CBL mutations do not frequently occur in paediatric acute myeloid leukaemia

RAS‐pathway mutations, causing a proliferative advantage, occur in acute myeloid leukaemia (AML) and MLL‐rearranged leukaemia. Recently, mutations in the Casitas B lineage lymphoma (CBL) gene were reported to be involved in RAS‐pathway activation in various myeloid malignancies, but their role in paediatric AML is still unknown. We performed mutation analysis of 283 newly diagnosed and 33 relapsed paediatric AML cases. Only two mutant cases (0·7%) were identified in the newly diagnosed paediatric AML samples, of which one was MLL‐rearranged. Both mutant cases showed CBL mRNA expression in the range of the non‐mutated cases. Phosphorylated extracellular signal‐regulated kinase (pERK) was not correlated with CBL protein expression (n = 11). In conclusion, we report a very low CBL mutation frequency in paediatric AML, which, together with the lack of difference in protein and mRNA expression, illustrates the limited role of CBL in paediatric AML.     

Postprandial gallbladder motility during long term treatment with the long-acting somatostatin analog SMS 201-995 in acromegaly

The effects on gallbladder motility of long term treatment with the somatostatin analog SMS 201-995 (SMS) were studied in five patients with acromegaly treated for 6-32 months with 200-300 micrograms SMS daily. SMS (100 micrograms) or placebo was injected sc 45 min before a standard breakfast. Gallbladder volume (ultrasonography), plasma cholecystokinin (CCK), and pancreatic polypeptide (PP) were measured until 120 min after the meal. SMS completely suppressed the postprandial gallbladder contraction, despite a blunted, though still statistically significant, increase in plasma CCK from 1.6 +/- 0.2 pmol/L to an average of 3.7 +/- 1.7 pmol/L (P less than 0.01). The postprandial plasma PP peak after placebo was replaced by a slight but statistically significant decrease after SMS (P less than 0.05). A statistically significant correlation between the plasma CCK values and corresponding gallbladder volumes was seen only after placebo injection, not in the SMS study. We conclude that during long term treatment of acromegalics with SMS, an injection of 100 micrograms, sc, completely abolishes gallbladder contraction for at least 2 h after a standard breakfast, despite blunted, but still significant, CCK release. The data suggest a decreased sensitivity of the gallbladder to endogenous CCK during long term treatment with SMS. Careful control of patients with respect to the formation of gallstones is recommended.     

Evaluation of bi-objective treatment planning for high-dose-rate prostate brachytherapy—A retrospective observer study

PurposeBi-objective treatment planning for high-dose-rate prostate brachytherapy is a novel treatment planning method with two separate objectives that represent target coverage and organ-at-risk sparing. In this study, we investigated the feasibility and plan quality of this method by means of a retrospective observer study.Methods and MaterialsCurrent planning sessions were recorded to configure a bi-objective optimization model and to assess its applicability to our clinical practice. Optimization software, GOMEA, was then used to automatically generate a large set of plans with different trade-offs in the two objectives for each of 18 patients treated with high-dose-rate prostate brachytherapy. From this set, five plans per patient were selected for comparison to the clinical plan in terms of satisfaction of planning criteria and in a retrospective observer study. Three brachytherapists were asked to evaluate the blinded plans and select the preferred one.ResultsRecordings demonstrated applicability of the bi-objective optimization model to our clinical practice. For 14/18 patients, GOMEA plans satisfied all planning criteria, compared with 4/18 clinical plans. In the observer study, in 53/54 cases, a GOMEA plan was preferred over the clinical plan. When asked for consensus among observers, this ratio was 17/18 patients. Observers highly appreciated the insight gained from comparing multiple plans with different trade-offs simultaneously.ConclusionsThe bi-objective optimization model adapted well to our clinical practice. GOMEA plans were considered equal or superior to the clinical plans. In addition, presenting multiple high-quality plans provided novel insight into patient-specific trade-offs.     

