Phase I dose-escalation trial of the oral AKT inhibitor uprosertib in combination with the oral MEK1/MEK2 inhibitor trametinib in patients with solid tumors.

PurposeThis study aimed to determine the safety, tolerability, and recommended phase II doses of trametinib plus uprosertib (GSK2141795) in patients with solid tumors likely to be sensitive to MEK and/or AKT inhibition.MethodsThis was a phase I, open-label, dose-escalation, and dose-expansion study in patients with triple-negative breast cancer or BRAF-wild type advanced melanoma. The primary outcome of the expansion study was investigator-assessed response. Among 126 enrolled patients, 63 received continuous oral daily dosing of trametinib and uprosertib, 29 received various alternative dosing schedules, and 34 were enrolled into expansion cohorts. Doses tested in the expansion cohort were trametinib 1.5 mg once daily (QD) + uprosertib 50 mg QD.ResultsAdverse events (AEs) were consistent with those reported in monotherapy studies but occurred at lower doses and with greater severity. Diarrhea was the most common dose-limiting toxicity; diarrhea and rash were particularly difficult to tolerate. Overall, 59% and 6% of patients reported AEs with a maximum severity of grade 3 and 4, respectively. Poor tolerability prevented adequate delivery of uprosertib with trametinib at a concentration predicted to have clinical activity. The study was terminated early based on futility in the continuous-dosing expansion cohorts and a lack of pharmacological or therapeutic advantage with intermittent dosing. The objective response rate was < 5% (1 complete response, 5 partial responses).ConclusionsContinuous and intermittent dosing of trametinib in combination with uprosertib was not tolerated, and minimal clinical activity was observed in all schedules tested

Improving EEG-Based Motor Imagery Classification for Real-Time Applications Using the QSA Method

We present an improvement to the quaternion-based signal analysis (QSA) technique to extract electroencephalography (EEG) signal features with a view to developing real-time applications, particularly in motor imagery (IM) cognitive processes. The proposed methodology (iQSA, improved QSA) extracts features such as the average, variance, homogeneity, and contrast of EEG signals related to motor imagery in a more efficient manner (i.e., by reducing the number of samples needed to classify the signal and improving the classification percentage) compared to the original QSA technique. Specifically, we can sample the signal in variable time periods (from 0.5 s to 3 s, in half-a-second intervals) to determine the relationship between the number of samples and their effectiveness in classifying signals. In addition, to strengthen the classification process a number of boosting-technique-based decision trees were implemented. The results show an 82.30% accuracy rate for 0.5 s samples and 73.16% for 3 s samples. This is a significant improvement compared to the original QSA technique that offered results from 33.31% to 40.82% without sampling window and from 33.44% to 41.07% with sampling window, respectively. We can thus conclude that iQSA is better suited to develop real-time applications

Dense Gas and Star Formation: Characteristics of Cloud Cores Associated with Water Masers

We have observed 150 regions of massive star formation, selected originally by the presence of a water maser, in the J = 5-4, 3-2, and 2-1 transitions of CS, and 49 regions in the same transitions of C$^{34}$S. Over 90% of the 150 regions were detected in the J = 2-1 and 3-2 transitions of CS and 75% were detected in the J=5-4 transition. We have combined the data with the J = 7-6 data from our original survey (Plume et al. 1992) to determine the density by analyzing the excitation of the rotational levels. Using Large Velocity Gradient (LVG) models, we have determined densities and column densities for 71 of these regions. The gas densities are very high (the mean log of the density is 5.9), but much less than the critical density of the J=7-6 line. Small maps of 25 of the sources in the J = 5-4 line yield a mean diameter of 1.0 pc. The mean virial mass is 3800 solar masses. The mean ratio of bolometric luminosity to virial mass (L/M) is 190, about 50 times higher than estimates using CO emission, suggesting that star formation is much more efficient in the dense gas probed in this study. The gas depletion time for the dense gas is roughly 1.3 x 10^7 yr. We find no statistically significant linewidth--size or density--size relationships in our data. Instead, both linewidth and density are larger for a given size than would be predicted by the usual relationships. We find that the linewidth increases with density, the opposite of what would be predicted by the usual arguments. We estimate that the luminosity of our Galaxy (excluding the inner 400 pc) in the CS J = 5-4 transition is 15 to 23 L_sun, considerably less than the luminosity in this line within the central 100 pc of NGC 253 and M82. In addition, the ratio of far-infrared luminosity to CS luminosity is higher in M82 than in any cloud in our sample.Comment: 26 pages, 6 postscript figures, 3 postscript tables. Uses AAS Latex macros, accepted for Astrophysical Journa

