Results of special mechanical analyses of Luna 16 material

The studies carried out on the Luna 16 regolith have confirmed the data that were already published internationally. By means of activation analysis under irradiation in the reactor, activation analysis with a 14 MeV U-generator, and mass spectroscopy on samples of 10 or 20 mg, six main and 63 trace elements were quantitatively determined and compared with known data

Adjuvant high-dose medroxyprogesterone acetate for early breast cancer: 13 years update in a multicentre randomized trial

The authors updated their report on a randomized trial initiated in 1982 comparing, in early breast cancer, high-dose IM Medroxyprogesterone acetate (HD-MPA) adjuvant hormonotherapy during 6 months with no hormonotherapy; node-positive patients also received 6 courses of IV CMF (day 1, day 8; q.4 weeks). 246 node-negative (NN) and 270 node-positive (NP) patients had been followed for a median duration of 13 years. Previous results were confirmed in this analysis on mature data. In NN patients, relapse-free survival (RFS) was improved in the adjuvant hormonotherapy arm, regardless of age while overall survival (OAS) was also increased in younger (less then 50 years) patients. In the whole group of NP patients, no difference was seen regarding RFS or OAS. However, an age-dependant opposite effect was observed: younger patients (< 50) experienced a worse and significant outcome of relapse-free and overall survivals when receiving adjuvant HD-MPA while older patients (> = 50) enjoyed a significant improvement of their relapse-free survival. For both NN and NP patients, differences in overall survivals observed in older women with a shorter follow-up, were no longer detected. © 2001 Cancer Research Campaign http://www.bjcancer.co

Carfilzomib, bendamustine, and dexamethasone in patients with advanced multiple myeloma: The EMN09 phase 1/2 study of the European Myeloma Network

Background: Combined therapy with carfilzomib, bendamustine, and dexamethasone was evaluated in this multicenter phase 1/2 trial conducted within the European Myeloma Network (EMN09 trial). Methods: Sixty-three patients with relapsed/refractory multiple myeloma who had received 652 lines of prior therapy were included. The phase 1 portion of the study determined the maximum tolerated dose of carfilzomib with bendamustine set at 70 mg/m2 on days 1 and 8. After 8 cycles, responding patients received maintenance therapy with carfilzomib and dexamethasone until progression. Results: On the basis of the phase 1 results, the recommended phase 2 dose for carfilzomib was 27 mg/m2 twice weekly in weeks 1, 2, and 3. Fifty-two percent of patients achieved a partial response or better, and 32% reached a very good partial response or better. The clinical benefit rate was 93%. After a median follow-up of 21.9 months, the median progression-free survival was 11.6 months, and the median overall survival was 30.4 months. The reported grade 653 hematologic adverse events (AEs) were lymphopenia (29%), neutropenia (25%), and thrombocytopenia (22%). The main nonhematologic grade 653 AEs were pneumonia, thromboembolic events (10%), cardiac AEs (8%), and hypertension (2%). Conclusions: In heavily pretreated patients who have relapsed/refractory multiple myeloma, combined carfilzomib, bendamustine, and dexamethasone is an effective treatment option administered in the outpatient setting. Infection prophylaxis and attention to patients with cardiovascular predisposition are required

Rice APC/CTE controls tillering by mediating the degradation of MONOCULM 1

Rice MONOCULM 1 (MOC1) and its orthologues LS/LAS (lateral suppressor in tomato and Arabidopsis) are key promoting factors of shoot branching and tillering in higher plants. However, the molecular mechanisms regulating MOC1/LS/LAS have remained elusive. Here we show that the rice tiller enhancer (te) mutant displays a drastically increased tiller number. We demonstrate that TE encodes a rice homologue of Cdh1, and that TE acts as an activator of the anaphase promoting complex/cyclosome (APC/C) complex. We show that TE coexpresses with MOC1 in the axil of leaves, where the APC/CTE complex mediates the degradation of MOC1 by the ubiquitin–26S proteasome pathway, and consequently downregulates the expression of the meristem identity gene Oryza sativa homeobox 1, thus repressing axillary meristem initiation and formation. We conclude that besides having a conserved role in regulating cell cycle, APC/CTE has a unique function in regulating the plant-specific postembryonic shoot branching and tillering, which are major determinants of plant architecture and grain yield

