Characterization of the Tumor Suppressor Capabilities of SWI/SNF Complex Member BAF155 in Cancer Cell Lines and Cooperation of SNF5 and p53 Pathways

Tumorigenesis is often attributed to aberrant gene expression leading to altered cell cycle control, abnormal differentiation, and inefficient DNA repair. The activity of chromatin remodeling complexes is vital to maintaining proper control of such gene expression. The SWI/SNF chromatin remodeling complex is responsible for remodeling up to 6% of the human genome, with many of those genes known to be associated with cell cycle control. Therefore, impaired or defective activity of this complex could encourage tumor development. Little is known, however, of how SWI/SNF accomplishes those tasks and the differing roles of the distinct members of the complex. Composed of more than ten members, several components are now known to have tumor suppressive roles, as their absence correlates with tumorigenic phenotypes. We propose also that core SWI/SNF member, BAF155, is also likely to be involved in controlling tumor progression. I have utilized two carcinoma cell lines lacking endogenous BAF155 expression to explore the role of BAF155 in cell cycle control and found that re-expression of BAF155 in these cells leads to a reduction in cell number due to replicative senescence. These BAF155 null cells were also found to be sensitive to Rb-mediated cell cycle arrest. This data imply a role for SWI/SNF member BAF155 in cell cycle control and in turn, tumor progression. To determine the pathways in which SWI/SNF core member SNF5 suppresses tumor progression we utilized mouse models to explore the relationship between the p53 pathway and that of SNF5/INI1 in controlling tumor progression and found that while double heterozygous mice still develop p53 wild type SNF5 null rhabdoid tumors similar to their SNF5+/- littermates, SNF5 loss of heterozygosity is accelerated on a p53+/- background leading to reduced latency and increased penetrance of p53 null SNF5 null rhabdoid tumors in alternate anatomical locations as well as the formation of lymphomas. The resulting rhabdoid tumors were found to express a pattern of markers similar to the human rhabdoid phenotype, solidifying this model as an appropriate recapitulation of human rhabdoid tumors. These studies shed light on the specific roles of SWI/SNF chromatin remodeling complex in tumor suppression

Experimental study of Cr incorporation in pargasite

Pargasite compositions corresponding to the nominal structural formula NaCa2 (Mg4Al1-xCrx)(Si6Al2)O22(OH)2, with 0 £ x £ 1, were investigated at 900 °C and 3 and 20 kbar PH2O. The aims of this work were to determine the extent of the solid solution, i.e., the maximum x value, as a function of experimental conditions, and to characterize the M3+ (Al3+ and/or Cr3+) distribution over the M sites. A first series of experiments at 900 °C and 3 kbar showed the presence of large amounts of Cr6+ as sodium chromate (Na2CrO4) and dichromate (Na2Cr2O7) in the final fluid phase, which promotes the extraction of Cr from the bulk solid (up to 45 mol%). The oxidizing agent was the oxygen from water, liberated by diffusion of hydrogen from water through the Pt tube wall. To prevent this oxidation, a new double-chamber tube was designed, one chamber containing powdered metallic Cr to trap the excess of oxygen and the second chamber initially containing the starting gel and water. Using this tube, (chromium)-pargasites were produced with a maximum Cr content around 0.43 apfu from EMP analyses (based on 23 O atoms), close to the maximum Cr solubility observed in naturally occurring pargasites. In FTIR spectra of Cr-free pargasite, two intense OH-stretching bands are observed at 3714 and 3681 cm–1, corresponding to OH groups adjacent to Mg3 and to Mg2Al, respectively, and pointing toward a filled A-site. A third band is observed at 3656 cm–1, which can be assigned to OH groups pointing toward vacant A-sites. Along the Al-Cr pargasite join, significant modifications are observed in the OH-stretching region: a new band appears at 3660 cm–1, which can be assigned to OH groups adjacent to Mg2Cr, and pointing toward a filled A-site. Its relative intensity increases regularly with the Cr content, showing that Cr3+ enters M site(s) adjacent to an OH group. Combining EMP and FTIR data, we conclude that up to 0.27 Cr per formula unit occupies the M3 site. However, these are more octahedral trivalent cations than expected, and these are balanced by lower tetrahedral Al and lower occupancies of the A and M4 sites. This charge arrangement, with important deviations from ideal stoichiometry, is apparently the only stable one under the conditions applied. Results were confirmed at 900 °C and 20 kbar PH2O, indicating that increasing pressure does not affect Cr solubility in pargasite

