Radiotherapy for Soft Tissue Sarcoma of the Proximal Lower Extremity

Soft-tissue sarcoma (STS) is a histopathologically diverse group of tumors accounting for approximately 10,000 new malignancies in the US each year. The proximal lower extremity is the most common site for STS, accounting for approximately one-third of all cases. Coordinated multimodality management in the form of surgery and radiation is often critical to local control, limb preservation, and functional outcome. Based on a review of currently available Medline literature and professional experience, this paper provides an overview of the treatment of STS of the lower extremity with a particular focus on the modern role of radiotherapy

Wave Intensity Analysis Provides Novel Insights Into Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension.

BACKGROUND: In contrast to systemic hypertension, the significance of arterial waves in pulmonary hypertension (PH) is not well understood. We hypothesized that arterial wave energy and wave reflection are augmented in PH and that wave behavior differs between patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). METHODS AND RESULTS: Right heart catheterization was performed using a pressure and Doppler flow sensor-tipped catheter to obtain simultaneous pressure and flow velocity measurements in the pulmonary artery. Wave intensity analysis was subsequently applied to the acquired data. Ten control participants, 11 patients with PAH, and 10 patients with CTEPH were studied. Wave speed and wave power were significantly greater in PH patients compared with controls, indicating increased arterial stiffness and right ventricular work, respectively. The ratio of wave power to mean right ventricular power was lower in PAH patients than CTEPH patients and controls. Wave reflection index in PH patients (PAH: ≈25%; CTEPH: ≈30%) was significantly greater compared with controls (≈4%), indicating downstream vascular impedance mismatch. Although wave speed was significantly correlated to disease severity, wave reflection indexes of patients with mildly and severely elevated pulmonary pressures were similar. CONCLUSIONS: Wave reflection in the pulmonary artery increased in PH and was unrelated to severity, suggesting that vascular impedance mismatch occurs early in the development of pulmonary vascular disease. The lower wave power fraction in PAH compared with CTEPH indicates differences in the intrinsic and/or extrinsic ventricular load between the 2 diseases

Supporting learners’ agentic engagement with feedback:a systematic review and a taxonomy of recipience processes

Much has been written in the educational psychology literature about effective feedback and how to deliver it. However, it is equally important to understand how learners actively receive, engage with, and implement feedback. This article reports a systematic review of the research evidence pertaining to this issue. Through an analysis of 195 outputs published between 1985 and early 2014, we identified various factors that have been proposed to influence the likelihood of feedback being used. Furthermore, we identified diverse interventions with the common aim of supporting and promoting learners' agentic engagement with feedback processes. We outline the various components used in these interventions, and the reports of their successes and limitations. Moreover we propose a novel taxonomy of four recipience processes targeted by these interventions. This review and taxonomy provide a theoretical basis for conceptualizing learners' responsibility within feedback dialogues and for guiding the strategic design and evaluation of interventions. Receiving feedback on one's skills and understanding is an invaluable part of the learning process, benefiting learners far more than does simply receiving praise or punishment (Black & Wiliam, 1998 Black, P., & Wiliam, D. (1998). Assessment and classroom learning. Assessment in Education: Principles, Policy & Practice, 5, 7–74. doi:10.1080/0969595980050102[Taylor & Francis Online]; Hattie & Timperley, 2007 Hattie, J., & Timperley, H. (2007). The power of feedback. Review of Educational Research, 77, 81–112. doi:10.3102/003465430298487[CrossRef], [Web of Science ®]). Inevitably, the benefits of receiving feedback are not uniform across all circumstances, and so it is imperative to understand how these gains can be maximized. There is increasing consensus that a critical determinant of feedback effectiveness is the quality of learners' engagement with, and use of, the feedback they receive. However, studies investigating this engagement are underrepresented in academic research (Bounds et al., 2013 Bounds, R., Bush, C., Aghera, A., Rodriguez, N., Stansfield, R. B., & Santeen, S. A. (2013). Emergency medicine residents' self-assessments play a critical role when receiving feedback. Academic Emergency Medicine, 20, 1055–1061. doi:10.1111/acem.12231[CrossRef], [PubMed], [Web of Science ®]), which leaves a “blind spot” in our understanding (Burke, 2009 Burke, D. (2009). Strategies for using feedback students bring to higher education. Assessment & Evaluation in Higher Education, 34, 41–50. doi:10.1080/02602930801895711[Taylor & Francis Online], [Web of Science ®]). With this blind spot in mind, the present work sets out to systematically map the research literature concerning learners' proactive recipience of feedback. We use the term “proactive recipience” here to connote a state or activity of engaging actively with feedback processes, thus emphasizing the fundamental contribution and responsibility of the learner (Winstone, Nash, Rowntree, & Parker, in press Winstone, N. E., Nash, R. A., Rowntree, J., & Parker, M. (in press). ‘It'd be useful, but I wouldn't use it’: Barriers to university students' feedback seeking and recipience. Studies in Higher Education. doi: 10.1080/03075079.2015.1130032[Taylor & Francis Online]). In other words, just as Reeve and Tseng (2011 Reeve, J., & Tseng, M. (2011). Agency as a fourth aspect of student engagement during learning activities. Contemporary Educational Psychology, 36, 257–267. doi:10.1016/j.cedpsych.2011.05.002[CrossRef], [Web of Science ®]) defined “agentic engagement” as a “student's constructive contribution into the flow of the instruction they receive” (p. 258), likewise proactive recipience is a form of agentic engagement that involves the learner sharing responsibility for making feedback processes effective