Caspase-2-mediated cell death is required for deleting aneuploid cells

Caspase-2, one of the most evolutionarily conserved of the caspase family, has been implicated in maintenance of chromosomal stability and tumour suppression. Caspase-2 deficient (Casp2-/-) mice develop normally but show premature ageing-related traits and when challenged by certain stressors, succumb to enhanced tumour development and aneuploidy. To test how caspase-2 protects against chromosomal instability, we utilized an ex vivo system for aneuploidy where primary splenocytes from Casp2-/- mice were exposed to anti-mitotic drugs and followed up by live cell imaging. Our data show that caspase-2 is required for deleting mitotically aberrant cells. Acute silencing of caspase-2 in cultured human cells recapitulated these results. We further generated Casp2C320S mutant mice to demonstrate that caspase-2 catalytic activity is essential for its function in limiting aneuploidy. Our results provide direct evidence that the apoptotic activity of caspase-2 is necessary for deleting cells with mitotic aberrations to limit aneuploidy.S Dawar, Y Lim, J Puccini, M White, P Thomas, L Bouchier-Hayes, D R Green, L Dorstyn and S Kuma

Expression of Constitutively Active CDK1 Stabilizes APC-Cdh1 Substrates and Potentiates Premature Spindle Assembly and Checkpoint Function in G1 Cells

Mitotic progression in eukaryotic cells depends upon the activation of cyclin-dependent kinase 1 (CDK1), followed by its inactivation through the anaphase-promoting complex (APC)/cyclosome-mediated degradation of M-phase cyclins. Previous work revealed that expression of a constitutively active CDK1 (CDK1AF) in HeLa cells permitted their division, but yielded G1 daughter cells that underwent premature S-phase and early mitotic events. While CDK1AF was found to impede the sustained activity of APC-Cdh1, it was unknown if this defect improperly stabilized mitotic substrates and contributed to the occurrence of these premature M phases. Here, we show that CDK1AF expression in HeLa cells improperly stabilized APC-Cdh1 substrates in G1-phase daughter cells, including mitotic kinases and the APC adaptor, Cdc20. Division of CDK1AF-expressing cells produced G1 daughters with an accelerated S-phase onset, interrupted by the formation of premature bipolar spindles capable of spindle assembly checkpoint function. Further characterization of these phenotypes induced by CDK1AF expression revealed that this early spindle formation depended upon premature CDK1 and Aurora B activities, and their inhibition induced rapid spindle disassembly. Following its normal M-phase degradation, we found that the absence of Wee1 in these prematurely cycling daughter cells permitted the endogenous CDK1 to contribute to these premature mitotic events, since expression of a non-degradable Wee1 reduced the number of cells that exhibited premature cyclin B1oscillations. Lastly, we discovered that Cdh1-ablated cells could not be forced into a premature M phase, despite cyclin B1 overexpression and proteasome inhibition. Together, these results demonstrate that expression of constitutively active CDK1AF hampers the destruction of critical APC-Cdh1 targets, and that this type of condition could prevent newly divided cells from properly maintaining a prolonged interphase state. We propose that this more subtle type of defect in activity of the APC-driven negative-feedback loop may have implications for triggering genome instability and tumorigenesis

TSPY potentiates cell proliferation and tumorigenesis by promoting cell cycle progression in HeLa and NIH3T3 cells

