancers especially Glioblastoma multiforme (GBM). METHODS: Here we investigate the expression of MB, and its correlation with the hypoxia markers carbonic anhydrase IX (CAIX) and lactate dehydrogenase A (LDHA), in human tissue microarrays of multiple organ tumors, brain tumors, and GBM tumors, and their respective cancer-adjacent normal tissues. Correlation between MB protein expression and tumor grade was also assessed. RESULTS: We show that MB protein is expressed in a wide variety of cancers, benign tumors, cancer-adjacent normal tissues, hyperplastic tissue samples and normal brain tissue, and low oxygen tensions modulate MB protein expression in different brain cancers, including GBM. Enhanced nuclear LDHA immune-reactivity in GBM was also observed. Finally, we report for the first time a positive correlation between MB expression and brain tumor grade. CONCLUSION: Our data suggest that hypoxia regulate MB expression in different brain cancers (including GBM) and that its expression is associated with a more aggressive phenotype as indicated by the positive correlation with the brain tumor grade. Additionally, a role for nuclear LDHA in promoting aggressive tumor phenotype is also suggested based on enhanced nuclear expression which was observed only in GBM.

Myoglobin variants are expressed in human glioblastoma cells­hypoxia effect?

Glioblastoma multiforme (GBM) is the most aggressive human brain cancer. Little is known regarding how these cells adapt to the harsh tumor microenvironment, and consequently survive and resist various treatments. Myoglobin (MB), the oxygen­binding hemoprotein, has been shown to be ectopically expressed in different human cancers and cell lines, and its expression is hypothesized to be an adaptation mechanism to hypoxia. The aim of the present study was to determine whether cancer­related and hypoxia­responsive MB mRNA splice variants are expressed in human GBM cells and glioblastoma tumor xenografts, and whether their expression is induced by hypoxia and correlated with hypoxia markers [lactate dehydrogenase A (LDHA), glucose transporter 1 (GLUT1), vascular endothelial growth factor (VEGF) and carbonic anhydrase IX (CAIX)]. Conventional reverse transcription (RT)­PCR, DNA sequencing, RT­quantitative PCR and immunohistochemistry were conducted to investigate MB expression in hypoxia­sensitive (M010b, M059J) and ­tolerant (M059K, M006xLo) GBM cell lines that also exhibit differential response towards radiation, rendering them a valuable translational GBM model. It was revealed that cancer­related MB variants 9, 10, 11 and 13 were expressed in GBM cells under normoxia, and following hypoxia, their expression exhibited modest­to­significant upregulation that correlated with hypoxia markers. It was also demonstrated that MB was upregulated in hypoxic microregions of glioblastoma tumor xenografts that were stained in matched tumor regions of serial tumor sections with the hypoxia markers, pimonidazole, CAIX, VEGF and LDHA. The present study identified myoglobin as a potential contributor to the hypoxia adaptation and survival strategies of glioblastoma, and may explain the aggressiveness and frequent recurrence rates associated with GBM.

A Loose Parts Randomized Controlled Trial to Promote Active Outdoor Play in Preschool-aged Children: Physical Literacy in the Early Years (PLEY) Project.

BACKGROUND: The Physical Literacy in the Early Years (PLEY) intervention is a randomized mixed-methods controlled trial focused on embedding loose parts materials into the outdoor play spaces of regulated child care centres across Nova Scotia. The aim is to evaluate the efficacy of the PLEY intervention versus standard regulated childcare practice in influencing thoughts and behaviors of children, parents, and educators. METHODS: Participating early child care centres (n = 19) were randomly assigned to intervention or control sites. Intervention sites received loose parts kits at the beginning of the project while control sites received kits upon project completion. The kits included items such as rocks, tree cookies, balls, wood planks, tubes, tires, ropes, and pulleys. Children (n = 183 at baseline) had their physical activity (accelerometers) and movement skills (TGMD-3 and PGMQ) measured before and after the intervention. All centres provided responses to environmental surveys (Go NAP SACC and Site Context Questionnaire), and educators in intervention sites participated in focus group and photovoice sessions. Educators were also provided with a full day professional development opportunity (plus ongoing mentoring) focused on physical activity, physical literacy, outdoor play, risk-taking, and loose parts. Parents participated in an interview addressing active outdoor play, physical literacy, and attitudes towards risk taking during play. DISCUSSION: This study will provide a better understanding of how integrating loose parts materials into outdoor play spaces impacts children's health, and the impact on educator and parent attitudes, beliefs, and understanding around physical literacy, active outdoor play and risk-taking during play.

