267 research outputs found
On the canonical degrees of curves in varieties of general type
A widely believed conjecture predicts that curves of bounded geometric genus
lying on a variety of general type form a bounded family. One may even ask
whether the canonical degree of a curve in a variety of general type is
bounded from above by some expression , where and are
positive constants, with the possible exceptions corresponding to curves lying
in a strict closed subset (depending on and ). A theorem of Miyaoka
proves this for smooth curves in minimal surfaces, with . A conjecture
of Vojta claims in essence that any constant is possible provided one
restricts oneself to curves of bounded gonality.
We show by explicit examples coming from the theory of Shimura varieties that
in general, the constant has to be at least equal to the dimension of the
ambient variety.
We also prove the desired inequality in the case of compact Shimura
varieties.Comment: 10 pages, to appear in Geometric and Functional Analysi
Endothelin-Receptor Antagonists beyond Pulmonary Arterial Hypertension: Cancer and Fibrosis.
The endothelin axis and in particular the two endothelin receptors, ETA and ETB, are targets for therapeutic intervention in human diseases. Endothelin-receptor antagonists are in clinical use to treat pulmonary arterial hypertension and have been under clinical investigation for the treatment of several other diseases, such as systemic hypertension, cancer, vasospasm, and fibrogenic diseases. In this Perspective, we review the molecules that have been evaluated in human clinical trials for the treatment of pulmonary arterial hypertension, as well as other cardiovascular diseases, cancer, and fibrosis. We will also discuss the therapeutic consequences of receptor selectivity with regard to ETA-selective, ETB-selective, or dual ETA/ETB antagonists. We will also consider which chemical characteristics are relevant to clinical use and the properties of molecules necessary for efficacy in treating diseases against which known molecules displayed suboptimal efficacy
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Convergence of measures on compactifications of locally symmetric spaces
We conjecture that the set of homogeneous probability measures on the maximal Satake compactification of an arithmetic locally symmetric space S=Γ∖G/K is compact. More precisely, given a sequence of homogeneous probability measures on S, we expect that any weak limit is homogeneous with support contained in precisely one of the boundary components (including S itself). We introduce several tools to study this conjecture and we prove it in a number of cases, including when G=SL3(R) and Γ=SL3(Z)
Combinatorial epigenetic therapy in diffuse large B cell lymphoma pre-clinical models and patients
BACKGROUND: Refractory and/or relapsed diffuse large B cell lymphoma (RR-DLBCL) patients are incurable with conventional chemotherapy due to the aggressiveness and the chemorefractory state of these tumors. DNA hypermethylation and histone deacetylation are two major epigenetic modifications by which aggressive DLBCL maintain their oncogenic state. We have previously reported that DNA methyltransferase inhibitors (DNMTI) affect RR-DLBCL growth and improve chemosensitivity. Here, we hypothesized that the combination of DNMTI with histone deacetylase inhibitor (HDI) would be an active and feasible therapeutic strategy in RR-DLBCL. Thus, we evaluated the anti-lymphoma activity of the HDI vorinostat (VST) in combination with the DNMTI azacitidine (AZA) or decitabine (DAC) in pre-clinical models of RR-DLBCL, and we determined the feasibility of the combination by conducting a phase Ib trial in RR-DLBCL patients. RESULTS: Concurrent combination of DNMTI and HDI resulted in synergistic anti-lymphoma effect toward RR-DLBCL cells in vitro and in vivo, with no significant toxicity increase. In a phase Ib trial, a total of 18 patients with a median of three prior therapies were treated with four different dose levels of AZA and VST. The most common toxicities were hematological, followed by gastrointestinal and metabolic. The clinical benefit was low as only one subject had a partial response and three subjects had stable disease. Interestingly, two of the seven patients that received additional chemotherapy post-study achieved a complete response and three others had a significant clinical benefit. These observations suggested that the combination might have a delayed chemosensitization effect that we were able to confirm by using in vitro and in vivo models. These studies also demonstrated that the addition of VST does not improve the chemosensitizing effect of DAC alone. CONCLUSIONS: Our data supports the strategy of epigenetic priming by employing DNMTI in RR-DLBCL patients in order to overcome resistance and improve their outcomes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13148-016-0245-y) contains supplementary material, which is available to authorized users
Increased endothelin-1 in colorectal cancer and reduction of tumour growth by ET A receptor antagonism
Endothelin-1 (ET-1) is a vasoconstrictor peptide which stimulates proliferation in vitro in different cell types, including colorectal cancer cells. Raised ET-1 levels have been detected both on tissue specimens and in the plasma of patients with cancers. To investigate the role of ET-1 in colorectal cancer: (i) ET-1 plasma levels in patients with colorectal cancer were measured by radioimmunoassay: group 1 = controls (n = 22), group 2 = primary colorectal cancer only (n = 39), group 3 = liver metastases only (n = 26); (ii) ET-1 expression in primary colorectal cancer specimens (n =10) was determined immunohistochemically and (iii) the effect of intraportally infused antagonists to the two ET-1 receptors, ET A and ET B, on the growth of liver metastases in a rat model was assessed. ET-1 plasma levels were significantly increased in both patients with primary tumour and patients with metastases, compared to controls (P < 0.01, 3.9 ± 1.4, 4.5 ± 1.5, vs. 2.75 ± 1.37 pg/ml, respectively). Immunohistochemically, strong expression of ET-1 was found in the cytoplasm, stroma and blood vessels of cancers, unlike the normal colon where only the apical layer of the epithelium, vascular endothelial cells and surrounding stroma were positively stained. In the rat model, there was significant reduction in liver tumour weights compared to controls, following treatment with the ET A antagonist (BQ123) 30 min after the intraportal inoculation of tumour cells (P < 0.05). These results suggest ET-1 is produced by colorectal cancers and may play a role in the growth of colorectal cancer acting through ET A receptors. ET A antagonists are indicated as potential anti-cancer agents. © 2001 Cancer Research Campaign http://www.bjcancer.co