BACKGROUND: TSPY is a repeated gene mapped to the critical region harboring the gonadoblastoma locus on the Y chromosome (GBY), the only oncogenic locus on this male-specific chromosome. Elevated levels of TSPY have been observed in gonadoblastoma specimens and a variety of other tumor tissues, including testicular germ cell tumors, prostate cancer, melanoma, and liver cancer. TSPY contains a SET/NAP domain that is present in a family of cyclin B and/or histone binding proteins represented by the oncoprotein SET and the nucleosome assembly protein 1 (NAP1), involved in cell cycle regulation and replication. METHODS: To determine a possible cellular function for TSPY, we manipulated the TSPY expression in HeLa and NIH3T3 cells using the Tet-off system. Cell proliferation, colony formation assays and tumor growth in nude mice were utilized to determine the TSPY effects on cell growth and tumorigenesis. Cell cycle analysis and cell synchronization techniques were used to determine cell cycle profiles. Microarray and RT-PCR were used to investigate gene expression in TSPY expressing cells. RESULTS: Our findings suggest that TSPY expression increases cell proliferation in vitro and tumorigenesis in vivo. Ectopic expression of TSPY results in a smaller population of the host cells in the G(2)/M phase of the cell cycle. Using cell synchronization techniques, we show that TSPY is capable of mediating a rapid transition of the cells through the G(2)/M phase. Microarray analysis demonstrates that numerous genes involved in the cell cycle and apoptosis are affected by TSPY expression in the HeLa cells. CONCLUSION: These data, taken together, have provided important insights on the probable functions of TSPY in cell cycle progression, cell proliferation, and tumorigenesis

NAHA, a Novel Hydroxamic Acid-Derivative, Inhibits Growth and Angiogenesis of Breast Cancer In Vitro and In Vivo

BACKGROUND: We have recently synthesized novel N-alkylated amino acid-derived hydroxamate, 2-[Benzyl-(2-nitro-benzenesulfonyl)-amino]-N-hydroxy-3-methyl-N-propyl-butyramide (NAHA). Here, we evaluate the anticancer activity of NAHA against highly invasive human breast cancer cells MDA-MB-231 in vitro and in vivo. METHODOLOGY/PRINCIPAL FINDINGS: Cell growth was evaluated by MTT and soft agar assays. Protein expression was determined by DNA microarray and Western blot analysis. Metastatic potential was evaluated by cell adhesion, migration, invasion, capillary morphogenesis, and ELISA assays. The anticancer activity in vivo was evaluated in mouse xenograft model. NAHA inhibited proliferation and colony formation of MDA-MB-231 cells together with the down-regulation of expression of Cdk2 and CDC20 proteins. NAHA inhibited cell adhesion, migration, and invasion through the suppression of secretion of uPA. NAHA suppressed secretion of VEGF from MDA-MB-231 cells and inhibited capillary morphogenesis of human aortic endothelial cells (HAECs). Finally, NAHA at 50 mg/kg was not toxic and decreased tumor volume and tumor weight in vivo. This suppression of tumor growth was associated with the inhibition of mitotic figures and induction of apoptosis, and the reduction of CD31 and VEGF positive cells in tumors. CONCLUSION: NAHA could be a novel promising compound for the development of new drugs for the therapy of invasive breast cancers

Bayesian Orthogonal Least Squares (BOLS) algorithm for reverse engineering of gene regulatory networks