Demonstration of the Effect of Generic Anatomical Divisions versus Clinical Protocols on Computed Tomography Dose Estimates and Risk Burden

Objective: Choosing to undertake a CT scan relies on balancing risk versus benefit, however risks associated with CT scanning have generally been limited to broad anatomical locations, which do not provided adequate information to evaluate risk against benefit. Our study aimed to determine differences in radiation dose and risk estimates associated with modern CT scanning examinations when computed for clinical protocols compared with those using anatomical area. Methods: Technical data were extracted from a tertiary hospital Picture Archiving Communication System for random samples of 20–40 CT examinations per adult clinical CT protocol. Organ and whole body radiation dose were calculated using ImPACT Monte Carlo simulation software and cancer incidence and mortality estimated using BEIR VII age and gender specific lifetime attributable risk weights. Results: Thirty four unique CT protocols were identified by our study. When grouped according to anatomic area the radiation dose varied substantially, particularly for abdominal protocols. The total estimated number of incident cancers and cancer related deaths using the mean dose of anatomical area were 86 and 69 respectively. Using more specific protocol doses the estimates rose to 214 and 138 incident cancers and cancer related deaths, at least doubling the burden estimated. Conclusions: Modern CT scanning produces a greater diversity of effective doses than much of the literature describes; where a lack of focus on actual scanning protocols has produced estimates that do not reflect the range and complexity of modern CT practice. To allow clinicians, patients and policy makers to make informed risk versus benefit decisions the individual and population level risks associated with modern CT practices are essential

Leptin-signaling inhibition results in efficient anti-tumor activity in estrogen receptor positive or negative breast cancer

Introduction: We have shown previously that treatment with pegylated leptin peptide receptor antagonist 2 (PEG-LPrA2) reduced the expression of vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor type 2 (VEGFR2) and growth of 4T1-breast cancer (BC) in syngeneic mice. In this investigation, PEG-LPrA2 was used to evaluate whether the inhibition of leptin signaling has differential impact on the expression of pro-angiogenic and pro-proliferative molecules and growth of human estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) BC xenografts hosted by immunodeficient mice. Methods: To test the contribution of leptin signaling to BC growth and expression of leptin-targeted molecules, PEG-LPrA2 treatment was applied to severe immunodeficient mice hosting established ER+ (MCF-7 cells; ovariectomized/supplemented with estradiol) and ER- (MDA-MB231 cells) BC xenografts. To further assess leptin and PEG-LPrA2 effects on ER+ and ER- BC, the expression of VEGF and VEGFR2 (protein and mRNA) was investigated in cell cultures. Results: PEG-LPrA2 more effectively reduced the growth of ER+ (>40-fold) than ER- BC (twofold) and expression of pro-angiogenic (VEGF/VEGFR2, leptin/leptin receptor OB-R, and IL-1 receptor type I) and pro-proliferative molecules (proliferating cell nuclear antigen and cyclin D1) in ER+ than in ER- BC. Mouse tumor stroma in ER+ BC expressed high levels of VEGF and leptin that was induced by leptin signaling. Leptin upregulated the transcriptional expression of VEGF/VEGFR2 in MCF-7 and MDA-MB231 cells. Conclusions: These results suggest that leptin signaling plays an important role in the growth of both ER+ and ER- BC that is associated with the leptin regulation of pro-angiogenic and pro-proliferative molecules. These data provide support for the potential use of leptin-signaling inhibition as a novel treatment for ER+ and ER- BC

LIGHTSITE III: 13-Month Efficacy and Safety Evaluation of Multiwavelength Photobiomodulation in Nonexudative (Dry) Age-Related Macular Degeneration Using the LumiThera Valeda Light Delivery System.