Examining a Novel Gamified Approach to Attentional Retraining: Effects of Single and Multiple Session Training

Negative attention biases (AB) may play a causal role in the development of emotional disorders. In order to examine this proposed causal role, researchers have developed Attention Bias Modification (ABM) paradigms to experimentally induce or reduce AB. To date, most ABM studies have been based on modified dot-probe tasks. However, this task is only moderately successful in changing patterns of AB. In two laboratory-based experiments, we explored the effects of a novel visual search ABM paradigm, called “Intrinsically-Motivating Playable Attentional Control Training”, on AB processes and mood in undergraduate participants. Motivation was fostered by active task involvement (i.e., searching for target faces while ignoring irrelevant faces) and gamification techniques. In both experiments, training performance significantly improved, but failed to transfer to attention and mood measures. Possible explanations for the failure to find transfer effects are discussed.     

Phytochemical and Pharmacological Investigations on Nymphoides indica Leaf Extracts

Nymphoides indica (L.) Kuntze (Menyanthaceae) is traditionally used in the Indian subcontinent. However, scientific data reporting its constituents are poor. This study aimed at evaluating its phytochemical constituents and various biological activities. Phytochemical investigations of the extracts and fractions resulted in the isolation of 5 lipophilic compounds, i.e. azelaic (nonanedioic) acid (1) and 4‐methyl‐heptanedioic acid (3), hexadecanoic (2) and stearic acid (5) and the fatty alcohol hexadecanol (4); 3 seco‐iridoids, i.e. 7‐epiexaltoside (6), 6″,7″‐dihydro‐7‐epiexaltoside (7) and menthiafolin (8); 3 flavonoids, i.e. 3,7‐di‐O‐methylquercetin‐4′‐O‐β‐glucoside (9), 3‐O‐methylquercetin‐7‐O‐β‐glucoside (10) and 3,7‐di‐O‐methylquercetin (11); scopoletin (12) and ferulic acid (13); and the monoterpenoids foliamenthoic acid (14) and 6,7‐dihydrofoliamenthoic acid methyl ester (15). Compounds 1–5 showed moderate antimicrobial activities, whereas compound 9 presented mild antiprotozoal activities against Trypanosoma brucei (IC₅₀ 8 μM), Leishmania infantum (IC₅₀ 32 μM) and Trypanosoma cruzi (IC₅₀ 30 μM). Antiglycation activity was shown by compounds 7 (IC₅₀ 0.36 mM), 10 (IC₅₀ 0.42 mM) and 15 (IC₅₀ 0.61 mM). Finally α‐glucosidase inhibition was shown by compounds 7, 9, 11 and 13–15. It could be concluded that N. indica leaf extracts possess mild to moderate antimicrobial, antiprotozoal, antioxidant and antidiabetic activities. Copyright © 2016 John Wiley & Sons, Ltd.     

Inflammation and Toll-like receptor ligation differentially affect the osteogenic potential of human mesenchymal stromal cells depending on their tissue origin

Mesenchymal stromal cells (MSCs) can be isolated not only from bone marrow (BM) but also from other tissues, including adipose tissue (AT) and umbilical cord Wharton's Jelly (WJ). Thanks to their ability to differentiate into various cell types, MSC are considered attractive candidates for cell-based regenerative therapy. In degenerative clinical settings, inflammation or infection is often involved. In the present work, we hypothesized that an inflammatory environment and/or Toll-like receptor (TLR) ligation could affect the MSC differentiation potential. MSC were isolated from BM, AT, and WJ. Inflammation was mimicked by a cytokine cocktail, and TLR activation was induced through TLR3 and TLR4 ligation. Osteogenesis was chosen as a model for differentiation. Osteogenic parameters were evaluated by measuring Ca2+ deposits and alkaline phosphatase (ALP) activity at day 7, 14, and 21 of the culture in an osteogenic medium. Our results show that WJ-MSC exhibit a much lower osteogenic potential than the other two MSC types. However, inflammation was able to strongly increase the osteogenic differentiation of WJ-MSC as calcification, and ALP activity appeared as early as day 7. However, this latter enzymatic activity remained much lower than that disclosed by BM-MSC. TLR3 or TLR4 triggering increased the osteogenesis in AT- and, to lesser extent, in BM-MSC. In conclusion, WJ-MSC constitutively disclose a lower osteogenic potential as compared with BM and AT-MSC, which is not affected by TLR triggering but is strongly increased by inflammation, then reaching the level of BM-MSC. These observations suggest that WJ-MSC could constitute an alternative of BM-MSC for bone regenerative applications, as WJ is an easy access source of large amounts of MSC that can effectively differentiate into osteoblasts in an inflammatory setting.     

