Potentiation of the anticancer effect of valproic acid, an antiepileptic agent with histone deacetylase inhibitory activity, by the kinase inhibitor Staurosporine or its clinically relevant analogue UCN-01

Histone deacetylase inhibitors (HDACIs) are novel anticancer agents with potent cytotoxicity against a wide range of malignancies. We have previously demonstrated that either Calphostin C (CC) (a protein kinase C (PKC) inhibitor) or Parthenolide (an NF-κB inhibitor) abrogates HDACI-induced transcriptional activation of NF-κB and p21, which is associated with profound potentiation of HDACI-mediated induction of apoptosis. Valproic acid (VA), a commonly used antiepileptic agent, has recently been shown to be an HDACI. This study was aimed to evaluate the anticancer property of VA in thoracic cancer cells and the development of clinically relevant strategies to enhance VA-mediated induction of apoptosis using kinase inhibitors Staurosporine (STP) or its analogue UCN-01. Treating cultured thoracic cancer cells with VA (0.62–10.0 mM) resulted in significant cell line- and dose-dependent growth inhibition (IC50 values: 4.1–6.0 mM) and cell cycle arrest at G1/S checkpoint with profound accumulation of cells at G0/G1 phase but little induction of apoptosis. Valproic acid, being an HDACI, caused significant dose-dependent accumulation of hyperacetylated histones, following 24 h of treatment. Valproic acid-mediated 5–20-fold upregulation of transcriptional activity of NF-κB was substantially (50–90%) suppressed by cotreatment with CC, STP or UCN-01. Whereas minimal death (<20%) was observed in cells treated with either VA (1.0 or 5.0 mM) alone or kinase inhibitors alone, 60–90% of cells underwent apoptosis following exposure to combinations of VA+kinase inhibitors. Kinase inhibitor-mediated suppression of NF-κB transcriptional activity played an important role in sensitising cancer cells to VA as direct inhibition of NF-κB by Parthenolide drastically synergised with VA to induce apoptosis (VA+Parthenolide: 60–90% compared to <20% following single-drug treatments). In conclusion, VA, a well-known antiepileptic drug, has mild growth-inhibitory activity on cultured cancer cells. The weak VA-mediated induction of apoptosis of thoracic cancer cells can be profoundly enhanced either by Parthenolide, a pharmacologic inhibitor of NF-κB, or by UCN-01 a kinase inhibitor that has already undergone phase I clinical development. Combinations of VA with either a PKC inhibitor or an NF-κB inhibitor are promising novel molecularly targeted therapeutics for thoracic cancers

Analysis of the Reaction Rate Coefficients for Slow Bimolecular Chemical Reactions

Simple bimolecular reactions $A_1+A_2\rightleftharpoons A_3+A_4$ are analyzed within the framework of the Boltzmann equation in the initial stage of a chemical reaction with the system far from chemical equilibrium. The Chapman-Enskog methodology is applied to determine the coefficients of the expansion of the distribution functions in terms of Sonine polynomials for peculiar molecular velocities. The results are applied to the reaction $H_2+Cl\rightleftharpoons HCl+H$, and the influence of the non-Maxwellian distribution and of the activation-energy dependent reactive cross sections upon the forward and reverse reaction rate coefficients are discussed.Comment: 11 pages, 5 figures, to appear in vol.42 of the Brazilian Journal of Physic

A Carrier Frequency Estimation Method of MPSK Signals and Its Systolic VLSI Implementation

In this paper we present an autocorrelation-based method for estimating the carrier frequency offset of an MPSK signal with random data modulation. Although autocorrelation-based techniques imply heavy usage of hardware resources, this technique is scalable and lends itself well to systolic VLSI implementations. The performance of the open-loop estimator presented is close to the Cramer-Rao lower bound (CRLB) for the frequency estimation from a block of random PSK symbols at low signal-to-noise (SNR) ratios. The estimator can be used in frequency acquisition of burst and continuous modems operating under low SNR and large frequency offset conditions. This paper has been submitted to 33rd Annual Conference on InformationSciences and Systems, March 17-19, 1999, John Hopkins University,Baltimore, Md.</I