A multiscale experimental analysis of mechanical properties and deformation behavior of sintered copper–silicon carbide composites enhanced by high‑pressure torsion
Experiments were conducted to investigate, within the framework of a multiscale approach, the mechanical enhancement, deformation and damage behavior of copper–silicon carbide composites (Cu–SiC) fabricated by spark plasma sintering (SPS) and the combination of SPS with high-pressure torsion (HPT). The mechanical properties of the metal–matrix composites were determined at three different length scales corresponding to the macroscopic, micro- and nanoscale. Small punch testing was employed to evaluate the strength of composites at the macroscopic scale. Detailed analysis of microstructure evolution related to SPS and HPT, sample deformation and failure of fractured specimens was conducted using scanning and transmission electron microscopy. A microstructural study revealed changes in the damage behavior for samples processed by HPT and an explanation for this behavior was provided by mechanical testing performed at the micro- and nanoscale. The strength of copper samples and the metal–ceramic interface was determined by microtensile testing and the hardness of each composite component, corresponding to the metal matrix, metal–ceramic interface, and ceramic reinforcement, was measured using nano-indentation. The results confirm the advantageous effect of large plastic deformation on the mechanical properties of Cu–SiC composites and demonstrate the impact on these separate components on the deformation and damage type
Endothelin-1 enhances fibrogenic gene expression, but does not promote DNA synthesis or apoptosis in hepatic stellate cells
BACKGROUND: In liver injury, the pool of hepatic stellate cell (HSC) increases and produces extracellular matrix proteins, decreasing during the resolution of fibrosis. The profibrogenic role of endothelin-1 (ET-1) in liver fibrosis remains disputed. We therefore studied the effect of ET-1 on proliferation, apoptosis and profibrogenic gene expression of HSCs. RESULTS: First passage HSC predominantly expressed endothelin A receptor (ETAR) mRNA and 4th passage HSC predominantly expressed the endothelin B receptor (ETBR) mRNA. ET-1 had no effect on DNA synthesis in 1st passage HSC, but reduced DNA synthesis in 4th passage HSC by more than 50%. Inhibition of proliferation by endothelin-1 was abrogated by ETBR specific antagonist BQ788, indicating a prominent role of ETBR in growth inhibition. ET-1 did not prevent apoptosis induced by serum deprivation or Fas ligand in 1st or 4th passage HSC. However, ET-1 increased procollagen α1(I), transforming growth factor β-1 and matrix metalloproteinase (MMP)-2 mRNA transcripts in a concentration-dependent manner in 1st, but not in 4th passage HSC. Profibrogenic gene expression was abrogated by ETAR antagonist BQ123. Both BQ123 and BQ788 attenuated the increase of MMP-2 expression by ET-1. CONCLUSION: We show that ET-1 stimulates fibrogenic gene expression for 1st passage HSC and it inhibits HSC proliferation for 4th passage HSC. These data indicate the profibrogenic and antifibrogenic action of ET-1 for HSC are involved in the process of liver fibrosis
Mechanical Tension Increases CCN2/CTGF Expression and Proliferation in Gingival Fibroblasts via a TGFβ-Dependent Mechanism
Unlike skin, oral gingival do not scar in response to tissue injury. Fibroblasts,
the cell type responsible for connective tissue repair and scarring, are exposed
to mechanical tension during normal and pathological conditions including wound
healing and fibrogenesis. Understanding how human gingival fibroblasts respond
to mechanical tension is likely to yield valuable insights not only into
gingival function but also into the molecular basis of scarless repair.
CCN2/connective tissue growth factor is potently induced in fibroblasts during
tissue repair and fibrogenesis. We subjected gingival fibroblasts to cyclical
strain (up to 72 hours) using the Flexercell system and showed that CCN2 mRNA
and protein was induced by strain. Strain caused the rapid activation of latent
TGFβ, in a fashion that was reduced by blebbistatin and FAK/src inhibition,
and the induction of endothelin (ET-1) mRNA and protein expression. Strain did
not cause induction of α-smooth muscle actin or collagen type I mRNAs
(proteins promoting scarring); but induced a cohort of pro-proliferative mRNAs
and cell proliferation. Compared to dermal fibroblasts, gingival fibroblasts
showed reduced ability to respond to TGFβ by inducing fibrogenic mRNAs;
addition of ET-1 rescued this phenotype. Pharmacological inhibition of the
TGFβ type I (ALK5) receptor, the endothelin A/B receptors and FAK/src
significantly reduced the induction of CCN2 and pro-proliferative mRNAs and cell
proliferation. Controlling TGFβ, ET-1 and FAK/src activity may be useful in
controlling responses to mechanical strain in the gingiva and may be of value in
controlling fibroproliferative conditions such as gingival hyperplasia;
controlling ET-1 may be of benefit in controlling scarring in response to injury
in the skin
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