A Drug Screening Pipeline Using 2D and 3D Patient-Derived In Vitro Models for Pre-Clinical Analysis of Therapy Response in Glioblastoma

Glioblastoma is one of the most common and lethal types of primary brain tumor. Despite aggressive treatment with chemotherapy and radiotherapy, tumor recurrence within 6–9 months is common. To overcome this, more effective therapies targeting cancer cell stemness, invasion, metabolism, cell death resistance and the interactions of tumor cells with their surrounding microenvironment are required. In this study, we performed a systematic review of the molecular mechanisms that drive glioblastoma progression, which led to the identification of 65 drugs/inhibitors that we screened for their efficacy to kill patient-derived glioma stem cells in two dimensional (2D) cultures and patient-derived three dimensional (3D) glioblastoma explant organoids (GBOs). From the screening, we found a group of drugs that presented different selectivity on different patient-derived in vitro models. Moreover, we found that Costunolide, a TERT inhibitor, was effective in reducing the cell viability in vitro of both primary tumor models as well as tumor models pre-treated with chemotherapy and radiotherapy. These results present a novel workflow for screening a relatively large groups of drugs, whose results could lead to the identification of more personalized and effective treatment for recurrent glioblastoma.     

Second allogeneic bone marrow transplantation in acute leukemia: a multicenter study from the Gruppo Italiano Trapianto Di Midollo Osseo (GITMO)

Thirty-eight second allogeneic bone marrow transplants (BMT) for acute leukemia relapsed after first BMT were performed in 13 Italian centers between 1987 and 1994. Twenty-one patients had acute myelogenous leukemia (AML), 17 acute lymphoblastic leukemia (ALL); at second BMT 24 patients were in complete remission (CR) and 14 in relapse. The median time to relapse after first BMT was 10 months (range 1-70). Grade II or greater acute graft-versus-host disease (GVHD) after second transplant occurred in 34.2% of patients and a chronic GVHD in 31.5% of patients. Twenty-four patients died: seven from early transplant-related mortality (TRM), 13 from relapse and four from late toxicity. As of 31 July 1996, at a median follow-up of 47 months (range 22-85), there are 14 survivors. The three-year probability of TRM, relapse and event-free survival (EFS) is 28%, 40% and 42% respectively. In 20 of 27 evaluable patients, remission duration after second BMT was longer than after the first BMT. A diagnosis of AML was correlated with a better outcome. These data support the usefulness of second allograft in selected patients with AML relapsing after a first BMT.     

Determination of stoichiometric association constants by a non-iterative computational method

Computational methods for the estimation of stoichiometric association constants for multiple-ligand binding systems are currently based on non-linear least-squares regression analysis. These computational methods require sophisticated, iterative algorithms to assure convergence to a solution, as well as initial parameter and error estimates. A simple procedure, called lambda-invariance testing (LIT), was developed that provides a single-pass (non-iterative) estimation of stoichiometric association constants. The LIT method was applied to simulated binding data containing Gaussian error and to real data drawn from the literature. This method provided parameter estimates essentially equivalent to those obtained by least-squares regression analysis, with no initial parameter or error estimates required.     

Depression and self-medication with nicotine: The modifying influence of the dopamine D4 receptor gene.

This study evaluated whether there are genetic subgroups of depressed individuals who are more or less predisposed to engage in self-medication smoking practices. Smokers (N?=?231) completed self-report questionnaires of depression and smoking practices and were genotyped for the dopamine D4 (DRD4) gene. A significant interaction (DRD4 Genotype?×?Depression) was found for stimulation smoking and negative-affect reduction smoking. Specifically, these smoking practices were significantly heightened in depressed smokers homozygous for the short alleles of DRD4 but not in those heterozygous or homozygous for the long alleles of DRD4. These preliminary results suggest that the rewarding effects of smoking and the beneficial effects of nicotine replacement therapy for depressed smokers may depend, in part, on genetic factors involved in dopamine transmission. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Lesbian couples: The implications of sex differences in separation–individuation.