Accelerometry-measured physical activity and sedentary behaviour of preschoolers in Nova Scotia, Canada.

The objective of this study was to describe the levels and bouts of physical activity (PA) and sedentary behaviour (SB) among preschoolers in Nova Scotia, Canada, and the proportion meeting PA and step guidelines. Children (75 boys, 49 girls; mean age = 4.2 (range = 3-5 years)) participating in the Physical Literacy in the Early Years (PLEY) study provided data. Average time (minutes, % of day) spent sedentary, in light PA (LPA), moderate-to-vigorous PA (MVPA), and total PA; average frequency; and duration of bouts of MVPA (≥5 min, ≥10 min) and sedentary bouts (≥10 min) per day were determined using published cut-points, using 15-s epochs. The proportion of children meeting PA and step guidelines was determined, and differences by sex explored. Children spent the majority (70.8%) of their day active; nearly all (≥97%) met PA guidelines. Most children met step guidelines on a weekly basis, but not daily. Only LPA differed by sex (greater in girls; p = 0.001). Little time was spent in sustained SB (bouts ≥10 min). Boys had greater and longer bouts of MVPA and spent more of their day in these (p < 0.05). Girls spent less time in sustained SB (p = 0.009). This is the first study to describe the PA and SB of Nova Scotia preschoolers using accelerometry. Findings suggest preschoolers spend the majority of their day active, and that there are sex-related differences in PA and SB, warranting further examination.

Let the Children Play: Scoping Review on the Implementation and Use of Loose Parts for Promoting Physical Activity Participation.

Active play has become a critical focus in terms of physical activity participation in young children. Unstructured or child-led play offers children the opportunity to interact with the environment in a range of different ways. Unstructured materials, often called loose parts, encourage child-led play, and therefore may also promote physical activity. The purpose of this scoping review was to determine what is currently known about how loose parts may influence physical activity participation. Following a systematic literature search, a total of 16 articles were retrieved, reviewed and categorized according to: (1) types of loose parts; (2) types of play; and (3) types of thinking. We found that there are currently a range of loose parts being used to support play, but the way in which they are implemented varies and there is a lack of clarity around how they might support the development of active outdoor play and physical literacy skills.

Effect of hypoxia on angiogenesis related factors in glioblastoma cells.

Pathological angiogenesis is a characteristic feature of glioblastoma multiforme (GBM) where the balance between pro-angiogenic and anti-angiogenic factors are shifted towards the pro-angiogenic phenotype. In this study we sought to determine whether angiostatins are expressed by GBM cells and whether their expression along with other related factors [matrix metalloproteinase (MMP)-2, MMP-9, and collagen type I α1 (COLIA1)] are altered by hypoxia and/or correlated with the levels of cancer stem cell marker CD133. Using qRT-PCR, western blotting, and gelatin zymography, we examined the expression of angiostatins, MMP-2, MMP-9, COLIA1 and CD133 in GBM cell lines cultured under aerobic conditions and hypoxia. Expression levels of MMP-2 and MMP-9 were significantly induced by hypoxia. Angiostatins were detected in all GBM cell lines and were increased by hypoxia while the angiostatin isoform of 38-kDa was the most abundant in GBM cells under aerobic and hypoxic conditions. COLIA1 and CD133 were significantly increased in several GBM cell lines under hypoxia. Despite expression and upregulation of anti-angiogenic factors (e.g. angiostatins) in GBM cells, they are overwhelmed by the overexpression of a larger number of angiogenic factors that shift the angiogenic balance towards the pro-angiogenic phenotype. Thus, an exogenous administration of anti-angiogenic factors may be required to improve the treatment of GBM tumors.

Hypoxia differentially upregulates the expression of embryonic, fetal and adult hemoglobin in human glioblastoma cells.

