Dynamic methylation and expression of alternative promoters for oestrogen receptor alpha in cell line models of fulvestrant resistance.

Oestrogen receptor alpha (ER; gene symbol ESR1) is the most important prognostic and treatment-predictive biomarker in breast cancer. Drugs targeting oestrogen and ER for endocrine therapy of breast cancer include aromatase inhibitors, the selective ER modulator tamoxifen and the selective ER degrader fulvestrant. Tumours can develop resistance to endocrine therapy through several mechanisms, which is often linked to altered expression of ER. To investigate the role of promoter methylation in the regulation of ESR1 expression, we used bisulfite sequencing to measure methylation at CpG sites in alternative ER promoter regions for six cell line models of fulvestrant resistance. Both CpG methylation and expression of alternative first exons changed dynamically, with striking differences between cell lines that had stable or unstable resistance upon fulvestrant withdrawal. Methylation at some CpG sites was strongly negatively correlated with expression of specific first exons. In a breast tumour cohort, higher relative expression of upstream alternative first exons was associated with worse prognosis in post-menopausal women with ER-positive tumours who received endocrine therapy.

Evaluation of hop test movement quality to enhance return to sport testing. A cross-sectional study.

Introduction: Return to Sport tests with functional hop tests are often used to decide when a person is ready to return to sport after an anterior cruciate ligament (ACL) injury. Poor movement quality, such as knee valgus, hip adduction and hip internal rotation is considered a risk factor for ACL injury. However, it is unclear whether existing tests adequately cover the aspect of movement quality. This study aims to investigate whether there is a relationship between the calculated limb symmetry index (LSI) of hop tests as an indication of performance and the total score of the "Quality First" assessment (movement quality). The second aim is to examine the reliability of the newly developed "Quality First" assessment for evaluating movement quality in hop tests. Methods: The cross-sectional study recruited 34 patients with an ACL reconstruction. The vertical hop, single-leg hop for distance, and side hop tests were performed and recorded. The video recordings were assessed using the "Quality First" assessment. The Spearman correlation coefficient was calculated using the LSI and the "Quality First" total score. Intraclass correlation coefficients (ICC) and standard error of measurements (SEM) were used to calculate intra- and interrater reliability. In addition, the minimal detectable change (MDC) was determined. Results: The correlation test between the LSI and the "Quality First" total score showed no correlation for all three jumps (r = -0.1-0.02/p-value = 0.65-0.93). The interrater reliability of the "Quality First" assessment showed fair to good reliability (ICC2: 0.45-0.60), with SEM ranging from 1.46 to 1.73 and the MDC from 4.06 to 4.8. Intrarater reliability was good to excellent (ICC3: 0.73-0.85), with SEM values ranging from 0.89 to 1.09 and the MDC from 2.47 to 3.01. Conclusion: The quality of movement, measured with the "Quality First" assessment, indicated no correlation with the calculated LSI from jump performance, therefore movement quality should also be examined in Return to Sport tests. The "Quality First" assessment shows fair to good reliability when used by different raters. When used multiple times by the same rater, the assessment has good to excellent reliability.

Content validity, interpretability, and internal consistency of the "Quality First" assessment to evaluate movement quality in hop tests following ACL rehabilitation. A cross-sectional study.

Introduction: Current approaches fail to adequately identify sport readiness after anterior cruciate ligament (ACL) rehabilitation. Altered landing biomechanics after ACL reconstruction are associated with increased risk of a noncontact ACL reinjury. There is a lack of objective factors to screen for deficient movement patterns. Therefore, the aim of this study was to investigate content validity, interpretability, and internal consistency for the newly developed "Quality First" assessment to evaluate movement quality during hop tests in patients after ACL rehabilitation. Method: Participants in this cross-sectional study were recruited in collaboration with the Altius Swiss Sportmed Center in Rheinfelden, Switzerland. After a successful ACL reconstruction, the movement quality of 50 hop test batteries was evaluated between 6 and 24 months postoperatively with the "Quality First" assessment. Content validity was assessed from the perspective of professionals. To check the interpretability, classical test theory was employed. Cronbach's α was calculated to evaluate internal consistency. Results: Content validity resulted in the inclusion of three different hop tests (single-leg hop for distance, vertical hop, and side hop). The "Quality First" assessment is enabled to evaluate movement quality in the sagittal, vertical, and the transversal plane. After the exclusion process, the "Quality First" assessment was free from floor and ceiling effects and obtained a sufficient Cronbach's α. The final version consists of 15 items, rated on a 4-point scale. Discussion: By means of further validations, the "Quality First" assessment could offer a possibility to evaluate movement quality after ACL rehabilitation during hop tests.

Development of Planning in Children with High-Functioning Autism Spectrum Disorders and/or Attention Deficit/Hyperactivity Disorder.

Planning impairment is often observed in children with high-functioning autism spectrum disorders (ASD), but attempts to differentiate planning in ASD from children with attention deficit hyperactivity disorder (ADHD) and typically developing children (TD) have yielded inconsistent results. This study examined differences between these groups by focusing on development and analyzing performance in searching ahead several steps ("search depth") in addition to commonly used global performance measures in planning. A cross-sectional consecutive sample of 83 male patients (6-13 years), subgrouped as ASD without (ASD-, n = 18) or with comorbid ADHD (ASD+, n = 23), ADHD only (n = 42) and n = 42 TD children (6-13 years) were tested with the Tower-of-London-task. For global performance, ASD+ showed the lowest accuracy in younger children, but similar performance as TD at older ages, suggesting delayed development. Typically, a prolongation of planning time with increasing problem difficulty is observed in older children as compared to younger children. Here, this was most pronounced in ASD-, but under-expressed in ADHD. In contrast to global performance, effects of search depth were independent of age. ASD-, but not ASD+, showed increased susceptibility to raised demands on mentally searching ahead, along with the longest planning times. Thus, examining both global and search depth performance across ages revealed discernible patterns of planning between groups. Notably, the potentially detrimental impact of two diagnosed disorders does not add up in ASD+ in this task. Rather, our results suggest paradoxical enhancement of performance, ostensibly attributable to disruption of behavioral rigidity through increased impulsivity, which did not take place in ASD-. Autism Res 2016, 9: 739-751. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.

Looking ahead from age 6 to 13: a deeper insight into the development of planning ability.

Planning ability gradually increases throughout childhood. However, it remains unknown whether this is attributable to global factors such as an increased ability and willingness to inhibit premature, impulsive responding, or due to the availability of specific planning operations, such as being able to mentally plan ahead more steps ('search depth') or to derive a clear temporal order of goals by the task layout ('goal hierarchy'). Here, we studied the development of planning ability with respect to these global and problem-specific aspects (search depth and goal hierarchy) of performance in 178 children from 6 to 13 years using the Tower of London task. As expected, global performance gradually developed with age. In accordance, planning durations increasingly reflected global problem demands with longer pre-planning in harder problems. Furthermore, specific planning parameters revealed that children were increasingly capable of mentally searching ahead more steps. In contrast, the ability to derive a goal hierarchy did not show age-related changes. While the global development of planning performance and adaptive planning durations were proposed to primarily reflect enhanced self-monitoring, the specific increase in search depth across childhood that most likely proceeds until young adult age represents more directly planning-related processes. Thus, development of planning ability is supported by multiple contributions.