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The purpose of this study was to examine student's perceptions of the iPad applications-assisted instruction as part of their learning. In this study, multiple features and applications were evaluated as an instructional tool. Fifteen participants responded to the survey indicating their perceptions of the iPad and applications used as part of their course delivery. Overall, participants favored the use of this technology as an instructional tool in their learning and indicated several aspects that could be improved. J Allied Health 2016; 45(3):e49-e57.

Nucleophilic substitution reactions of alcohols are among the most fundamental and strategically important transformations in organic chemistry. For over half a century, these reactions have been achieved by using stoichiometric, and often hazardous, reagents to activate the otherwise unreactive alcohols. Here, we demonstrate that a specially designed phosphine oxide promotes nucleophilic substitution reactions of primary and secondary alcohols in a redox-neutral catalysis manifold that produces water as the sole by-product. The scope of the catalytic coupling process encompasses a range of acidic pronucleophiles that allow stereospecific construction of carbon-oxygen and carbon-nitrogen bonds.

BACKGROUNDPatients with sickle cell disease (SCD) frequently receive RBC units stored near the end of their permissible storage duration. We aimed to determine whether RBC storage duration influences recipient hematological, metabolic, and clinical chemistry parameters.METHODSIn a randomized, prospective, double-blind trial, 24 adults with SCD receiving chronic transfusion therapy were assigned to receive three consecutive outpatient transfusions with RBCs stored for either ≤10 days (short-stored; n = 13) or ≥30 days (long-stored; n = 11). Blood samples were collected from transfused units and from recipients at predefined time points for metabolomics, cytokine, and clinical laboratory analyses. The primary outcomes included post-transfusion hemoglobin and RBC count increments, metabolic markers of oxidative stress, iron metabolism, inflammation, and renal function.RESULTSTransfusion of short-stored RBCs was associated with significantly higher circulating 2,3-bisphosphoglycerate levels for up to 2 weeks after transfusion. Nadir RBC counts and hemoglobin A levels were higher in recipients of short-stored RBCs. In contrast, recipients of long-stored RBCs had higher transferrin saturation and plasma iron levels, elevated markers of oxidative stress and renal dysfunction, and increased proinflammatory cytokines and immunomodulatory metabolites. Metabolomics revealed storage age-dependent alterations in glycolysis, purine, and sphingolipid metabolism. Cytokine profiles and hematologic parameters corroborated the metabolic findings, indicating improved post-transfusion metabolic and inflammatory status with short-stored RBCs.CONCLUSIONTransfusion of short-stored RBCs yielded favorable metabolic and hematologic outcomes in adults with SCD, independent of immediate clinical endpoints.TRIAL REGISTRATIONClinicalTrials.gov NCT03704922FUNDINGNational Heart, Lung, and Blood Institute (NHLBI), NIH (K23HL136787, R01HL148151, R01HL146442, and R01HL149714).

Oncological use of anti-angiogenic VEGF inhibitors has been limited by the lack of informative biomarkers. Previously we reported circulating Tie2 as a vascular response biomarker for bevacizumab-treated ovarian cancer patients. Using advanced MRI and circulating biomarkers we have extended these findings in metastatic colorectal cancer ( n  = 70). Bevacizumab (10 mg/kg) was administered to elicit a biomarker response, followed by FOLFOX6-bevacizumab until disease progression. Bevacizumab induced a correlation between Tie2 and the tumor vascular imaging biomarker, K trans ( R :−0.21 to 0.47) implying that Tie2 originated from the tumor vasculature. Tie2 trajectories were independently associated with pre-treatment tumor vascular characteristics, tumor response, progression free survival (HR for progression = 3.01, p  = 0.00014; median PFS 248 vs. 348 days p  = 0.0008) and the modeling of progressive disease ( p  < 0.0001), suggesting that Tie2 should be monitored clinically to optimize VEGF inhibitor use. A vascular response is defined as a 30% reduction in Tie2; vascular progression as a 40% increase in Tie2 above the nadir. Tie2 is the first, validated, tumor vascular response biomarker for VEGFi. Identification of response biomarkers is a key step towards the development of personalised care. Here, Jayson et al. identify plasma Tie2 as a biomarker for the response of the tumor vasculature to anti-angiogenics in patients with metastatic colorectal cancer, suggesting that monitoring Tie2 levels may help guide therapy in the clinics.