Hemoglobin is produced mainly in erythroid cells. However, it has been reported in non-erythroid cells of human and rodents. We have shown previously that neuroglobin, cytoglobin and hemoglobin are expressed in human glioblastoma multiforme (GBM) cells. We sought to determine whether hemoglobin expression is upregulated by hypoxia, and whether its expression is restricted to the cancer stem cell populations in different GBM cell lines or GBM brain tumor initiating cells (BTICs). Flow cytometry, magnetic cell sorting and qRT-PCR were used to examine the hypoxic upregulation of hemoglobins as well as erythropoietin (EPO) and erythropoietin receptor (EPOR) in GBM cell lines (M006x, M059J, M059K, U87R and U87T) and GBM-BTICs. The data showed significantly increased expression in globins (α, ß, γ, δ, ζ and ε), EPO and EPOR mRNA levels under hypoxia. Globin expression is not limited to the stem cell populations or GBM-BTICs but is a property of the entire GBM population. We assumed that the total expression of mRNA of different normalized globins (α, ß, γ, δ, ζ and ε) at different time­points for the same cell line is 100%. Under aerobic conditions, ε globin was predominantly expressed, and then decreased gradually with increasing time in hypoxia. This was coupled to a concomitant increase in α and γ globins. Our findings suggest that hypoxic upregulation of hemoglobin expression in GBM cells may be a part of a repertoire of active defence and adaptation mechanisms enabling these cells to acquire resistance to aggressive multimodality treatments of chemotherapy and radiotherapy. New therapeutic strategies to interfere with hemoglobin expression or function in GBM cells are required.

Adult, embryonic and fetal hemoglobin are expressed in human glioblastoma cells.

Hemoglobin is a hemoprotein, produced mainly in erythrocytes circulating in the blood. However, non-erythroid hemoglobins have been previously reported in other cell types including human and rodent neurons of embryonic and adult brain, but not astrocytes and oligodendrocytes. Human glioblastoma multiforme (GBM) is the most aggressive tumor among gliomas. However, despite extensive basic and clinical research studies on GBM cells, little is known about glial defence mechanisms that allow these cells to survive and resist various types of treatment. We have shown previously that the newest members of vertebrate globin family, neuroglobin (Ngb) and cytoglobin (Cygb), are expressed in human GBM cells. In this study, we sought to determine whether hemoglobin is also expressed in GBM cells. Conventional RT-PCR, DNA sequencing, western blot analysis, mass spectrometry and fluorescence microscopy were used to investigate globin expression in GBM cell lines (M006x, M059J, M059K, M010b, U87R and U87T) that have unique characteristics in terms of tumor invasion and response to radiotherapy and hypoxia. The data showed that α, ß, γ, δ, ζ and ε globins are expressed in all tested GBM cell lines. To our knowledge, we are the first to report expression of fetal, embryonic and adult hemoglobin in GBM cells under normal physiological conditions that may suggest an undefined function of those expressed hemoglobins. Together with our previous reports on globins (Ngb and Cygb) expression in GBM cells, the expression of different hemoglobins may constitute a part of series of active defence mechanisms supporting these cells to resist various types of treatments including chemotherapy and radiotherapy.

Knockdown of cytoglobin expression sensitizes human glioma cells to radiation and oxidative stress.

Cytoglobin is a recently identified vertebrate globin whose functions include scavenging reactive oxygen and nitrosative species. In tumor cells, CYGB may function as a tumor suppressor gene. Here we show that knockdown of cytoglobin expression can sensitize human glioma cells to oxidative stress induced by chemical inhibitors of the electron transport chain and as well can increase cellular radiosensitivity. When treated with antimycin A, an inhibitor of the mitochondrial electron transport chain, cytoglobin-deficient cells showed significantly higher H2O2 levels, whereas H2O2 levels were significantly reduced in cytoglobin-overexpressing cells. In addition, cytoglobin knockdown significantly decreased the doubling time of glioma cell lines, consistent with a putative tumor suppressor function. These finding suggest that modulating cytoglobin levels may be a promising treatment strategy for sensitizing human glioma cells to oxidative stress that is induced by ionizing radiation, certain chemotherapies and ischemia-reperfusion.

Notch signaling as a therapeutic target for breast cancer treatment?

Aberrant Notch signaling can induce mammary gland carcinoma in transgenic mice, and high expressions of Notch receptors and ligands have been linked to poor clinical outcomes in human patients with breast cancer. This suggests that inhibition of Notch signaling may be beneficial for breast cancer treatment. In this review, we critically evaluate the evidence that supports or challenges the hypothesis that inhibition of Notch signaling would be advantageous in breast cancer management. We find that there are many remaining uncertainties that must be addressed experimentally if we are to exploit inhibition of Notch signaling as a treatment approach in breast cancer. Nonetheless, Notch inhibition, in combination with other therapies, is a promising avenue for future management of breast cancer. Furthermore, since aberrant Notch4 activity can induce mammary gland carcinoma in the absence of RBPjκ, a better understanding of the components of RBPjκ-independent oncogenic Notch signaling pathways and their contribution to Notch-induced tumorigenesis would facilitate the deployment of Notch inhibition strategies for effective treatment of breast cancer.