What supervisors and universities can do to enhance doctoral student experience (and how they can help themselves)

Over the past two decades, there has been a flurry of government papers and policy reports worldwide calling for increased number and diversity of doctoral researchers and a broadening of the curriculum to meet the developing needs of respective national 'knowledge-driven' economies. This has been followed by position papers and best practice examples of employability skills development in boundary-crossing doctoral programmes, especially in response to these initiatives. However, there is a disassociation between this ample literature expounding the new doctorate with its broader remit, inclusivity and production of 'industry-ready' graduates, and the comparatively sparse literature on the doctoral candidates' experiences of their programmes and career readiness. Within this review, we briefly outline international government initiatives and examples of the responses by Life Science and Biomedical doctoral programmes to address these various challenges. Further, we explore the recent literature on the lived experience of doctoral researchers by examining their perception of the recent changes to the research context to make recommendations for universities and supervisors on how to better support an ever more diverse doctoral population for a wide range of career opportunities. Examples of how doctoral researchers themselves can make the best of currently available opportunities are also provided

A high-resolution map of human evolutionary constraint using 29 mammals.

The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ∼4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ∼60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease

Epidermal growth factor mediates detachment from and invasion through collagen I and Matrigel in Capan-1 pancreatic cancer cells

BACKGROUND: Pancreatic adenocarcinoma is a highly invasive neoplasm. Epidermal growth factor (EGF) and its receptor are over expressed in pancreatic cancer, and expression correlates with invasion and metastasis. We hypothesized that EGF receptor and integrin signalling pathways interact in mediating cellular adhesion and invasion in pancreatic cancer, and that invasiveness correlates temporally with detachment from extracellular matrix. METHODS: We tested this hypothesis by investigating the role of EGF in mediating adhesion to and invasion through collagen I and Matrigel in the metastatic pancreatic adenocarcinoma cell line Capan-1. Adhesion and invasion were measured using in vitro assays of fluorescently-labeled cells. Adhesion and invasion assays were also performed in the primary pancreatic adenocarcinoma cell line MIA PaCa-2. RESULTS: EGF inhibited adhesion to collagen I and Matrigel in Capan-1 cells. The loss of adhesion was reversed by AG825, an inhibitor of erbB2 receptor signalling and by wortmannin, a PI3K inhibitor, but not by the protein synthesis inhibitor cycloheximide. EGF stimulated invasion through collagen I and Matrigel at concentrations and time courses similar to those mediating detachment from these extracellular matrix components. Adhesion to collagen I was different in MIA PaCa-2 cells, with no significant change elicited following EGF treatment, whereas treatment with the EGF family member heregulin-alpha elicited a marked increase in adhesion. Invasion through Matrigel in response to EGF, however, was similar to that observed in Capan-1 cells. CONCLUSION: An inverse relationship exists between adhesion and invasion capabilities in Capan-1 cells but not in MIA PaCa-2 cells. EGF receptor signalling involving the erbB2 and PI3K pathways plays a role in mediating these events in Capan-1 cells