<p>Abstract</p> <p>Background</p> <p>A reverse engineering of gene regulatory network with large number of genes and limited number of experimental data points is a computationally challenging task. In particular, reverse engineering using linear systems is an underdetermined and ill conditioned problem, i.e. the amount of microarray data is limited and the solution is very sensitive to noise in the data. Therefore, the reverse engineering of gene regulatory networks with large number of genes and limited number of data points requires rigorous optimization algorithm.</p> <p>Results</p> <p>This study presents a novel algorithm for reverse engineering with linear systems. The proposed algorithm is a combination of the orthogonal least squares, second order derivative for network pruning, and Bayesian model comparison. In this study, the entire network is decomposed into a set of small networks that are defined as unit networks. The algorithm provides each unit network with P(D|H_i), which is used as confidence level. The unit network with higher P(D|H_i) has a higher confidence such that the unit network is correctly elucidated. Thus, the proposed algorithm is able to locate true positive interactions using P(D|H_i), which is a unique property of the proposed algorithm.</p> <p>The algorithm is evaluated with synthetic and <it>Saccharomyces cerevisiae </it>expression data using the dynamic Bayesian network. With synthetic data, it is shown that the performance of the algorithm depends on the number of genes, noise level, and the number of data points. With Yeast expression data, it is shown that there is remarkable number of known physical or genetic events among all interactions elucidated by the proposed algorithm.</p> <p>The performance of the algorithm is compared with Sparse Bayesian Learning algorithm using both synthetic and <it>Saccharomyces cerevisiae </it>expression data sets. The comparison experiments show that the algorithm produces sparser solutions with less false positives than Sparse Bayesian Learning algorithm.</p> <p>Conclusion</p> <p>From our evaluation experiments, we draw the conclusion as follows: 1) Simulation results show that the algorithm can be used to elucidate gene regulatory networks using limited number of experimental data points. 2) Simulation results also show that the algorithm is able to handle the problem with noisy data. 3) The experiment with Yeast expression data shows that the proposed algorithm reliably elucidates known physical or genetic events. 4) The comparison experiments show that the algorithm more efficiently performs than Sparse Bayesian Learning algorithm with noisy and limited number of data.</p

Co-expression network of neural-differentiation genes shows specific pattern in schizophrenia

Background: Schizophrenia is a neurodevelopmental disorder with genetic and environmental factors contributing to its pathogenesis, although the mechanism is unknown due to the difficulties in accessing diseased tissue during human neurodevelopment. The aim of this study was to find neuronal differentiation genes disrupted in schizophrenia and to evaluate those genes in post-mortem brain tissues from schizophrenia cases and controls. Methods: We analyzed differentially expressed genes (DEG), copy number variation (CNV) and differential methylation in human induced pluripotent stem cells (hiPSC) derived from fibroblasts from one control and one schizophrenia patient and further differentiated into neuron (NPC). Expression of the DEG were analyzed with microarrays of post-mortem brain tissue (frontal cortex) cohort of 29 schizophrenia cases and 30 controls. A Weighted Gene Co-expression Network Analysis (WGCNA) using the DEG was used to detect clusters of co-expressed genes that werenon-conserved between adult cases and controls brain samples. Results: We identified methylation alterations potentially involved with neuronal differentiation in schizophrenia, which displayed an over-representation of genes related to chromatin remodeling complex (adjP = 0.04). We found 228 DEG associated with neuronal differentiation. These genes were involved with metabolic processes, signal transduction, nervous system development, regulation of neurogenesis and neuronal differentiation. Between adult brain samples from cases and controls there were 233 DEG, with only four genes overlapping with the 228 DEG, probably because we compared single cell to tissue bulks and more importantly, the cells were at different stages of development. The comparison of the co-expressed network of the 228 genes in adult brain samples between cases and controls revealed a less conserved module enriched for genes associated with oxidative stress and negative regulation of cell differentiation. Conclusion: This study supports the relevance of using cellular approaches to dissect molecular aspects of neurogenesis with impact in the schizophrenic brain. We showed that, although generated by different approaches, both sets of DEG associated to schizophrenia were involved with neocortical development. The results add to the hypothesis that critical metabolic changes may be occurring during early neurodevelopment influencing faulty development of the brain and potentially contributing to further vulnerability to the illness.We thank the patients, doctors and nurses involved with sample collection and the Stanley Medical Research Institute. This research was supported by either Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq #17/2008) and Fundação Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ). MM (CNPq 304429/2014-7), ACT (FAPESP 2014/00041-1), LL (CAPES 10682/13-9) HV (CAPES) and BP (PPSUS 137270) were supported by their fellowshipsinfo:eu-repo/semantics/publishedVersio