Characterization and comparison of protein complexes initiated by the intracellular domain of individual Notch paralogs.

The Notch signaling pathway is essential for embryonic development, organogenesis, and tissue homeostasis. Aberrant Notch signaling is associated with several types of cancers. The active form of Notch receptor is its intracellular domain (NICD), which is released from the cell membrane by serial proteolytic cleavages following ligand binding. Dose-dependent effects of NICD on cellular phenotypes have been observed under several conditions although the underlying mechanisms have not been well studied. Moreover, there are four mammalian Notch paralogs that have redundant as well as unique functions. The molecular basis for this variability is also not well understood. In this study, we used size exclusion chromatography to examine the overall distribution of NICD among NICD-containing protein complexes under conditions of increasing NICD abundance. We found that the assembly of NICD protein complexes was dose-dependent and that the abundance of the canonical complex was limited by, MAML, one of the proteins involved in the formation of canonical NICD transactivation complex, which became saturated with increasing NICD abundance. In addition, N4ICD showed a unique elution profile among the four NICDs. These results help to explain the dose-dependent and paralog-specific activities of NICD. These results are informative for the development of new reagents to block Notch signaling for therapeutic benefit.

Tumour xenograft detection through quantitative analysis of the metabolic profile of urine in mice.

The metabolic content of urine from NIH III nude mice (n = 22) was analysed before and after inoculation with human glioblastoma multiforme (GBM) cancer cells. An age- and gender-matched control population (n = 14) was also studied to identify non-tumour-related changes. Urine samples were collected daily for 6 weeks, beginning 1 week before cell injection. Metabolite concentrations were obtained via targeted profiling with Chenomx Suite 5.1, based on nuclear magnetic resonance (NMR) spectra acquired on an Oxford 800 MHz cold probe NMR spectrometer. The Wilcoxon rank sum test was used to evaluate the significance of the change in metabolite concentration between the two time points. Both the metabolite concentrations and the ratios of pairs of metabolites were studied. The complicated inter-relationships between metabolites were assessed through partial least-squares discriminant analysis (PLS-DA). Receiver operating characteristic (ROC) curves were generated for all variables and the area under the curve (AUC) calculated. The data indicate that the number of statistically significant changes in metabolite concentrations was more pronounced in the tumour-bearing population than in the control animals. This was also true of the ratios of pairs of metabolites. ROC analysis suggests that the ratios were better able to differentiate between the pre- and post-injection samples compared to the metabolite concentrations. PLS-DA models produced good separation between the populations and had the best AUC results (all models exceeded 0.937). These results demonstrate that metabolomics may be used as a screening tool for GBM cells grown in xenograft models in mice.

ADC response to radiation therapy correlates with induced changes in radiosensitivity.

PURPOSE: Magnetic resonance imaging was used to compare the responses of human glioma tumor xenografts to a single fraction of radiation, where a change in radiosensitivity was induced by use of a suture-based ligature. METHODS: Ischemia was induced by use of a suture-based ligature. Six mice were treated with 800 cGy of 200 kVp x rays while the ligature was applied. An additional six mice had the ligature applied for the same length of time but were not irradiated. Quantitative maps of each tumor were produced of water apparent diffusion coefficient (ADC) and transverse relaxation time (T2). Mice were imaged before and at multiple points after treatment. Volumetric, ADC, and T2 responses of the ligated groups were compared to previously measured responses of the same tumor model to the same radiation treatment, as well as those from an untreated control group. RESULTS: Application of the ligature without irradiation did not affect tumor ADC values, but did produce a temporary decrease in tumor T2 values. Average tumor T2 was reduced by 6.2% 24 h after the ligature was applied. Average tumor ADC increased by 9.6% 7 days after irradiation with a ligature applied. This response was significantly less than that observed in the same tumor model when no ligature is present (21.8% at 7 days after irradiation). CONCLUSIONS: These observations indicate that the response of ADC to radiation therapy is not determined entirely by physical dose deposition, but at least in part by radiosensitivity and resultant biological response.

Hypoxic regulation of cytoglobin and neuroglobin expression in human normal and tumor tissues.