Addresses the relational dynamic of merging in lesbian couples from an object relations perspective. It is contended that merging in lesbian couples does exist, that it is a function of the fact that 2 women are relating to each other, and that preoedipal gender differences in the intrapsychic process of separation–individuation account for this pattern. It is suggested that gay male couples manifest the opposite pattern—emotional distancing—and that the determining factor is gender not homosexuality. Different patterns in lesbian and gay male couples illustrate crucial gender issues for both homosexuals and heterosexuals, and sex differences in separation–individuation and adult love relationships are discussed. It is concluded that the general nature of each sex's ego development affects the overall pattern of that sex's relational style. (23 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Acoustical conditioning and retention in the common carp (Cyprinus carpio)

Classical acoustic conditioning was investigated with the common carp (Cyprinus carpio) to determine its potential as a management tool for this invasive species. Groups of five juvenile carp were trained to associate a 400 Hz pure tone stimulus with a food reward in small laboratory tanks (≤ 1000 L). Following three days of training, the majority of fish showed a consistent and rapid (< 30 s) ability to localize the sound. All groups (n = 5) displayed retention without subsequent reinforcement for at least four months, and three groups maintained the conditioned behavior after 5 months. Additional trials were conducted in a 24,000 L outdoor pool to mimic more natural conditions. Carp again displayed relatively short learning curves and high accuracy (84.4%) in localizing the sound source. These findings indicate that carp are readily conditioned to an acoustic signal and are able to retain this behavior for months, suggesting that acoustical conditioning may be used as a management strategy in which the movement of wild carp can be manipulated for trapping and removal within a lake system.     

Ultrasonic NDE of solid-state bonds: Inertia and friction welds

This paper discusses a number of special ultrasonic NDE problems of particular interest to inertia and friction welds, but most of the results can be readily applied to other similar or dissimilar solid-state bonds as well. One of the major problems associated with dissimilar bonds is the blinding effect of the strong interface reflection caused by the inherent elastic discontinuity at the otherwise flawless boundary. A novel signal-processing technique based on the symmetric part of the boundary reflections from the two opposite sides of the interface is introduced and shown to yield a quantitative measure of boundary imperfection even for very good, apparently flawless bonds. The second problem addressed in this paper is the so-called cold-weld effect. As a combined result of heat softening and external pressure, intimate mechanical contact can be achieved without real fusion. Frequency analysis of the reflected ultrasonic signal from such cold-welded areas is shown to be capable of measuring the degree of plastic deformation at the contacting surfaces and, indirectly, to assess interface pressure and temperature. The third problem considered in this paper is the ultrasonic evaluation of the characteristic layered distribution of the grain structure in flawless inertia and friction welds. As an example, the thickness of the heat-affected zone (HAZ) was determined by ultrasonic spectroscopy, and the results were found to be in good agreement with independent optical profile measurements. Furthermore, the HAZ thickness is shown to be strongly correlated to welding pressure, therefore it offers a sensitive indicator for bond quality assessment as well.     

Measuring the impact of a blended learning model on early literacy growth

In the context of trying to improve reading proficiency in elementary school students, this study investigated the use of digital technology as part of a blended learning program, Core5, in kindergarten and first grade classes. A quasi-experimental design compared 283 treatment students instructed in schools using Core5 with 237 control students in schools using traditional instruction in an urban school district. At the beginning of the school year, all students were pretested with Dynamic Indicators of Basic Early Literacy Skills (DIBELS), a commonly used reading assessment. During the school year, the treatment schools implemented Core5, which includes the online component and offline teacher-led lessons. The English Language Arts curriculum was evaluated and found to be similar across treatment and control schools. At the end of the school year, all students were post-tested with DIBELS. Results from propensity score analyses showed that treatment students outperformed control students and that the discrepancy between treatment and control groups on post-test scores was more pronounced when students had lower pretest scores. These outcomes point to the value of using Core5 for reading instruction in early elementary grades.