Src and ADAM-17-Mediated Shedding of Transforming Growth Factor-alpha Is a Mechanism of Acute Resistance to TRAIL

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo-2L) has emerged as a promising anticancer agent. However, resistance to TRAIL is likely to be a major problem, and sensitization of cancer cells to TRAIL may therefore be an important anticancer strategy. In this study, we examined the effect of the epidermal growth factor receptor (EGFR)tyrosine kinase inhibitor (TKI) gefitinib and a human epidermal receptor 2 (HER2)-TKI (M578440) on the sensitivity of human colorectal cancer (CRC) cell lines to recombinant human TRAIL (rhTRAIL). A synergistic interaction between rhTRAIL and gefitinib and rhTRAIL and M578440 was observed in both rhTRAIL-sensitive and resistant CRC cells. This synergy correlated with an increase in EGFR and HER2 activation after rhTRAIL treatment. Furthermore, treatment of CRC cells with rhTRAIL resulted in activation of the Src family kinases (SFK). Importantly, we found that rhTRAIL treatment induced shedding of transforming growth factor-alpha (TGF-alpha) that was dependent on SFK activity and the protease ADAM-17. Moreover, this shedding of TGF-alpha was critical for rhTRAIL-induced activation of EGFR. In support of this, SFK inhibitors and small interfering RNAs targeting ADAM-17 and TGF-alpha also sensitized CRC cells to rhTRAIL-mediated apoptosis. Taken together, our findings indicate that both rhTRAIL-sensitive and resistant CRC cells respond to rhTRAIL treatment by activating an EGFR/HER2-mediated survival response and that these cells can be sensitized to rhTRAIL using EGFR/HER2-targeted therapies. Furthermore, this acute response to rhTRAIL is regulated by SFK-mediated and ADAM-17-mediated shedding of TGF-alpha, such that targeting SFKs or inhibiting ADAM-17, in combination with rhTRAIL, may enhance the response of CRC tumors to rhTRAIL. [Cancer Res 2008;68(20):8312-21]

High bax expression is a good prognostic indicator in acute myeloid leukaemia

Most cytotoxic drugs kill cells by instigating the process of apoptosis and it has been suggested that apoptotic markers may provide an indication of tumour chemosensitivity. The aim of this study was to determine if such a relationship exists in acute myeloid leukaemia (AML). The levels of spontaneous apoptosis, bcl-2 and bax were evaluated in 56 newly diagnosed AML patients to determine if they correlated with a response to cytotoxic therapy. Spontaneous apoptosis was lower, but bcl-2, bax and the bcl-2/bax ratio were higher in AML compared with normal individuals. AML patients with high bax expression at diagnosis had significantly better prognosis for disease-free survival, event-free survival and overall survival (P = 0.016). In the standard risk group, high bax expression was in keeping with significantly improved survival. Multivariate analysis revealed bax to be an independent predictor of survival. There was a significant reduction in bcl-2 and bax expression when AML patients entered complete remission and also in relapsed AML patients who entered a second remission. This study suggests that bax is a useful prognostic indicator in AML and may assist with therapeutic decision-making for patients in the standard risk category.

Probabilistic classification of acute myocardial infarction from multiple cardiac markers

Logistic regression and Gaussian mixture model (GMM) classifiers have been trained to estimate the probability of acute myocardial infarction (AMI) in patients based upon the concentrations of a panel of cardiac markers. The panel consists of two new markers, fatty acid binding protein (FABP) and glycogen phosphorylase BB (GPBB), in addition to the traditional cardiac troponin I (cTnI), creatine kinase MB (CKMB) and myoglobin. The effect of using principal component analysis (PCA) and Fisher discriminant analysis (FDA) to preprocess the marker concentrations was also investigated. The need for classifiers to give an accurate estimate of the probability of AMI is argued and three categories of performance measure are described, namely discriminatory ability, sharpness, and reliability. Numerical performance measures for each category are given and applied. The optimum classifier, based solely upon the samples take on admission, was the logistic regression classifier using FDA preprocessing. This gave an accuracy of 0.85 (95% confidence interval: 0.78-0.91) and a normalised Brier score of 0.89. When samples at both admission and a further time, 1-6 h later, were included, the performance increased significantly, showing that logistic regression classifiers can indeed use the information from the five cardiac markers to accurately and reliably estimate the probability AMI. © Springer-Verlag London Limited 2008.

