Lipschitz continuity of polyhedral Skorokhod maps

We show that a special stability condition of the associated system of oblique projections (the so-called ℓ-paracontractivity) guarantees that the corresponding polyhedral Skorokhod problem in a Hilbert space X is solvable in the space of absolutely continuous functions with values in X. If moreover the oblique projections are transversal, the solution exists and is unique for each continuous input and the Skorokhod map is Lipschitz continuous in both C([0,T]; X) and W1,1(0,T; X). An explicit upper bound for the Lipschitz constant is derived

Stress-controlled hysteresis and long-time dynamics of implicit differential equations arising in hypoplasticity

summary:A long-time dynamic for granular materials arising in the hypoplastic theory of Kolymbas type is investigated. It is assumed that the granular hardness allows exponential degradation, which leads to the densification of material states. The governing system for a rate-independent strain under stress control is described by implicit differential equations. Its analytical solution for arbitrary inhomogeneous coefficients is constructed in closed form. Under cyclic loading by periodic pressure, finite ratcheting for the void ratio is derived in explicit form, which converges to a limiting periodic process (attractor) when the number of cycles tends to infinity

On feasibility of rate-independent stress paths under proportional deformations within hypoplastic constitutive model for granular materials

We study stress paths that are obtained under proportional deformations within the rate-independent hypoplasticity theory of Kolymbas type describing granular materials like soil and broken rock. For a particular simplified hypoplastic constitutive model by Bauer, a closed-form solution of the corresponding system of non-linear ordinary differential equations is available. Since only negative principal stresses are relevant for the granular body, the feasibility of the solution consistent with physics is investigated in dependence of the direction of a proportional strain path and constitutive parameters of the model

Retrospective-Cost Adaptive Control of Uncertain Hammerstein-Wiener Systems with Memoryless and Hysteretic Nonlinearities

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97108/1/AIAA2012-4449.pd

Virial coefficients and vapor-liquid equilibria of the EXP6 and 2-Yukawa fluids

Virial coefficients B₂ through B₄ and the vapor-liquid equilibria for the EXP6 and 2-Yukawa (2Y) fluids have been determined using numerical integrations and Gibbs ensemble simulations, respectively. The chosen 2Y models have been recently determined as an appropriate reference fluid for the considered EXP6 models.Вiрiальнi коефiцiєнти в iд B₂ до B₄ i фазова рiвновага пара - рiдина у EXP6 та 2-Юкава (2Y) плинах розрахованi, вiдповiдно, з допомогою чисельного iнтегрування та на основi комп’ютерного експерименту з використанням ансамблю Гiбса. Вибранi 2Y модельнi системи нещодавно були запропонованi як базиснi для EXP6 плинiв, що розглядаються

The CHK1 inhibitor MU380 significantly increases the sensitivity of human docetaxel-resistant prostate cancer cells to gemcitabine through the induction of mitotic catastrophe.

As treatment options for patients with incurable metastatic castration-resistant prostate cancer (mCRPC) are considerably limited, novel effective therapeutic options are needed. Checkpoint kinase 1 (CHK1) is a highly conserved protein kinase implicated in the DNA damage response (DDR) pathway that prevents the accumulation of DNA damage and controls regular genome duplication. CHK1 has been associated with prostate cancer (PCa) induction, progression, and lethality; hence, CHK1 inhibitors SCH900776 (also known as MK-8776) and the more effective SCH900776 analog MU380 may have clinical applications in the therapy of PCa. Synergistic induction of DNA damage with CHK1 inhibition represents a promising therapeutic approach that has been tested in many types of malignancies, but not in chemoresistant mCRPC. Here, we report that such therapeutic approach may be exploited using the synergistic action of the antimetabolite gemcitabine (GEM) and CHK1 inhibitors SCH900776 and MU380 in docetaxel-resistant (DR) mCRPC. Given the results, both CHK1 inhibitors significantly potentiated the sensitivity to GEM in a panel of chemo-naïve and matched DR PCa cell lines under 2D conditions. MU380 exhibited a stronger synergistic effect with GEM than clinical candidate SCH900776. MU380 alone or in combination with GEM significantly reduced spheroid size and increased apoptosis in all patient-derived xenograft 3D cultures, with a higher impact in DR models. Combined treatment induced premature mitosis from G1 phase resulting in the mitotic catastrophe as a prestage of apoptosis. Finally, treatment by MU380 alone, or in combination with GEM, significantly inhibited tumor growth of both PC339-DOC and PC346C-DOC xenograft models in mice. Taken together, our data suggest that metabolically robust and selective CHK1 inhibitor MU380 can bypass docetaxel resistance and improve the effectiveness of GEM in DR mCRPC models. This approach might allow for dose reduction of GEM and thereby minimize undesired toxicity and may represent a therapeutic option for patients with incurable DR mCRPC

