Histone modification enhances the effectiveness of IL-13 receptor targeted immunotoxin in murine models of human pancreatic cancer

<p>Abstract</p> <p>Background</p> <p>Interleukin-13 Receptor α2 (IL-13Rα2) is a tumor-associated antigen and target for cancer therapy. Since IL-13Rα2 is heterogeneously overexpressed in a variety of human cancers, it would be highly desirable to uniformly upregulate IL-13Rα2 expression in tumors for optimal targeting.</p> <p>Methods</p> <p>We examined epigenetic regulation of <it>IL-13Rα2 </it>in a murine model of human pancreatic cancer by Bisulfite-PCR, sequencing for DNA methylation and chromatin immunoprecipitation for histone modification. Reverse transcription-PCR was performed for examining changes in IL-13Rα2 mRNA expression after treatment with histone deacetylase (HDAC) and c-jun inhibitors. <it>In vitro </it>cytotoxicity assays and <it>in vivo </it>testing in animal tumor models were performed to determine whether HDAC inhibitors could enhance anti-tumor effects of IL-13-PE in pancreatic cancer. Mice harboring subcutaneous tumors were treated with HDAC inhibitors systemically and IL-13-PE intratumorally.</p> <p>Results</p> <p>We found that CpG sites in <it>IL-13Rα2 </it>promoter region were not methylated in all pancreatic cancer cell lines studied including IL-13Rα2-positive and IL-13Rα2-negative cell lines and normal cells. On the other hand, histones at IL-13Rα2 promoter region were highly-acetylated in IL-13Rα2-positive but much less in receptor-negative pancreatic cancer cell lines. When cells were treated with HDAC inhibitors, not only histone acetylation but also IL-13Rα2 expression was dramatically enhanced in receptor-negative pancreatic cancer cells. In contrast, HDAC inhibition did not increase IL-13Rα2 in normal cell lines. In addition, c-jun in IL-13Rα2-positive cells was expressed at higher level than in negative cells. Two types of c-jun inhibitors prevented increase of IL-13Rα2 by HDAC inhibitors. HDAC inhibitors dramatically sensitized cancer cells to immunotoxin in the cytotoxicity assay <it>in vitro </it>and increased IL-13Rα2 in the tumors subcutaneously implanted in the immunodeficient animals but not in normal mice tissues. Combination therapy with HDAC inhibitors and immunotoxin synergistically inhibited growth of not only IL-13Rα2-positive but also IL-13Rα2-negative tumors.</p> <p>Conclusions</p> <p>We have identified a novel function of histone modification in the regulation of IL-13Rα2 in pancreatic cancer cell lines <it>in vitro </it>and <it>in vivo</it>. HDAC inhibition provides a novel opportunity in designing combinatorial therapeutic approaches not only in combination with IL-13-PE but with other immunotoxins for therapy of pancreatic cancer and other cancers.</p

Promoter Polymorphism of RGS2 Gene Is Associated with Change of Blood Pressure in Subjects with Antihypertensive Treatment: The Azelnidipine and Temocapril in Hypertensive Patients with Type 2 Diabetes Study

We performed a prospective study to examine the genetic effect on the response to a calcium (Ca) channel blocker, azelnidipine and an ACE inhibitor, temocapril treatment in patients with hypertension, as a part of the prior clinical trial, the Azelnidipine and Temocapril in Hypertensive Patients with Type 2 Diabetes Study (ATTEST). Methods and Results. All subjects who gave informed consent for genetic research were divided into two groups: the subjects treated with azelnidipine or temocapril, for 52 weeks. We selected 18 susceptible genes for hypertension and determined their genotypes using TaqMan PCR method. RNA samples were extracted from peripheral blood, and quantitative real time PCR for all genes was performed using TaqMan method. One of the polymorphisms of the RGS2 gene was extracted as being able to influence the effect of these treatments to reduce BP. At eight weeks, BP change showed a significant interaction between the A-638G polymorphism of Regulator of G protein signaling-2 (RGS2) gene and treatment with azelnidipine or temocapril. There was no gene whose expression was associated with BP phenotypes or the polymorphisms of each gene. Conclusions. A-638G polymorphism of the RGS-2 gene could be a predictive factor for therapeutic performance of Ca channel blockers

