Correlated insulated phase suggests bond order between band and mott insulators in two dimensions.

We investigate the ground state phase diagram of the half-filled repulsive Hubbard model in two dimensions in the presence of a staggered potential Delta, the so-called ionic Hubbard model, using cluster dynamical mean-field theory. We find that for large Coulomb repulsion, U >> Delta, the system is a Mott insulator (MI). For weak to intermediate values of Delta, on decreasing U, the Mott gap closes at a critical value Uc1(Delta) beyond which a correlated insulating phase with possible bond order is found. Further, this phase undergoes a first-order transition to a band insulator (BI) at Uc2(Delta) with a finite charge gap at the transition. For large Delta, there is a direct first-order transition from a MI to a BI with a single metallic point at the phase boundary.

Dynamical breakup of the fermi surface in a doped Mott insulator.

The evolution from an anomalous metallic phase to a Mott insulator within the two-dimensional Hubbard model is investigated by means of the cellular dynamical mean-field theory. We show that approaching the density-driven Mott metal-insulator transition the Fermi surface is strongly renormalized and the quasiparticle description breaks down in a very anisotropic fashion. Regions where the quasiparticles are strongly scattered (hot spots) and regions where the scattering rate is relatively weak (cold spot) form irrespective of whether the parent insulator has antiferromagnetic long-range order, while their location is not universal and is determined by the interplay of the renormalization of the scattering rate and the Fermi surface shape.

Specific membrane receptor gene expression targeted with radiolabeled peptide employing the erbB-2 and DF3 promoter elements in adenoviral vectors.

Radioimmunotherapy is limited by a variety of factors, including poor tumor penetration of monoclonal antibodies and low levels of intratumoral antigen expression. To address these limitations, a gene therapy strategy was devised to genetically induce tumor cells to express enhanced levels of membrane receptors with high affinity for a radiolabeled peptide. We designated this approach as genetic radioisotope targeting strategy. To this end, an adenoviral vector (AdCMVGRPr) encoding the murine gastrin-releasing peptide receptor (GRPr) was used to achieve a high level of binding of radiolabeled bombesin (BBN). To achieve genetic induction of membrane GRPr specifically to tumor cells, we constructed two adenoviral vectors encoding the GRPr gene under the control of the tumor-specific regulatory elements, DF3 (AdDF3GRPr) or erbB-2 (AderbGRPr). We investigated the binding of [125I]BBN to the GRPr following infection with AdDF3GRPr and AderbGRPr in a panel of human breast, pancreatic, and cholangiocarcinoma tumor cell lines. [125I]BBN binding and GRPr expression increased with increasing multiplicities of infection of AdCMVGRPr in all of the cell lines tested. Breast cancer cell lines expressing erbB-2 showed significant GRPr expression using AderbGRPr. A similar result was observed in breast and cholangiocarcinoma cells infected with AdDF3GRPr expressing MUC1 as detected by immunohistochemistry but was not seen in the pancreatic cell lines tested. Thus, adenoviral vectors with tissue-specific promoter elements can be used to achieve a selective expression of membrane receptors that can be targeted with a radiolabeled peptide. The use of such a transcriptional targeting approach may restrict gene expression to tumors and limit the radiation dose deposited in normal tissues in vivo.

Combined cytosine deaminase expression, 5-fluorocytosine exposure, and radiotherapy increases cytotoxicity to cholangiocarcinoma cells.

Cholangiocarcinoma is a malignancy that is resistant to current therapy. We applied the toxin gene therapy strategy of cytosine deaminase conversion of the nontoxic producing 5-fluorocytosine to 5-fluorouracil combined with radiotherapy to cholangiocarcinoma. The transduction efficiency of SK-ChA-1 cholangiocarcinoma cells was determined by fluorescence-activated cell-sorting analysis following infection with recombinant adenovirus AdCMVLacZ, which encodes thc gene for Beta-galactosidase. To evaluate cytosine deaminase-mediated conversion of 5-fluorocytosine to 5-fluorouracil and subsequent cytotoxicity, SK-ChA-1 cells were infected with the recombinant adenovirus AdCMVCD, which encodes cytosine deaminase, and exposed to 5-fluorocytosine for 6 to 8 days. Additive cytotoxicity of radiation therapy was evaluated by cobalt-60 exposure following AdCMVCD infection and 5-fluorocytosine treatment. SK-ChA-1 cells were transduced (98.4%) by AdCMVLacZ at 100 plaque-forming units per cell. Following infection with AdCMVCD and exposure to 5 to 100 microgram/ml of 5-fluorocytosine, 20% to 64% of SK-ChA-1 cells were killed. A combination of radiation and cytosine deaminase/5-fluorocytosine therapy resulted in enhanced cell killing (83.5% to 91.5%). Cholangiocarcinoma cells were transduced by recombinant adenoviral vectors and were killed by cytosine deaminase-mediated production of 5-fluorouracil. Enhanced cytotoxicity was seen with the addition of external beam radiation. These results provide a foundation for multimodality therapy for human cholangiocarcinoma that combines gene therapy technology with radiation therapy.