Canine Morphology: Hunting for Genes and Tracking Mutations

In this essay, Abigail Shearin and Elaine Ostrander discuss the proposed genomic mechanisms for the extraordinary level of phenotypic variation observed in the domestic dog and the evidence detailing the variants responsible for the many shapes, sizes, textures, and colors of man's best friend

Patterns of leisure-time physical activity across pregnancy and adverse pregnancy outcomes

Background Although leisure-time physical activity (PA) contributes to overall health, including pregnancy health, patterns across pregnancy have not been related to birth outcomes. We hypothesized that women with sustained low leisure-time PA would have excess risk of adverse pregnancy outcomes, and that changing patterns across pregnancy (high to low and low to high) may also be related to risk of adverse pregnancy outcomes. Methods Nulliparous women (n = 10,038) were enrolled at 8 centers early in pregnancy (mean gestational age in weeks [SD] = 12.05 [1.51]. Frequency, duration, and intensity (metabolic equivalents) of up to three leisure activities reported in the first, second and third trimesters were analyzed. Growth mixture modeling was used to identify leisure-time PA patterns across pregnancy. Adverse pregnancy outcomes (preterm birth, [PTB, overall and spontaneous], hypertensive disorders of pregnancy [HDP], gestational diabetes [GDM] and small-for-gestational-age births [SGA]) were assessed via chart abstraction. Results Five patterns of leisure-time PA across pregnancy were identified: High (35%), low (18%), late decreasing (24%), early decreasing (10%), and early increasing (13%). Women with sustained low leisure-time PA were younger and more likely to be black or Hispanic, obese, or to have smoked prior to pregnancy. Women with low vs. high leisure-time PA patterns had higher rates of PTB (10.4 vs. 7.5), HDP (13.9 vs. 11.4), and GDM (5.7 vs. 3.1, all p < 0.05). After adjusting for maternal factors (age, race/ethnicity, BMI and smoking), the risk of GDM (Odds ratio 2.00 [95% CI 1.47, 2.73]) remained higher in women with low compared to high patterns. Early and late decreasing leisure-time PA patterns were also associated with higher rates of GDM. In contrast, women with early increasing patterns had rates of GDM similar to the group with high leisure-time PA (3.8% vs. 3.1%, adjusted OR 1.16 [0.81, 1.68]). Adjusted risk of overall PTB (1.31 [1.05, 1.63]) was higher in the low pattern group, but spontaneous PTB, HDP and SGA were not associated with leisure-time PA patterns. Conclusions Sustained low leisure-time PA across pregnancy is associated with excess risk of GDM and overall PTB compared to high patterns in nulliparous women. Women with increased leisure-time PA early in pregnancy had low rates of GDM that were similar to women with high patterns, raising the possibility that early pregnancy increases in activity may be associated with improved pregnancy health. Trial registration Registration number NCT02231398

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol.

Adding abiraterone acetate with prednisolone (AAP) or docetaxel with prednisolone (DocP) to standard-of-care (SOC) each improved survival in STAMPEDE: a multi-arm multi-stage platform randomised controlled protocol recruiting patients with high-risk locally advanced or metastatic PCa starting long-term androgen deprivation therapy (ADT). The protocol provides the only direct, randomised comparative data of SOC+AAP vs SOC+DocP