Angle-resolved photoemission study of MX-chain compound [Ni(chxn)2_2Br]Br2_2

We report on the results of angle-resolved photoemission experiments on a quasi-one-dimensional $MX$-chain compound [Ni(chxn)$_2$Br]Br$_2$ (chxn = 1$R$,2$R$-cyclohexanediamine), a one-dimensional Heisenberg system with $S=1/2$ and $J \sim 3600$ K, which shows a gigantic non-linear optical effect. A "band" having about 500 meV energy dispersion is found in the first half of the Brillouin zone $(0\le kb/\pi <1/2)$, but disappears at $kb / \pi \sim 1/2$. Two dispersive features, expected from the spin-charge separation, as have been observed in other quasi-one-dimensional systems like Sr$_2$CuO$_3$, are not detected. These characteristic features are well reproduced by the $d$-$p$ chain model calculations with a small charge-transfer energy $\Delta$ compared with that of one-dimensional Cu-O based compounds. We propose that this smaller $\Delta$ is the origin of the absence of clear spin- and charge-separation in the photoemission spectra and strong non-linear optical effect in [Ni(chxn)$_2$Br]Br$_2$.Comment: 4 pages, 3 figure

All Optical Cellular Quantum Computer having Ancilla Bits for Operations in Each Cell

A quantum cellular network with a qubit and ancilla bits in each cell is proposed. The whole circuit works only with the help of external optical pulse sequences. In the operation, some of the ancilla bits are activated, and autonomous single- and two-qubit operations are made. In the sleep mode of a cell, the decoherence of the qubit is negligibly small. Since only two cells at most are active at once, the coherence can be maintained for a sufficiently long time for practical purposes. A device structure using a quantum dot array with possible operation and measurement schemes is also proposed.Comment: 14 pages, 5 figures RevTeX ;a single sentense is modified for the clarit

Cysteamine Suppresses Invasion, Metastasis and Prolongs Survival by Inhibiting Matrix Metalloproteinases in a Mouse Model of Human Pancreatic Cancer

Background: Cysteamine, an anti-oxidant aminothiol, is the treatment of choice for nephropathic cystinosis, a rare lysosomal storage disease. Cysteamine is a chemo-sensitization and radioprotection agent and its antitumor effects have been investigated in various tumor cell lines and chemical induced carcinogenesis. Here, we investigated whether cysteamine has anti-tumor and anti-metastatic effects in transplantable human pancreatic cancer, an aggressive metastatic disease. Methodology/Principal Findings: Cysteamine’s anti-invasion effects were studied by matrigel invasion and cell migration assays in 10 pancreatic cancer cell lines. To study mechanism of action, we examined cell viability and matrix metalloproteinases (MMPs) activity in the cysteamine-treated cells. We also examined cysteamine’s anti-metastasis effect in two orthotopic murine models of human pancreatic cancer by measuring peritoneal metastasis and survival of animals. Cysteamine inhibited both migration and invasion of all ten pancreatic cancer cell lines at concentrations (,25 mM) that caused no toxicity to cells. It significantly decreased MMPs activity (IC50 38–460 mM) and zymographic gelatinase activity in a dose dependent manner in vitro and in vivo; while mRNA and protein levels of MMP-9, MMP-12 and MMP-14 were slightly increased using the highest cysteamine concentration. In vivo, cysteamine significantly decreased metastasis in two established pancreatic tumor models, although it did not affect the size of primary tumors. Additionally, cysteamin

Minimal triangulation of a graph and optimal pivoting order in a sparse matrix

AbstractThis paper considers the problem of finding a minimal triangulation of an undirected graph G = (V, E), where a triangulation is a set T such that every cycle in G = (V, E ∪ T) has a chord. A triangulation T is minimal (minimum) if no triangulation F exists such that F is a proper subset of T (¦F¦ < ¦T¦), and an ordering α is optimal (optimum) if a minimal (minimum) triangulation is generated by α. A minimum triangulation (optimum ordering) is necessarily minimal (optimal), but the converse is not necessarily true. A necessary and sufficient condition for a triangulation to be minimal is presented. This leads to an algorithm for finding an optimal ordering α which produces a minimal set of “fill-in” when the process is viewed as triangular factorization of a sparse matrix

Crossing Minimization in the Straight-Line Embedding of Graphs.

The problem of embedding a graph in the plane with the minimum number of edgecrossings arises in some circuit layout problems. It has been known that this problem is in general NP-hard. An interesting and relevant problem in the area of book embedding was recently shown to be NP-hard. This result implies that the former problem is NP-hard even when the vertices are placed on a straight line l and the edges are drawn completely on either side of l. In this paper, we show that the problem remains NP-hard even if, in addition to these constraints, the positions of the vertices on SCRIPT l are predetermined