Radiosensitization mediated by a transfected anti-erbB-2 single-chain antibody in vitro and in vivo.

PURPOSE: The erbB-2 receptor is overexpressed in several human cancers, including ovarian, prostate, and breast. We have developed plasmid and adenoviral vectors expressing an anti-erbB-2 single chain antibody (sFv), directed to the endoplasmic reticulum (ER) of target cells, that is cytotoxic to tumor cells overexpressing erbB-2 through induction of apoptosis. The anti-erbB-2 sFv also sensitizes erbB-2 overexpressing cells to the cytotoxic effects of cisplatin. On this basis, we hypothesized that human ovarian cancer cells expressing anti-erbB-2 sFv with downregulated erbB-2 product, p185erbB-2, also would be sensitized to ionizing radiation. Therefore, we designed experiments to test the ability of the anti-erbB-2 sFv to radiosensitize human ovarian cancer cells in vitro and in vivo. METHODS AND MATERIALS: To test our hypothesis, we established subcutaneous (s.c.) tumors in the flanks of nude mice with SKOV3.ip1 human ovarian cancer cells and SKOV3 cells stably expressing the ER directed anti-erbB-2 sFv (SKOV3/pGT21). The tumors were treated with 10 Gy 60Co, or received no radiation. We then determined the regression rate, delay in regrowth, and time to tumor doubling of the tumors treated with radiation in the transfected group and controls. In addition, SKOV3.ip1 and SKOV3/pGT21 tumors were dissected from the irradiated animals and assayed for differences in p185erbB-2 expression at 12 weeks after irradiation by immunohistochemistry. Further, in vitro clonogenic survival assays were performed on the parental SKOV3.ip1 and SKOV3/pGT21 cell lines. RESULTS: A statistical analysis of the combined data was done for two in vivo experiments. The analysis of the combined data showed that animals with irradiated tumor SKOV3/pGT21 had a significantly higher regression rate (p = 0.0055), longer delay in regrowth (p = 0.0001) and time to tumor doubling (p = 0.0004), than those animals with tumor SKOV3.ip1 that received radiation. We observed a similar significant effect for the same parameters in the unirradiated tumor SKOV3/pGT21 compared to unirradiated tumor SKOV3.ip1. Immunohistochemical analysis of the SKOV3/pGT21 tumor cells demonstrated focal accumulation of p185erbB-2 in scattered clumps of cells and less p185erbB-2 membrane expression than cells of SKOV3.ip1 tumors. However, SKOV3.ip1 and SKOV3/pGT21 cells had similar in vitro sensitivity to radiation. CONCLUSIONS: These data support the hypothesis that tumors with reduced p185erbB-2 expression mediated by the anti-erbB-2 sFv are rendered more susceptible in vivo to the cytotoxic effects of ionizing radiation than tumors that maintain their normal expression of p185erbB-2. However, a similar effect was not observed with the same tumor cells in vitro. Thus, as has been described by others (1, 2), in vitro and in vivo results do not always correlate. Therefore, appropriate assays to assess clinical relevance need to be determined for each particular system studied.

Molecular chemotherapy combined with radiation therapy enhances killing of cholangiocarcinoma cells in vitro and in vivo.