BACKGROUND: Cytoglobin (Cygb) and neuroglobin (Ngb) are recently identified globin molecules that are expressed in vertebrate tissues. Upregulation of Cygb and Ngb under hypoxic and/or ischemic conditions in vitro and in vivo increases cell survival, suggesting possible protective roles through prevention of oxidative damage. We have previously shown that Ngb is expressed in human glioblastoma multiforme (GBM) cell lines, and that expression of its transcript and protein can be significantly increased after exposure to physiologically relevant levels of hypoxia. In this study, we extended this work to determine whether Cygb is also expressed in GBM cells, and whether its expression is enhanced under hypoxic conditions. We also compared Cygb and Ngb expression in human primary tumor specimens, including brain tumors, as well as in human normal tissues. Immunoreactivity of carbonic anhydrase IX (CA IX), a hypoxia-inducible metalloenzyme that catalyzes the hydration of CO2 to bicarbonate, was used as an endogenous marker of hypoxia. RESULTS: Cygb transcript and protein were expressed in human GBM cells, and this expression was significantly increased in most cells following 48 h incubation under hypoxia. We also showed that Cygb and Ngb are expressed in both normal tissues and human primary cancers, including GBM. Among normal tissues, Cygb and Ngb expression was restricted to distinct cell types and was especially prominent in ductal cells. Additionally, certain normal organs (e.g. stomach fundus, small bowel) showed distinct regional co-localization of Ngb, Cygb and CA IX. In most tumors, Ngb immunoreactivity was significantly greater than that of Cygb. In keeping with previous in vitro results, tumor regions that were positively stained for CA IX were also positive for Ngb and Cygb, suggesting that hypoxic upregulation of Ngb and Cygb also occurs in vivo. CONCLUSIONS: Our finding of hypoxic up-regulation of Cygb/Ngb in GBM cell lines and human tumor tissues suggests that these globin molecules may be part of the repertoire of defense mechanisms that allow cancer cells to survive in hypoxic microenvironments.

Monitoring T2 and ADC at 9.4 T following fractionated external beam radiation therapy in a mouse model.

The purpose of this study is to investigate the response of transverse relaxation time (T2) and apparent diffusion coefficient (ADC) in human glioma tumor xenografts during and after fractionated radiotherapy. Tumor-bearing mice were divided into four treatment groups (n=6 per group) that received a total dose of 800 cGy of 200 kVp x-rays, given over two or three fractions, with a fraction spacing of either 24 or 72 h. A fifth treatment group received 800 cGy in a single fraction, and a sixth group of mice served as an untreated control. All mice were scanned pretreatment, before each fraction and at multiple points after treatment using a 9.4 T magnetic resonance imaging (MRI) system. Quantitative T2 and ADC maps were produced. All treated groups showed an increase in mean tumor ADC, though the time for this response to reach a maximum and return toward baseline was delayed in the fractionated groups. The highest ADC was measured 7 days after the final fraction of treatment for all groups. There were no significant differences in the maximum measured change in ADC between any of the treated groups, with the average measured maximum value being 20.5% above baseline. After treatment, all groups showed an increase in mean tumor T2, with the average measured maximum T2 being 4.7% above baseline. This increase was followed by a transition to mean T2 values below baseline values, with the average measured tumor T2 being 92.4% of the pretreatment value. The transition between elevated and depressed T2 values was delayed in the cases of fractionated therapies and occurred between 3.6 and 7.3 days after the last fraction of treatment. These results further the understanding of the temporal evolution of T2 and ADC during fractionated radiotherapy and support their potential use as time-sensitive biomarkers for tumor response.

Temporal and dose dependence of T2 and ADC at 9.4 T in a mouse model following single fraction radiation therapy.

The purpose of this study is to use magnetic resonance imaging to monitor the response of human glioma tumor xenografts to single fraction radiation therapy. Mice were divided into four treatment groups (n = 6 per group) that received 50, 200, 400, or 800 cGy of 200 kVp x rays. A fifth group (n = 6) received no radiation dose and served as the control. Quantitative maps of the treated tumor tissue were produced of water apparent diffusion coefficient (ADC) and transverse relaxation time (T2). Mice were imaged before and at multiple time points after treatment. There was a statistically significant difference in tumor growth relative to that of the control for all treatment groups. Only the highest dose group showed T2 values that were significantly different at all measured time points after treatment. In this group, there was an 8.3% increase in T2 relative to controls 2 days after treatment, but when measured 14 days after treatment, mean tumor T2 had dropped to 10.1% below the initial value. ADC showed statistically significant differences from the control at all dose points. A radiation dose dependence was observed. In the highest dose group, the fractional increases in ADC were higher than those observed for T2. ADC was sensitive to radiation-induced changes in lower dose groups that did not have significant T2 change. At all doses, elevation of mean tumor ADC preceded deviations in tumor growth from the control. These observations support the potential application of ADC as a time and dose sensitive marker of tumor response to radiation therapy.