Mechanisms that link the oncogenic epithelial–mesenchymal transition to suppression of anoikis

The oncogenic epithelial–mesenchymal transition (EMT) contributes to tumor progression in various context-dependent ways, including increased metastatic potential, expansion of cancer stem cell subpopulations, chemo-resistance and disease recurrence. One of the hallmarks of EMT is resistance of tumor cells to anoikis. This resistance contributes to metastasis and is a defining property not only of EMT but also of cancer stem cells. Here, we review the mechanistic coupling between EMT and resistance to anoikis. The discussion focuses on several key aspects. First, we provide an update on new pathways that lead from the loss of E-cadherin to anoikis resistance. We then discuss the relevance of transcription factors that are crucial in wound healing in the context of oncogenic EMT. Next, we explore the consequences of the breakdown of cell-polarity complexes upon anoikis sensitivity, through the Hippo, Wnt and transforming growth factor β (TGF-β) pathways, emphasizing points of crossregulation. Finally, we summarize the direct regulation of cell survival genes through EMT-inducing transcription factors, and the roles of the tyrosine kinases focal adhesion kinase (FAK) and TrkB neurotrophin receptor in EMT-related regulation of anoikis. Emerging from these studies are unifying principles that will lead to improvements in cancer therapy by reprogramming sensitivity of anoikis

Minimal Basis Iterative Stockholder: Atoms in Molecules for Force-Field Development

Atomic partial charges appear in the Coulomb term of many force-field models and can be derived from electronic structure calculations with a myriad of atoms-in-molecules (AIM) methods. More advanced models have also been proposed, using the distributed nature of the electron cloud and atomic multipoles. In this work, an electrostatic force field is defined through a concise approximation of the electron density, for which the Coulomb interaction is trivially evaluated. This approximate "pro-density" is expanded in a minimal basis of atom-centered s-type Slater density functions, whose parameters are optimized by minimizing the Kullback-Leibler divergence of the pro-density from a reference electron density, e.g. obtained from an electronic structure calculation. The proposed method, Minimal Basis Iterative Stockholder (MBIS), is a variant of the Hirshfeld AIM method but it can also be used as a density-fitting technique. An iterative algorithm to refine the pro-density is easily implemented with a linear-scaling computational cost, enabling applications to supramolecular systems. The benefits of the MBIS method are demonstrated with systematic applications to molecular databases and extended models of condensed phases. A comparison to 14 other AIM methods shows its effectiveness when modeling electrostatic interactions. MBIS is also suitable for rescaling atomic polarizabilities in the Tkatchenko-Sheffler scheme for dispersion interactions.Comment: 61 pages, 12 figures, 2 table

Grainyhead-like 2 inhibits the coactivator p300, suppressing tubulogenesis and the epithelial–mesenchymal transition

Developmental morphogenesis and tumor progression require a transient or stable breakdown of epithelial junctional complexes to permit programmed migration, invasion, and anoikis resistance, characteristics endowed by the epithelial–mesenchymal transition (EMT). The epithelial master-regulatory transcription factor Grainyhead-like 2 (GRHL2) suppresses and reverses EMT, causing a mesenchymal–epithelial transition to the default epithelial phenotype. Here we investigated the role of GRHL2 in tubulogenesis of Madin–Darby canine kidney cells, a process requiring transient, partial EMT. GRHL2 was required for cystogenesis, but it suppressed tubulogenesis in response to hepatocyte growth factor. Surprisingly, GRHL2 suppressed this process by inhibiting the histone acetyltransferase coactivator p300, preventing the induction of matrix metalloproteases and other p300-dependent genes required for tubulogenesis. A 13–amino acid region of GRHL2 was necessary for inhibition of p300, suppression of tubulogenesis, and interference with EMT. The results demonstrate that p300 is required for partial or complete EMT occurring in tubulogenesis or tumor progression and that GRHL2 suppresses EMT in both contexts through inhibition of p300

The Role of Hydrogen Bonds in the Stabilization of Silver-Mediated Cytosine Tetramers

Peer reviewe

Trends in permanent pacemaker implantation in the United States from 1993 to 2009: increasing complexity of patients and procedures.

OBJECTIVES: This study sought to define contemporary trends in permanent pacemaker use by analyzing a large national database. BACKGROUND: The Medicare National Coverage Determination for permanent pacemaker, which emphasized single-chamber pacing, has not changed significantly since 1985. We sought to define contemporary trends in permanent pacemaker use by analyzing a large national database. METHODS: We queried the Nationwide Inpatient Sample to identify permanent pacemaker implants between 1993 and 2009 using the International Classification of Diseases-Ninth Revision-Clinical Modification procedure codes for dual-chamber (DDD), single-ventricular (VVI), single-atrial (AAI), or biventricular (BiV) devices. Annual permanent pacemaker implantation rates and patient demographics were analyzed. RESULTS: Between 1993 and 2009, 2.9 million patients received permanent pacemakers in the United States. Overall use increased by 55.6%. By 2009, DDD use increased from 62% to 82% (p \u3c 0.001), whereas single-chamber ventricular pacemaker use fell from 36% to 14% (p = 0.01). Use of DDD devices was higher in urban, nonteaching hospitals (79%) compared with urban teaching hospitals (76%) and rural hospitals (72%). Patients with private insurance (83%) more commonly received DDD devices than Medicaid (79%) or Medicare (75%) recipients (p \u3c 0.001). Patient age and Charlson comorbidity index increased over time. Hospital charges ($2011) increased 45.3%, driven by the increased cost of DDD devices. CONCLUSIONS: There is a steady growth in the use of permanent pacemakers in the United States. Although DDD device use is increasing, whereas single-chamber ventricular pacemaker use is decreasing. Patients are becoming older and have more medical comorbidities. These trends have important health care policy implications

16-year trends in the infection burden for pacemakers and implantable cardioverter-defibrillators in the United States 1993 to 2008.