Training-induced changes in the pattern of triceps to biceps activation during reaching tasks after chronic and severe stroke

This exploratory study was undertaken to investigate the mechanisms that contributed to improvements in upper limb function following a novel training program. Surface electromyography (EMG) was used to examine training-induced changes in the pattern of triceps and biceps activation during reaching tasks in stroke survivors with severe paresis in the chronic stage of recovery. The EMG data were obtained in the context of a single blind randomised clinical trial conducted with 42 stroke survivors with minimal upper limb muscle activity and who were more than 6 months post-stroke. Of the 33 participants who completed the study, 10 received training of reaching using a non-robotic upper limb training device, the SMART Arm, with EMG triggered functional electrical stimulation (EMG-stim), 13 received training of reaching using the SMART Arm alone, and 10 received no intervention. Each intervention group engaged in 12 1-h training sessions over a 4-week period. Clinical and laboratory measures of upper limb function were administered prior to training (0 weeks), at completion (4 weeks) and 2 months (12 weeks) after training. The primary outcome measure was 'upper arm function' which is Item 6 of the Motor Assessment Scale (MAS). Laboratory measures consisted of two multijoint reaching tasks to assess 'maximum isometric force' and 'maximum distance reached'. Surface EMG was used to monitor triceps brachii and biceps brachii during the two reaching tasks. To provide a comparison with normal values, seven healthy adults were tested on one of the reaching tasks according to the same procedure. Study findings demonstrated a statistically significant improvement in upper limb function for stroke participants in the two training groups compared to those who received no training however no difference was found between the two training groups. For the reaching tasks, all stroke participants, when compared to normal healthy adults, exhibited lower triceps and biceps activation and a lower ratio of triceps to biceps activation. Following training, stroke participants demonstrated increased triceps activation and an increased ratio of triceps to biceps activation for the task that was trained. Better performance was associated with greater triceps activation and a higher ratio of triceps to biceps activation. The findings suggest that increased activation of triceps as an agonist and an improved coordination between triceps and biceps could have mediated the observed changes in arm function. The changes in EMG activity were small relative to the changes in arm function indicating that factors, such as the contribution of other muscles of reaching, may also be implicated.

The impact of dose escalation and resistance modulation in older patients with acute myeloid leukaemia and high risk myelodysplastic syndrome: the results of the LRF AML14 trial.:the results of the LRF AML14 trial

The acute myeloid leukaemia (AML)14 trial addressed four therapeutic questions in patients predominantly aged over 60 years with AML and High Risk Myelodysplastic Syndrome: (i) Daunorubicin 50 mg/m(2) vs. 35 mg/m(2); (ii) Cytarabine 200 mg/m(2) vs. 400 mg/m(2) in two courses of DA induction; (iii) for part of the trial, patients allocated Daunorubicin 35 mg/m(2) were also randomized to receive, or not, the multidrug resistance modulator PSC-833 in a 1:1:1 randomization; and (iv) a total of three versus four courses of treatment. A total of 1273 patients were recruited. The response rate was 62% (complete remission 54%, complete remission without platelet/neutrophil recovery 8%); 5-year survival was 12%. No benefits were observed in either dose escalation randomization, or from a fourth course of treatment. There was a trend for inferior response in the PSC-833 arm due to deaths in induction. Multivariable analysis identified cytogenetics, presenting white blood count, age and secondary disease as the main predictors of outcome. Although patients with high Pgp expression and function had worse response and survival, this was not an independent prognostic factor, and was not modified by PSC-833. In conclusion, these four interventions have not improved outcomes in older patients. New agents need to be explored and novel trial designs are required to maximise prospects of achieving timely progress.

Fathers’ Views and Understanding of their Roles in Families with a Child with Acute Lymphoblastic Leukaemia: An Interpretative Phenomenological Analysis

This study explored how fathers of children diagnosed with acute lymphoblastic leukaemia (ALL) perceived and understood the roles they had within their family over the course of their child’s illness and treatment. In-depth semi-structured interviews were conducted with five fathers. Transcripts were analysed using interpretative phenomenological analysis (IPA). The major themes that emerged were: adjusting to the diagnosis; the experience of maternal gate-keeping; striving for normalization; experiences of giving and receiving support. Overall, the fathers perceived themselves as having significant responsibility in helping their child and family cope with the illness experience. Clinical implications, including the need for professionals to recognize and more openly acknowledge the father’s position, are considered.

Increased cerebral output of free radicals during hypoxia: implications for acute mountain sickness?

Bailey DM, Taudorf S, Berg RMG, Lundby C, McEneny J, Young IS, Evans KA, James PE, Shore A, Hullin DA, McCord JM, Pedersen BK, Moller K. Increased cerebral output of free radicals during hypoxia: implications for acute mountain sickness? Am J Physiol Regul Integr Comp Physiol 297: R1283-R1292, 2009. First published September 2, 2009; doi: 10.1152/ajpregu.00366.2009.-This study examined whether hypoxia causes free radical-mediated disruption of the blood-brain barrier (BBB) and impaired cerebral oxidative metabolism and whether this has any bearing on neurological symptoms ascribed to acute mountain sickness (AMS). Ten men provided internal jugular vein and radial artery blood samples during normoxia and 9-h passive exposure to hypoxia (12.9% O-2). Cerebral blood flow was determined by the Kety-Schmidt technique with net exchange calculated by the Fick principle. AMS and headache were determined with clinically validated questionnaires. Electron paramagnetic resonance spectroscopy and ozone-based chemiluminescence were employed for direct detection of spin-trapped free radicals and nitric oxide metabolites. Neuron-specific enolase (NSE), S100 beta, and 3-nitrotyrosine (3-NT) were determined by ELISA. Hypoxia increased the arterio-jugular venous concentration difference (a-v(D)) and net cerebral output of lipid-derived alkoxyl-alkyl free radicals and lipid hydroperoxides (P