PURPOSE The LIGHTSITE III study evaluated multiwavelength photobiomodulation (PBM) therapy in nonexudative (dry) AMD using the LumiThera Valeda® Light Delivery System. METHODS LIGHTSITE III is a randomized, controlled trial to assess the safety and effectiveness of PBM in dry AMD. Subjects were treated with multiwavelength PBM (590, 660 and 850 nm) or Sham treatment delivered 9 treatments over 3-5 weeks every four months over 24 months. Subjects were assessed for efficacy and safety outcomes. Data from the 13-month analysis are presented in this report. RESULTS A total of 100 subjects (148 eyes) with dry AMD were randomized. LIGHTSITE III met the primary efficacy BCVA endpoint with a significant difference between PBM (n = 91 eyes) and Sham (n = 54 eyes) groups (Between group difference: 2.4 letters (SE 1.15), CI: -4.7 - -0.1, p = 0.02)(PBM alone: 5.4 letters (SE 0.96), CI: 3.5 - 7.3, p < 0.0001; Sham alone: 3.0 letters (SE 1.13), CI: 0.7 - 5.2, p < 0.0001). The PBM group showed a significant decrease in new onset GA (p = 0.024, Fisher exact test, odds ratio 9.4). A favorable safety profile was observed. CONCLUSIONS LIGHTSITE III provides a prospective, randomized controlled trial showing improved clinical and anatomical outcomes in intermediate dry AMD following PBM

Insulin-like growth factor 2 (IGF2) protects against Huntington's disease through the extracellular disposal of protein aggregates

Impaired neuronal proteostasis is a salient feature of many neurodegenerative diseases, highlighting alterations in the function of the endoplasmic reticulum (ER). We previously reported that targeting the transcription factor XBP1, a key mediator of the ER stress response, delays disease progression and reduces protein aggregation in various models of neurodegeneration. To identify disease modifier genes that may explain the neuroprotective effects of XBP1 deficiency, we performed gene expression profiling of brain cortex and striatum of these animals and uncovered insulin-like growth factor 2 (Igf2) as the major upregulated gene. Here, we studied the impact of IGF2 signaling on protein aggregation in models of Huntington's disease (HD) as proof of concept. Cell culture studies revealed that IGF2 treatment decreases the load of intracellular aggregates of mutant huntingtin and a polyglutamine peptide. These results were validated using induced pluripotent stem cells (iPSC)-derived medium spiny neurons from HD patients and spinocerebellar ataxia cases. The reduction in the levels of mutant huntingtin was associated with a decrease in the half-life of the intracellular protein. The decrease in the levels of abnormal protein aggregation triggered by IGF2 was independent of the activity of autophagy and the proteasome pathways, the two main routes for mutant huntingtin clearance. Conversely, IGF2 signaling enhanced the secretion of soluble mutant huntingtin species through exosomes and microvesicles involving changes in actin dynamics. Administration of IGF2 into the brain of HD mice using gene therapy led to a significant decrease in the levels of mutant huntingtin in three different animal models. Moreover, analysis of human postmortem brain tissue and blood samples from HD patients showed a reduction in IGF2 level. This study identifies IGF2 as a relevant factor deregulated in HD, operating as a disease modifier that buffers the accumulation of abnormal protein species

Corrigendum to "Translating big data to better treatment in bipolar disorder - a manifesto for coordinated action [European Neuropsychopharmacology (2020) 36, 121-136]"

The authors regret that there was an error in the author list, this should appear as above. The authors apologise for any inconvenience caused

Sarcoma treatment in the era of molecular medicine

Sarcomas are heterogeneous and clinically challenging soft tissue and bone cancers. Although constituting only 1% of all human malignancies, sarcomas represent the second most common type of solid tumors in children and adolescents and comprise an important group of secondary malignancies. More than 100 histological subtypes have been characterized to date, and many more are being discovered due to molecular profiling. Owing to their mostly aggressive biological behavior, relative rarity, and occurrence at virtually every anatomical site, many sarcoma subtypes are in particular difficult-to-treat categories. Current multimodal treatment concepts combine surgery, polychemotherapy (with/without local hyperthermia), irradiation, immunotherapy, and/or targeted therapeutics. Recent scientific advancements have enabled a more precise molecular characterization of sarcoma subtypes and revealed novel therapeutic targets and prognostic/predictive biomarkers. This review aims at providing a comprehensive overview of the latest advances in the molecular biology of sarcomas and their effects on clinical oncology; it is meant for a broad readership ranging from novices to experts in the field of sarcoma.Peer reviewe