Low cycle fatigue behaviour of a precipitation hardened Cu-Ni-Si alloy

International audienceLow cycle fatigue tests were performed at room temperature to investigate the role of the microstructure of a Cu-Ni-Si alloy on the stress response to strain cycling and on the fatigue resistance. The cyclic accommodation consisted in a hardening followed by a softening. TEM analysis showed that in some grains dislocations remained isolated and confined between precipitates while in other grains dislocations piled up at δ-Ni 2 Si precipitates and then cut them. Repetitive cutting allows their dissolution and formation of precipitate-free bands where the plastic deformation is localised. The Manson-Coffin diagram exhibited two regimes according to the proportion of grains involved in the plastic deformation accommodation

Identification of a core member of the SWI/SNF complex, BAF155/SMARCC1, as a human tumor suppressor gene

Recent studies have established that two core members of the SWI/SNF chromatin remodeling complex, BRG1 and SNF5/INI1, possess tumor-suppressor activity in human and mouse cancers. While the third core member, BAF155, has been implicated by several studies as having a potential role in tumor development, direct evidence for its tumor suppressor activity has remained lacking. Therefore, we screened for BAF155 deficiency in a large number of human tumor cell lines. We identified two cell lines, the SNUC2B colon carcinoma and the SKOV3 ovarian carcinoma, displaying a complete loss of protein expression while maintaining normal levels of mRNA expression. The SKOV3 cell line possesses a heterozygous 4 bp deletion that results in an 855AA truncated protein, while the cause of the loss of BAF155 expression in the SNUC2B cell line appears due to a post-transcriptional error. However, the lack of detectable BAF155 expression did not affect sensitivity to RB-mediated cell cycle arrest. Re-expression of full length but not a truncated form of BAF155 in the two cancer cell lines leads to reduced colony forming ability characterized by replicative senescence but not apoptosis. Collectively, these data suggest that loss of BAF155 expression represents another mechanism for inactivation of SWI/SNF complex activity in the development in human cancer. Our results further indicate that the c-terminus proline-glutamine rich domain plays a critical role in the tumor suppressor activity of this protein

Contrasting the Harmonic Balance and Linearized Methods for Oscillating-Flap Simulations

In the framework of unsteady aerodynamics, forced-harmonic-motion simulations can be used to compute unsteady loads. In this context, the present paper assesses two alternatives to the unsteady Reynolds-averaged Navier–Stokes approach, the linearized unsteady Reynolds-averaged Navier–Stokes equations method, and the harmonic balance approach. The test case is a NACA 64A006 airfoil with an oscillating ␣ap mounted at 75% of the chord. Emphasis is put on examining the performances of the methods in terms of accuracy and computational cost over a range of physical conditions. It is found that, for a subsonic ␣ow, the linearized unsteady Reynolds-averaged Navier–Stokes method is the most ef␣cient one. In the transonic regime, the linearized unsteady Reynolds-averaged Navier–Stokes method remains the fastest approach, but with limited accuracy around shocks, whereas a one- harmonic harmonic balance solution is in closer agreement with the unsteady Reynolds-averaged Navier–Stokes solution. In the case of separation in the transonic regime, the linearized unsteady Reynolds-averaged Navier–Stokes method fails to converge, whereas the harmonic balance remains robust and accurate

Inactivation of SNF5 cooperates with p53 loss to accelerate tumor formation in Snf5 +/− ; p53 +/− mice

Malignant rhabdoid tumors (MRTs) are poorly differentiated pediatric cancers that arise in various anatomical locations and have a very poor outcome. The large majority of these malignancies are caused by loss of function of the SNF5/INI1 component of the SWI/SNF chromatin remodeling complex. However, the mechanism of tumor development associated with SNF5 loss remains unclear. Multiple studies have demonstrated a role for SNF5 in the regulation of cyclin D1, p16INK4A and pRbf activities suggesting it functions through the SWI/SNF complex to affect transcription of genes involved in cell cycle control. Previous studies in genetically engineered mouse models (GEMM) have shown that loss of SNF5 on a p53 null background significantly accelerates tumor development. Here, we use established GEMM to further define the relationship between the SNF5 and p53 tumor suppressor pathways. Combined haploinsufficiency of p53 and Snf5 leads to decreased latency for MRTs arising in alternate anatomical locations but not for the standard facial MRTs. We also observed acceleration in the appearance of T-cell lymphomas in the p53+/-;Snf5+/- mice. Our studies suggest that loss of SNF5 activity does not bestow a selective advantage on the p53 spectrum of tumors in the p53+/-;Snf5+/- mice. However, reduced p53 expression specifically accelerated the growth of a subset of MRTs in these mice

Rickettsial Infections and Fever, Vientiane, Laos

Rickettsia spp. are an underrecognized cause of undifferentiated febrile illness

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)