Vision-Based Microtribological Characterization of Linear Microball Bearings

Microball bearings can potentially provide robust and low friction support in micromachines such as micromotors and microgenerators. Their microtribological behavior needs to be investigated for design and control of such micromachines. In this paper a vision-based, non-intrusive measurement method is presented for characterization of friction in linear microball bearings. Infrared imaging is used to directly observe the dynamics of microballs and track the motion of bearing components. It is verified that microballs roll most of the time with occasional sliding or bumping resulting from fabrication nonuniformity. The friction-velocity curve demonstrates evident hysteresis. The dependence of frictional behavior on several factors is studied

Hydrodynamic fluctuations in the Kolmogorov flow: Linear regime

The Landau-Lifshitz fluctuating hydrodynamics is used to study the statistical properties of the linearized Kolmogorov flow. The relative simplicity of this flow allows a detailed analysis of the fluctuation spectrum from near equilibrium regime up to the vicinity of the first convective instability threshold. It is shown that in the long time limit the flow behaves as an incompressible fluid, regardless of the value of the Reynolds number. This is not the case for the short time behavior where the incompressibility assumption leads in general to a wrong form of the static correlation functions, except near the instability threshold. The theoretical predictions are confirmed by numerical simulations of the full nonlinear fluctuating hydrodynamic equations.Comment: 20 pages, 4 figure

Behavioural syndrome in a solitary predator is independent of body size and growth rate.

Models explaining behavioural syndromes often focus on state-dependency, linking behavioural variation to individual differences in other phenotypic features. Empirical studies are, however, rare. Here, we tested for a size and growth-dependent stable behavioural syndrome in the juvenile-stages of a solitary apex predator (pike, Esox lucius), shown as repeatable foraging behaviour across risk. Pike swimming activity, latency to prey attack, number of successful and unsuccessful prey attacks was measured during the presence/absence of visual contact with a competitor or predator. Foraging behaviour across risks was considered an appropriate indicator of boldness in this solitary predator where a trade-off between foraging behaviour and threat avoidance has been reported. Support was found for a behavioural syndrome, where the rank order differences in the foraging behaviour between individuals were maintained across time and risk situation. However, individual behaviour was independent of body size and growth in conditions of high food availability, showing no evidence to support the state-dependent personality hypothesis. The importance of a combination of spatial and temporal environmental variation for generating growth differences is highlighted

Risk-Sensitive Mean-Field Type Control under Partial Observation

We establish a stochastic maximum principle (SMP) for control problems of partially observed diffusions of mean-field type with risk-sensitive performance functionals.Comment: arXiv admin note: text overlap with arXiv:1404.144

Correction to: The genetic architecture of Plakophilin 2 cardiomyopathy

PURPOSE: The genetic architecture of Plakophilin 2 (PKP2) cardiomyopathy can inform our understanding of its variant pathogenicity and protein function. METHODS: We assess the gene-wide and regional association of truncating and missense variants in PKP2 with arrhythmogenic cardiomyopathy (ACM), and arrhythmogenic right ventricular cardiomyopathy (ARVC) specifically. A discovery data set compares genetic testing requisitions to gnomAD. Validation is performed in a rigorously phenotyped definite ARVC cohort and non-ACM individuals in the Geisinger MyCode cohort. RESULTS: The etiologic fraction (EF) of ACM-related diagnoses from truncating variants in PKP2 is significant (0.85 [0.80,0.88], p < 2 × 10-16), increases for ARVC specifically (EF = 0.96 [0.94,0.97], p < 2 × 10-16), and is highest in definite ARVC versus non-ACM individuals (EF = 1.00 [1.00,1.00], p < 2 × 10-16). Regions of missense variation enriched for ACM probands include known functional domains and the C-terminus, which was not previously known to contain a functional domain. No regional enrichment was identified for truncating variants. CONCLUSION: This multicohort evaluation of the genetic architecture of PKP2 demonstrates the specificity of PKP2 truncating variants for ARVC within the ACM disease spectrum. We identify the PKP2 C-terminus as a potential functional domain and find that truncating variants likely cause disease irrespective of transcript position