Using Functional Signatures to Identify Repositioned Drugs for Breast, Myelogenous Leukemia and Prostate Cancer

The cost and time to develop a drug continues to be a major barrier to widespread distribution of medication. Although the genomic revolution appears to have had little impact on this problem, and might even have exacerbated it because of the flood of additional and usually ineffective leads, the emergence of high throughput resources promises the possibility of rapid, reliable and systematic identification of approved drugs for originally unintended uses. In this paper we develop and apply a method for identifying such repositioned drug candidates against breast cancer, myelogenous leukemia and prostate cancer by looking for inverse correlations between the most perturbed gene expression levels in human cancer tissue and the most perturbed expression levels induced by bioactive compounds. The method uses variable gene signatures to identify bioactive compounds that modulate a given disease. This is in contrast to previous methods that use small and fixed signatures. This strategy is based on the observation that diseases stem from failed/modified cellular functions, irrespective of the particular genes that contribute to the function, i.e., this strategy targets the functional signatures for a given cancer. This function-based strategy broadens the search space for the effective drugs with an impressive hit rate. Among the 79, 94 and 88 candidate drugs for breast cancer, myelogenous leukemia and prostate cancer, 32%, 13% and 17% respectively are either FDA-approved/in-clinical-trial drugs, or drugs with suggestive literature evidences, with an FDR of 0.01. These findings indicate that the method presented here could lead to a substantial increase in efficiency in drug discovery and development, and has potential application for the personalized medicine

Novel Quinazolinone MJ-29 Triggers Endoplasmic Reticulum Stress and Intrinsic Apoptosis in Murine Leukemia WEHI-3 Cells and Inhibits Leukemic Mice

The present study was to explore the biological responses of the newly compound, MJ-29 in murine myelomonocytic leukemia WEHI-3 cells in vitro and in vivo fates. We focused on the in vitro effects of MJ-29 on ER stress and mitochondria-dependent apoptotic death in WEHI-3 cells, and to hypothesize that MJ-29 might fully impair the orthotopic leukemic mice. Our results indicated that a concentration-dependent decrease of cell viability was shown in MJ-29-treated cells. DNA content was examined utilizing flow cytometry, whereas apoptotic populations were determined using annexin V/PI, DAPI staining and TUNEL assay. Increasing vital factors of mitochondrial dysfunction by MJ-29 were further investigated. Thus, MJ-29-provaked apoptosis of WEHI-3 cells is mediated through the intrinsic pathway. Importantly, intracellular Ca2+ release and ER stress-associated signaling also contributed to MJ-29-triggered cell apoptosis. We found that MJ-29 stimulated the protein levels of calpain 1, CHOP and p-eIF2α pathways in WEHI-3 cells. In in vivo experiments, intraperitoneal administration of MJ-29 significantly improved the total survival rate, enhanced body weight and attenuated enlarged spleen and liver tissues in leukemic mice. The infiltration of immature myeloblastic cells into splenic red pulp was reduced in MJ-29-treated leukemic mice. Moreover, MJ-29 increased the differentiations of T and B cells but decreased that of macrophages and monocytes. Additionally, MJ-29-stimulated immune responses might be involved in anti-leukemic activity in vivo. Based on these observations, MJ-29 suppresses WEHI-3 cells in vitro and in vivo, and it is proposed that this potent and selective agent could be a new chemotherapeutic candidate for anti-leukemia in the future

Endocrinologic, neurologic, and visual morbidity after treatment for craniopharyngioma