Cholangiocarcinoma is a virtually incurable tumor, resistant to current surgical, chemotherapy, and radiotherapy interventions. We applied the gene therapy strategy of toxin gene conversion of nontoxic prodrug to chemotherapeutic drug in combination with radiation therapy to the treatment of cholangiocarcinoma. In this regard, 5-fluorouracil (5-FU) is an accepted radiosensitizing and chemotherapeutic agent presently used in cancer therapy. The Escherichia coli enzyme cytosine deaminase (CD) converts the prodrug 5-fluorocytosine (5-FC) to 5-FU. Therefore, our goal was to express the CD gene in the human cholangiocarcinoma cell line, SK-ChA-1, assess the cytotoxicity of intracellular production of 5-FU, and determine any enhanced cell killing by the addition of external beam radiation. The susceptibility of SK-ChA-1 cells to recombinant adenoviral infection was determined by fluorescence-activated cell sorting analysis. We used the recombinant adenoviral vector AdCMVLacZ, encoding the E. coli beta-galactosidase reporter gene under control of the human cytomegalovirus (CMV) promoter, to infect SK-ChA-1 and HeLa cells at 10 and 100 plaque forming units (pfu)/cell, followed by FACS analysis. To evaluate CD-mediated conversion of 5-FC to 5-FU and subsequent cytotoxicity, SK-ChA-1 cells were infected with the recombinant adenovirus AdCMVCD, which encodes CD. Cells were then plated in 96-well microtiter plates and exposed to varying concentrations of 5-FC. Cell proliferation assays (tetrazolium salt conversion to formazan colorimetric assay) were performed beginning 2-8 days after plating. We evaluated the effects of external beam radiation using a single 8 Gy 60Co dose to AdCMVCD infected cells, with prior exposure to 5-FC for 2-3 days. MTS assays were performed following radiation treatment. Radiation dose-response analysis, via clonogenic assay, was used as a more sensitive assay to confirm the interaction of the treatment conditions. s.c. SK-ChA-1 tumors in athymic nude mice were established, which then received three intratumoral injections of 1 x 10(9) pfu AdCMVCD. Mice received i.p. injections of 400 mg/kg of 5-FC twice daily for 7 days beginning the day of initial AdCMVCD injection (day -2). The radiation treatment group received 10 Gy of 60Co exposure to their tumor on day 0. SK-ChA-1 cells were efficiently transduced (48.7 and 99.2%) by 10 and 100 pfu/cell of AdCMVLacZ, respectively. From 37.9 to 84.4% of SK-ChA-1 cells were killed following infection with 10 pfu/cell AdCMVCD and 8 days of exposure to various concentrations of 5-FC (5, 10, 30, 50, and 100 microg/ml). Higher 5-FC concentrations and longer duration of exposure resulted in greater cell killing. Radiation treatment (8 Gy) enhanced cell killing by greater than 70% when combined with 10 or 20 microg/ml of 5-FC. Radiation dose-response analysis with clonogenic assay confirmed enhanced SK-ChA-1 cell cytotoxicity as a result of radiation treatment following AdCMVCD infection and 5-FC exposure, with radiobiological parameters alpha = 0.44 and D0 = 0.96. Combined treatment of SK-ChA-1 tumors with AdCMVCD, 5-FC, and radiation in animals resulted in significantly greater survival, time to tumor regrowth, and doubling time compared to the nonradiation treatment group (P = 0.03, 0.015, and 0.002, respectively). Significantly greater change in tumor size, smaller ratio of final tumor size to original tumor size, and smaller final tumor size were observed in the radiation treatment group compared to the no radiation treatment group (P = 0.02, 0.03, and 0.03, respectively). Human cholangiocarcinoma cells were transduced with a recombinant adenovirus in vitro at high efficiency and were susceptible to CD-mediated intracellular 5-FU production. Radiobiological survival curve parameters confirmed an interactive cytotoxic effect when viral infection and prodrug therapy were combined with external beam radiation exposure. (ABSTRACT TRUNCATED)

Renal angioplasty in a case of renovascular hypertension presenting with stroke.

A young female patient with renovascular hypertension due to fibromuscular dysplasia of the right renal artery presenting with stroke is described. The patient was treated by renal angioplasty.

Effect of high-fat diet on cholesterol distribution in plasma lipoproteins, cholesterol esterifying activity in leucocytes, and erythrocyte membrane components studied: importance of body weight.

Effects of isocaloric changes in dietary fat on plasma lipoproteins and lipids and enzymes of erythrocytes and leucocytes were assessed. Subjects with a higher Brocca index showed increase in total and LDL cholesterol, significant reduction in HDL cholesterol, and increased total cholesterol:HDL cholesterol ratio after high-fat diet consumption. Due to high-fat diet feeding, erythrocyte membrane and leucocyte cholesterol and phospholipid contents were increased, cholesterol:phospholipid molar ratio was elevated, and erythrocyte enzymes (G6PD and 6PGD) and leucocyte enzymes (CEH and CES) were elevated. Erythrocyte membrane glycoprotein components showed marked increase, indicating possible alterations of membrane surfaces. The metabolic alterations were reversed slowly after resumption of the normal (low-fat) diet. Body weight plays an important role in the alterations in major lipoprotein cholesterol contents in response to changes in dietary fat composition. Cellular changes indicate alterations in structure and function of blood cells due to high-fat diet feeding.