TAL1 cooperates with PI3K/AKT pathway activation in T-cell acute lymphoblastic leukemia

TAL1 is ectopically expressed in about 30% of T-cell acute lymphoblastic leukemia (T-ALL) due to chromosomal rearrangements leading to the STIL-TAL1 fusion genes or due to non-coding mutations leading to a de novo enhancer driving TAL1 expression. Analysis of sequence data from T-ALL cases demonstrates a significant association between TAL1 expression and activating mutations of the PI3K-AKT pathway. We investigated the oncogenic function of TAL1 and the possible cooperation with PI3K-AKT pathway activation using isogenic pro-T-cell cultures ex vivo and in vivo leukemia models. We found that TAL1 on its own suppressed T-cell growth, in part by affecting apoptosis genes, while the combination with AKT pathway activation reduced apoptosis and was strongly driving cell proliferation ex vivo and leukemia development in vivo. As a consequence, we found that TAL1+AKT^E17K transformed cells are more sensitive to PI3K-AKT pathway inhibition compared to AKT^E17K transformed cells, related to the negative effect of TAL1 in the absence of activated PI3K-AKT signaling. We also found that both TAL1 and PI3K-AKT signaling increased the DNA-repair signature in T cells resulting in synergy between PARP and PI3K-AKT pathway inhibition. In conclusion, we have developed a novel mouse model for TAL1+AKT^E17K driven T-ALL development and have identified a vulnerability of these leukemia cells to PI3K-AKT and PARP inhibitors.     

A self‐portrait: Design opportunities for a tool that supports children's involvement in brain‐related health care

IntroductionPaediatric patients with disorders that involve brain functioning are particularly vulnerable with respect to including them in shared decision‐making. Current tools are mostly paper or digital patient information. We lay the groundwork for improving engagement with a concept that we coined ‘the Self‐Portrait’. The main goals were to identify (1) obstacles and (2) design parameters that enable patient participation.MethodsA research‐through‐design approach was utilized in nine patients with brain‐related disorders (4–12 years), 15 parents and 15 medical professionals, involving contextual research (interviews and observations) within the paediatric hospital and patients'' homes and codesign. Sensitizing materials and early instances of design solutions were deployed as catalysts for communication. Five rounds of enriched interviews and design reviews were thematically analysed to answer the research questions.ResultsObstacles to child involvement were related to children''s level of understanding, the time and energy necessary for information processing and lack of perceived relevance of the information. Patients'' engagement is supported by design features that extend the time frame of interaction beyond the consultation, transfer information interactively and give control and influence during the consultation.ConclusionObstacles were detected that complicate child engagement, which differ between stakeholders. Promising design features were identified that have the potential to play an important role in enabling active child involvement. These findings show that applying principles of human‐centred design research and codesign can bring together patients, parents and medical professionals around a tool that provides a shared language and focus, which are prerequisites to increase child engagement.Patient or Public ContributionPatients, parents and clinicians contributed as design informants during contextual research and design reviews. Clinicians provided feedback on the initial outcomes of thematic analysis. Two researchers assisted in consensus sessions during the thematic analysis.     

Reproductive preferences of pregnant women under shifting probabilities of vertical HIV transmission

Pregnant women, imagining they were HIV-positive, were asked whether they would have an abortion or avoid pregnancy under shifting probabilities of vertical transmission.     

In Vivo Induced Malignant Hyperthermia in Pigs. I. Physiological and Biochemical Changes and the Influence of Dantrolene Sodium

The effects of an induced malignant hyperthermia (MH) crisis have been studied in the intact pig. Both physiological and biochemical changes in skeletal muscle were studied. MH was induced with 3% halothane plus a bolus injection of succinylcholine. In the prechallenge period a significant difference was observed in the concentration of certain muscle metabolites, comparing the MH-susceptible (MH+) with the non-susceptible (MH^-) pigs. A lower level was measured for phosphocreatine (PCr), inosine monophosphate (IMP) and an increased level of lactate and creatine (Cr) in the susceptible pigs (MH+). The challenge caused a significant reduction of the level of PCr and adenosine in MH+ pigs, compared to the prechallenge period. After administration of dantrolene sodium, a significant decrease was measured in the level of lactate, compared to the prechallenge period as well as during the challenge. In contrast, in the control pigs no significant changes were observed in muscle metabolites, either after induction of MH or after the administration of dantrolene sodium. Enzyme activity determinations of muscle adenylate kinase and adenosine monophosphate (AMP)- deaminase did not show any difference in activity either before or during the MH crisis or after treatment with dantrolene sodium. The earliest physiological change during an induced MH crisis in our study was thrapid increase of the end-tidal CO₂. Within 5 min after MH induction, end-tidal CO₂ was doubled. It is concluded that the monitoring of the end-tidal CO2 is essential to diagnose MH at a very early stage.     

Post-operative Analgesia by Epidural Versus Intramuscular Nicomorphine after Thoracotomy. Part II

One hundred and sixty-three patients subjected to three different types of thoracic operation were allocated randomly either to balanced intravenous anaesthesia including i.v. opiates with post-operative intramuscular opiates (intramuscular group) or to balanced intravenous anaesthesia without i.v. opiates but with high thoracic epidural regional block during the operation as well as epidural nicomorphine post-operatively (epidural group). Post-operative nicomorphine in either group was given only at the request of the patient and as frequently as needed to obtain satisfactory pain relief. Patients in the epidural group were given nicomorphine exclusively by epidural injection. Patients in the epidural group required significantly less nicomorphine for effective pain relief (29 mg (sd = 10) over a period of 3 days compared to 52 mg (sd = 27) in the intramuscular group. Significantly fewer pulmonary complications in the epidural group were observed (9 atelectases in 83 patients in the epidural group compared to 24 atelectases in 80 patients in the intramuscular group). Only one patient developed pneumonia (intramuscular group). Although the epidural catheter was inserted at the T3-T4 level, no signs of ventilatory depression were found; on the contrary, respiration in the epidural group was significantly better than the intramuscular group. None of the patients, in either analgesia group, needed to be ventilated post-operatively.     

Ascorbic acid effect on methylcholanthrene-induced transformation in C3H10T1/2 clone 8 cells

Ascorbic acid (50 μg/ml), added to the culture medium on a biweekly basis, suppresses the methylcholanthrene-induced transformation of C₃H10T1/2 cells.     

Ultrasound-guided subgluteal sciatic nerve blocks with stimulating catheters in children: a descriptive study

We describe our clinical experience of combining ultrasound guidance and nerve stimulation for the insertion of subgluteal sciatic catheters in children. Ten children scheduled for lower limb surgery with a combined general anesthetic and a subgluteal sciatic catheter placement for both operative anesthesia and postoperative pain relief were studied. Under ultrasonographic guidance the sciatic catheter was placed using an 17-gauge 50-mm Arrow continuous peripheral nerve block needle and a 19-gauge stimulating catheter (Stimucath). The minimal electrical current required for muscle contraction on the stimulating needle and catheter differed widely among patients. Based on the visualization of the spread of local anesthetic during injection through the catheter, a successful prediction for the sciatic block was made in all patients. All catheters were successfully placed and provided excellent postoperative pain relief without complications.