Objectives To measure dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) biomarker repeatability in patients with non-small cell lung cancer (NSCLC). To use these statistics to identify which individual target lesions show early biological response. Materials and methods A single-centre, prospective DCE-MRI study was performed between September 2015 and April 2017. Patients with NSCLC were scanned before standard-of-care radiotherapy to evaluate biomarker repeatability and two weeks into therapy to evaluate biological response. Volume transfer constant ( K trans ), extravascular extracellular space volume fraction ( v e ) and plasma volume fraction ( v p ) were measured at each timepoint along with tumour volume. Repeatability was assessed using a within-subject coefficient of variation (wCV) and repeatability coefficient (RC). Cohort treatment effects on biomarkers were estimated using mixed-effects models. RC limits of agreement revealed which individual target lesions changed beyond that expected with biomarker daily variation. Results Fourteen patients (mean age, 67 years +/− 12, 8 men) had 22 evaluable lesions (12 primary tumours, 8 nodal metastases, 2 distant metastases). The wCV (in 8/14 patients) was between 9.16% to 17.02% for all biomarkers except for v p , which was 42.44%. Cohort-level changes were significant for K trans and v e ( p  < 0.001) and tumour volume ( p  = 0.002). K trans and tumour volume consistently showed the greatest number of individual lesions showing biological response. In distinction, no individual lesions had a real change in v e despite the cohort-level change. Conclusion Identifying individual early biological responders provided additional information to that derived from conventional cohort cohort-level statistics, helping to prioritise which parameters would be best taken forward into future studies. Clinical relevance statement Dynamic contrast-enhanced magnetic resonance imaging biomarkers K trans and tumour volume are repeatable and detect early treatment-induced changes at both cohort and individual lesion levels, supporting their use in further evaluation of radiotherapy and targeted therapeutics. Key Points Few literature studies report quantitative imaging biomarker precision, by measuring repeatability or reproducibility . Several DCE-MRI biomarkers of lung cancer tumour microenvironment were highly repeatable . Repeatability coefficient measurements enabled lesion-specific evaluation of early biological response to therapy, improving conventional assessment .

Background Patients with metastatic colorectal cancer are treated with cytotoxic chemotherapy supplemented by molecularly targeted therapies. There is a critical need to define biomarkers that can optimise the use of these therapies to maximise efficacy and avoid unnecessary toxicity. However, it is important to first define the changes in potential biomarkers following cytotoxic chemotherapy alone. This study reports the impact of standard cytotoxic chemotherapy across a range of circulating and imaging biomarkers. Methods A single-centre, prospective, biomarker-driven study. Eligible patients included those diagnosed with colorectal cancer with liver metastases that were planned to receive first line oxaliplatin plus 5-fluorouracil or capecitabine. Patients underwent paired blood sampling and magnetic resonance imaging (MRI), and biomarkers were associated with progression-free survival (PFS) and overall survival (OS). Results Twenty patients were recruited to the study. Data showed that chemotherapy significantly reduced the number of circulating tumour cells as well as the circulating concentrations of Ang1, Ang2, VEGF-A, VEGF-C and VEGF-D from pre-treatment to cycle 2 day 2. The changes in circulating concentrations were not associated with PFS or OS. On average, the MRI perfusion/permeability parameter, K trans , increased in response to cytotoxic chemotherapy from pre-treatment to cycle 2 day 2 and this increase was associated with worse OS (HR 1.099, 95%CI 1.01–1.20, p  = 0.025). Conclusions In patients diagnosed with colorectal cancer with liver metastases, treatment with standard chemotherapy changes cell- and protein-based biomarkers, although these changes are not associated with survival outcomes. In contrast, the imaging biomarker, K trans , offers promise to direct molecularly targeted therapies such as anti-angiogenic agents.