OBJECTIVES: We analyzed the infection burden associated with the implantation of cardiac implantable electrophysiological devices (CIEDs) in the United States for the years 1993 to 2008. BACKGROUND: Recent data suggest that the rate of infection following CIED implantation may be increasing. METHODS: The Nationwide Inpatient Sample (NIS) discharge records were queried between 1993 and 2008 using the 9th Revision of the International Classification of Diseases (ICD-9-CM). CIED infection was defined as either: 1) ICD-9 code for device-related infection (996.61) and any CIED procedure or removal code; or 2) CIED procedure code along with systemic infection. Patient health profile was evaluated by coding for renal failure, heart failure, respiratory failure, and diabetes mellitus. The infection burden and patient health profile were calculated for each year, and linear regression was used to test for changes over time. RESULTS: During the study period (1993 to 2008), the incidence of CIED infection was 1.61%. The annual rate of infections remained constant until 2004, when a marked increase was observed, which coincided with an increase in the incidence of major comorbidities. This was associated with a marked increase in mortality and in-hospital financial charges. CONCLUSIONS: The infection burden associated with CIED implantation is increasing over time and is associated with prolonged hospital stays and high financial costs

Plasma Turbulence in the Local Bubble

Turbulence in the Local Bubble could play an important role in the thermodynamics of the gas that is there. The best astronomical technique for measuring turbulence in astrophysical plasmas is radio scintillation. Measurements of the level of scattering to the nearby pulsar B0950+08 by Philips and Clegg in 1992 showed a markedly lower value for the line-of-sight averaged turbulent intensity parameter $$than is observed for other pulsars, consistent with radio wave propagation through a highly rarefied plasma. In this paper, we discuss the observational progress that has been made since that time. At present, there are four pulsars (B0950+08, B1133+16, J0437-4715, and B0809+74) whose lines of sight seem to lie mainly within the local bubble. The mean densities and line of sight components of the interstellar magnetic field along these lines of sight are smaller than nominal values for pulsars, but not by as much expected. Three of the four pulsars also have measurements of interstellar scintillation. The value of the parameter$$ is smaller than normal for two of them, but is completely nominal for the third. This inconclusive status of affairs could be improved by measurements and analysis of ``arcs'' in ``secondary spectra'' of pulsars.Comment: Submitted to Space Science Reviews as contribution to Proceedings of ISSI (International Space Science Institute) workshop "From the Heliosphere to the Local Bubble". Refereed version accepted for publicatio

Bim and Bmf synergize to induce apoptosis in Neisseria gonorrhoeae infection

Abstract: Bcl-2 family proteins including the pro-apoptotic BH3-only proteins are central regulators of apoptotic cell death. Here we show by a focused siRNA miniscreen that the synergistic action of the BH3-only proteins Bim and Bmf is required for apoptosis induced by infection with Neisseria gonorrhoeae (Ngo). While Bim and Bmf were associated with the cytoskeleton of healthy cells, they both were released upon Ngo infection. Loss of Bim and Bmf from the cytoskeleton fraction required the activation of Jun-N-terminal kinase-1 (JNK-1), which in turn depended on Rac-1. Depletion and inhibition of Rac-1, JNK-1, Bim, or Bmf prevented the activation of Bak and Bax and the subsequent activation of caspases. Apoptosis could be reconstituted in Bim-depleted and Bmf-depleted cells by additional silencing of antiapoptotic Mcl-1 and Bcl-XL, respectively. Our data indicate a synergistic role for both cytoskeletal-associated BH3-only proteins, Bim, and Bmf, in an apoptotic pathway leading to the clearance of Ngo-infected cells. Author Summary: A variety of physiological death signals, as well as pathological insults, trigger apoptosis, a genetically programmed form of cell death. Pathogens often induce host cell apoptosis to establish a successful infection. Neisseria gonorrhoeae (Ngo), the etiological agent of the sexually transmitted disease gonorrhoea, is a highly adapted obligate human-specific pathogen and has been shown to induce apoptosis in infected cells. Here we unveil the molecular mechanisms leading to apoptosis of infected cells. We show that Ngo-mediated apoptosis requires a special subset of proapoptotic proteins from the group of BH3-only proteins. BH3-only proteins act as stress sensors to translate toxic environmental signals to the initiation of apoptosis. In a siRNA-based miniscreen, we found Bim and Bmf, BH3-only proteins associated with the cytoskeleton, necessary to induce host cell apoptosis upon infection. Bim and Bmf inactivated different inhibitors of apoptosis and thereby induced cell death in response to infection. Our data unveil a novel pathway of infection-induced apoptosis that enhances our understanding of the mechanism by which BH3-only proteins control apoptotic cell death