Breast cancer-specific mutations in CK1ε inhibit Wnt/β-catenin and activate the Wnt/Rac1/JNK and NFAT pathways to decrease cell adhesion and promote cell migration

Introduction Breast cancer is one of the most common types of cancer in women. One of the genes that were found mutated in breast cancer is casein kinase 1 epsilon (CK1ε). Because CK1ε is a crucial regulator of the Wnt signaling cascades, we determined how these CK1ε mutations interfere with the Wnt pathway and affect the behavior of epithelial breast cancer cell lines. Methods We performed in silico modeling of various mutations and analyzed the kinase activity of the CK1ε mutants both in vitro and in vivo. Furthermore, we used reporter and small GTPase assays to identify how mutation of CK1ε affects different branches of the Wnt signaling pathway. Based on these results, we employed cell adhesion and cell migration assays in MCF7 cells to demonstrate a crucial role for CK1ε in these processes. Results In silico modeling and in vivo data showed that autophosphorylation at Thr 44, a site adjacent to the breast cancer point mutations in the N-terminal lobe of human CK1ε, is involved in positive regulation of the CK1ε activity. Our data further demonstrate that, in mammalian cells, mutated forms of CK1ε failed to affect the intracellular localization and phosphorylation of Dvl2; we were able to demonstrate that CK1ε mutants were unable to enhance Dvl-induced TCF/LEF-mediated transcription, that CK1ε mutants acted as loss-of-function in the Wnt/β-catenin pathway, and that CK1ε mutants activated the noncanonical Wnt/Rac-1 and NFAT pathways, similar to pharmacological inhibitors of CK1. In line with these findings, inhibition of CK1 promoted cell migration as well as decreased cell adhesion and E-cadherin expression in the breast cancer-derived cell line MCF7. Conclusions In summary, these data suggest that the mutations of CK1ε found in breast cancer can suppress Wnt/β-catenin as well as promote the Wnt/Rac-1/JNK and Wnt/NFAT pathways, thus contributing to breast cancer development via effects on cell adhesion and migration. In terms of molecular mechanism, our data indicate that the breast cancer point mutations in the N-terminal lobe of CK1ε, which are correlated with decreased phosphorylation activities of mutated forms of CK1ε both in vitro and in vivo, interfere with positive autophosphorylation at Thr 4

Sex and age differences in sST2 in cardiovascular disease

AimsThe goal of this study was to determine whether sex and age differences exist for soluble ST2 (sST2) for several cardiovascular diseases (CVDs).MethodsWe examined sST2 levels using an ELISA kit for myocarditis (n = 303), cardiomyopathy (n = 293), coronary artery disease (CAD) (n = 239), myocardial infarct (MI) (n = 159), and congestive heart failure (CHF) (n = 286) and compared them to controls that did not have CVDs (n = 234).ResultsMyocarditis occurred in this study in relatively young patients around age 40 while the other CVDs occurred more often in older individuals around age 60. We observed a sex difference in sST2 by age only in myocarditis patients (men aged 38, women 46, p = 0.0002), but not for other CVDs. Sera sST2 levels were significantly elevated compared to age-matched controls for all CVDs: myocarditis (p ≤ 0.0001), cardiomyopathy (p = 0.0009), CAD (p = 0.03), MI (p = 0.034), and CHF (p < 0.0001) driven by elevated sST2 levels in females for all CVDs except myocarditis, which was elevated in both females (p = 0.002) and males (p ≤ 0.0001). Sex differences in sST2 levels were found for myocarditis and cardiomyopathy but no other CVDs and were higher in males (myocarditis p = 0.0035; cardiomyopathy p = 0.0047). sST2 levels were higher in women with myocarditis over 50 years of age compared to men (p = 0.0004) or women under 50 years of age (p = 0.015). In cardiomyopathy and MI patients, men over 50 had significantly higher levels of sST2 than women (p = 0.012 and p = 0.043, respectively) but sex and age differences were not detected in other CVDs. However, women with cardiomyopathy that experienced early menopause had higher sST2 levels than those who underwent menopause at a natural age range (p = 0.02).ConclusionWe found that sex and age differences in sera sST2 exist for myocarditis, cardiomyopathy, and MI, but were not observed in other CVDs including CAD and CHF. These initial findings in patients with self-reported CVDs indicate that more research is needed into sex and age differences in sST2 levels in individual CVDs