Craniopharyngiomas are locally aggressive tumors which typically are focused in the sellar and suprasellar region near a number of critical neural and vascular structures mediating endocrinologic, behavioral, and visual functions. The present study aims to summarize and compare the published literature regarding morbidity resulting from treatment of craniopharyngioma. We performed a comprehensive search of the published English language literature to identify studies publishing outcome data of patients undergoing surgery for craniopharyngioma. Comparisons of the rates of endocrine, vascular, neurological, and visual complications were performed using Pearson’s chi-squared test, and covariates of interest were fitted into a multivariate logistic regression model. In our data set, 540 patients underwent surgical resection of their tumor. 138 patients received biopsy alone followed by some form of radiotherapy. Mean overall follow-up for all patients in these studies was 54 ± 1.8 months. The overall rate of new endocrinopathy for all patients undergoing surgical resection of their mass was 37% (95% CI = 33–41). Patients receiving GTR had over 2.5 times the rate of developing at least one endocrinopathy compared to patients receiving STR alone or STR + XRT (52 vs. 19 vs. 20%, χ2P < 0.00001). On multivariate analysis, GTR conferred a significant increase in the risk of endocrinopathy compared to STR + XRT (OR = 3.45, 95% CI = 2.05–5.81, P < 0.00001), after controlling for study size and the presence of significant hypothalamic involvement. There was a statistical trend towards worse visual outcomes in patients receiving XRT after STR compared to GTR or STR alone (GTR = 3.5% vs. STR 2.1% vs. STR + XRT 6.4%, P = 0.11). Given the difficulty in obtaining class 1 data regarding the treatment of this tumor, this study can serve as an estimate of expected outcomes for these patients, and guide decision making until these data are available

Позиционный электропривод механизма перемещения

Объектом исследования является позиционный асинхронный электропривод механизма горизонтального перемещения груза. Цель работы – исследовать основные характеристики асинхронного электропривода с трехконтурной системой управления положением вала двигателя. В процессе исследования проводились выбор асинхронного двигателя для механизма перемещения, расчет параметров двигателя, его статических и динамических характеристик, выбор преобразователя частоты, синтез трехконтурной системы управления следящим электроприводом на базе регулируемого с векторным управлением.The object of the study is a positional asynchronous electric drive mechanism for the horizontal movement of cargo. The purpose of the work is to investigate the basic characteristics of an asynchronous electric drive with a three-circuit control system for positioning the motor shaft. In the process of research, the choice of an asynchronous motor for the displacement mechanism, calculation of the engine parameters, its static and dynamic characteristics, choice of a frequency converter, synthesis of a three-circuit control system for a servomotor drive based on an adjustable vector control were made

Cardiovascular magnetic resonance feature-tracking assessment of myocardial mechanics: Intervendor agreement and considerations regarding reproducibility.

To assess intervendor agreement of cardiovascular magnetic resonance feature tracking (CMR-FT) and to study the impact of repeated measures on reproducibility.Ten healthy volunteers underwent cine imaging in short-axis orientation at rest and with dobutam

Cardiovascular magnetic resonance feature-tracking assessment of myocardial mechanics: Intervendor agreement and considerations regarding reproducibility.

AIM: To assess intervendor agreement of cardiovascular magnetic resonance feature tracking (CMR-FT) and to study the impact of repeated measures on reproducibility. MATERIALS AND METHODS: Ten healthy volunteers underwent cine imaging in short-axis orientation at rest and with dobutamine stimulation (10 and 20&nbsp;μg/kg/min). All images were analysed three times using two types of software (TomTec, Unterschleissheim, Germany and Circle, cvi(42), Calgary, Canada) to assess global left ventricular circumferential (Ecc) and radial (Err) strains and torsion. Differences in intra- and interobserver variability within and between software types were assessed based on single and averaged measurements (two and three repetitions with subsequent averaging of results, respectively) as determined by Bland-Altman analysis, intraclass correlation coefficients (ICC), and coefficient of variation (CoV). RESULTS: Myocardial strains and torsion significantly increased on dobutamine stimulation with both types of software (p&lt;0.05). Resting Ecc and torsion as well as Ecc values during dobutamine stimulation were lower measured with Circle (p&lt;0.05). Intra- and interobserver variability between software types was lowest for Ecc (ICC 0.81 [0.63-0.91], 0.87 [0.72-0.94] and CoV 12.47% and 14.3%, respectively) irrespective of the number of analysis repetitions. Err and torsion showed higher variability that markedly improved for torsion with repeated analyses and to a lesser extent for Err. On an intravendor level TomTec showed better reproducibility for Ecc and torsion and Circle for Err. CONCLUSIONS: CMR-FT strain and torsion measurements are subject to considerable intervendor variability, which can be reduced using three analysis repetitions. For both vendors, Ecc qualifies as the most robust parameter with the best agreement, albeit lower Ecc values obtained using Circle, and warrants further investigation of incremental clinical merit