Antimalarial efficacy of a quantified extract of Nauclea pobeguinii stem bark in human adult volunteers with diagnosed uncomplicated falciparum malaria. Part 1: a clinical phase IIA trial

The aim of this phase IIA clinical trial was to assess the efficacy of an 80?% ethanolic quantified extract (containing 5.6?% strictosamide as the putative active constituent) from Nauclea pobeguinii stem bark denoted as PR 259 CT1 in a small group of adult patients diagnosed with uncomplicated falciparum malaria. Results obtained from a phase I clinical trial on healthy male volunteers indicated that the oral administration during meals of two 500?mg capsules three times daily (each eight hours) during seven days was well tolerated and showed only mild and self-resolving adverse effects. This PR 259 CT1 drug regimen was obtained by mathematical conversion of animal doses obtained in several in vivo studies in mice to human equivalent doses as in falciparum malaria patients. The phase IIA study was an open cohort study in eleven appraisable adult patients suffering from proven Plasmodium falciparum malaria. The study was specifically designed to assess the efficacy of PR 259 CT1 administered with a dose regimen of two 500?mg capsules three times daily for three days, followed by outpatient treatment of one 500?mg capsule three times daily for the next four days, in order to prove that this therapeutic dose, which was calculated from animal doses, was effective to treat adult malaria patients and consequently useful for a future Phase IIB clinical trial. This study would then substitute a dose-escalating trial, which in general is used to find the appropriate dose for clinical studies. The phase IIA clinical trial was carried out according to the WHO 2003 14-day test, and the results revealed that all eleven patients were completely cleared of parasitemia and fever on days 3, 7, and 14 except for one patient, who experienced a recurrence of parasitemia at days 7 until 14. Besides this adequate clinical and parasitological response (ACPR), this trial also demonstrated that PR 259 CT1 was well tolerated with only mild and self-resolving adverse effects including fatigue and headache, which were in accordance with those found in the phase I clinical trial. Moreover, all symptoms progressively disappeared, and no symptoms were observed on day 14. Although the number of patients included in this study was rather limited, the statistical analysis nevertheless suggested the efficacy and tolerability of PR 259 CT1, which indicated that this herbal medicinal product might be considered as a putative candidate for a large scale clinical trial.     

Roles for the pre-supplementary motor area and the right inferior frontal gyrus in stopping action: electrophysiological responses and functional and structural connectivity

Both the pre-supplementary motor area (preSMA) and the right inferior frontal gyrus (rIFG) are important for stopping action outright. These regions are also engaged when preparing to stop. We aimed to elucidate the roles of these regions by harnessing the high spatio-temporal resolution of electrocorticography (ECoG), and by using a task that engages both preparing to stop and stopping outright. First, we validated the task using fMRI in 16 healthy control participants to confirm that both the preSMA and the rIFG were active. Next, we studied a rare patient with intracranial grid coverage of both these regions, using macrostimulation, diffusion tractography, cortico-cortical evoked potentials (CCEPs) and task-based ECoG. Macrostimulation of the preSMA induced behavioral motor arrest. Diffusion tractography revealed a structural connection between the preSMA and rIFG. CCEP analysis showed that stimulation of the preSMA evoked strong local field potentials within 30 ms in rIFG. During the task, when preparing to stop, there was increased high gamma amplitude (~ 70-250 Hz) in both regions, with preSMA preceding rIFG by ~ 750 ms. For outright stopping there was also a high gamma amplitude increase in both regions, again with preSMA preceding rIFG. Further, at the time of stopping, there was an increase in beta band activity (~ 16 Hz) in both regions, with significantly stronger inter-regional coherence for successful vs. unsuccessful stop trials. The results complement earlier reports of a structural/functional action control network between the preSMA and rIFG. They go further by revealing between-region timing differences in the high gamma band when preparing to stop and stopping outright. They also reveal strong between-region coherence in the beta band when stopping is successful. Implications for theories of action control are discussed.