Imaging biomarkers require technical, biological, and clinical validation to be translated into robust tools in research or clinical settings. This study contributes to the technical validation of radiomic features from magnetic resonance imaging (MRI) by evaluating the repeatability of features from four MR sequences: pre-contrast T1- and T2-weighted images, pre-contrast quantitative T1 maps (qT1), and contrast-enhanced T1-weighted images. Fifty-one patients with colorectal cancer liver metastases were scanned twice, up to 7 days apart. Repeatability was quantified using the intraclass correlation coefficient (ICC) and repeatability coefficient (RC), and the impact of non-Gaussian feature distributions and image normalisation was evaluated. Most radiomic features had non-Gaussian distributions, but Box-Cox transformations enabled ICCs and RCs to be calculated appropriately for an average of 97% of features across sequences. ICCs ranged from 0.30 to 0.99, with volume and other shape features tending to be most repeatable; volume ICC > 0.98 for all sequences. 19% of features from non-normalised images exhibited significantly different ICCs in pair-wise sequence comparisons. Normalisation tended to increase ICCs for pre-contrast T1- and T2-weighted images, and decrease ICCs for qT1 maps. RCs tended to vary more between sequences than ICCs, showing that evaluations of feature performance depend on the chosen metric. This work suggests that feature-specific repeatability, from specific combinations of MR sequence and pre-processing steps, should be evaluated to select robust radiomic features as biomarkers in specific studies. In addition, as different repeatability metrics can provide different insights into a specific feature, consideration of the appropriate metric should be taken in a study-specific context.

BACKGROUND. Patients with sickle cell disease (SCD) frequently receive RBC units stored near the end of their permissible storage duration. We aimed to determine whether RBC storage duration influences recipient hematological, metabolic, and clinical chemistry parameters. METHODS. In a randomized, prospective, double-blind trial, 24 adults with SCD receiving chronic transfusion therapy were assigned to receive three consecutive outpatient transfusions with RBCs stored for either <10 days (short-stored; ? = 13) or 230 days (long-stored; ? = 11). Blood samples were collected from transfused units and from recipients at predefined time points for metabolomics, cytokine, and clinical laboratory analyses. The primary outcomes included post-transfusion hemoglobin and RBC count increments, metabolic markers of oxidative stress, iron metabolism, inflammation, and renal function. RESULTS. Transfusion of short-stored RBCs was associated with significantly higher circulating 2,3-bisphosphoglycerate levels for up to 2 weeks after transfusion. Nadir RBC counts and hemoglobin A levels were higher in recipients of short-stored RBCs. In contrast, recipients of long-stored RBCs had higher transferrin saturation and plasma iron levels, elevated markers of oxidative stress and renal dysfunction, and increased proinflammatory cytokines and immunomodulatory metabolites. Metabolomics revealed storage age-dependent alterations in glycolysis, purine, and sphingolipid metabolism. Cytokine profiles and hematologic parameters corroborated the metabolic findings, indicating improved post-transfusion metabolic and inflammatory status with short-stored RBCs. CONCLUSION. Transfusion of short-stored RBCs yielded favorable metabolic and hematologic outcomes in adults with SCD, independent of immediate clinical endpoints. TRIAL REGISTRATION. ClinicalTrials.gov NCT03704922 FUNDING. National Heart, Lung, and Blood Institute (NHLBI), NIH (K23HL136787, RO1HL148151, RO1HL146442, and RO1HL149714).

Gene amplification at chromosome 4q12 is a common alteration in human high grade gliomas including glioblastoma, a CNS tumour with consistently poor prognosis. This locus harbours the known oncogenes encoding the receptor tyrosine kinases PDGFRA, KIT, and VEGFR2. These receptors are potential targets for novel therapeutic intervention in these diseases, with expression noted in tumour cells and/or associated vasculature. Despite this, a detailed assessment of their relative contributions to different high grade glioma histologies and the underlying heterogeneity within glioblastoma has been lacking. We studied 342 primary high grade gliomas for individual gene amplification using specific FISH probes, as well as receptor expression in the tumour and endothelial cells by immunohistochemistry, and correlated our findings with specific tumour cell morphological types and patterns of vasculature. We identified amplicons which encompassed PDGFRA only, PDGFRA/KIT, and PDGFRA/KIT/VEGFR2, with distinct phenotypic correlates. Within glioblastoma specimens, PDGFRA amplification alone was linked to oligodendroglial, small cell and sarcomatous tumour cell morphologies, and rare MGMT promoter methylation. A younger age at diagnosis and better clinical outcome in glioblastoma patients is only seen when PDGFRA and KIT are co-amplified. IDH1 mutation was only found when all three genes are amplified; this is a subgroup which also harbours extensive MGMT promoter methylation. Whilst PDGFRA amplification was tightly linked to tumour expression of the receptor, this was not the case for KIT or VEGFR2. Thus we have identified differential patterns of gene amplification and expression of RTKs at the 4q12 locus to be associated with specific phenotypes which may reflect their distinct underlying mechanisms.