Up-regulation of folate receptor (FR) type-␤ in acute myelogenous leukemia (AML) by all-trans retinoic acid (ATRA) and its restricted normal tissue distribution makes it a potential target for therapeutic intervention. The FR-␤ in peripheral blood granulocytes was unable to bind folate and appeared to have a variant GPI membrane anchor, evident from its insensitivity to phosphatidylinositol-specific phospholipase C but not nitrous acid. Granulocyte FR-␤ lacked mutations, and neither deglycosylation nor detergent solubilization restored folate binding. The posttranslational modification causing its nonfunctionality was evi- IntroductionAcute myelogenous leukemia (AML) is the most common type of acute leukemia in adults. Standard chemotherapy results in a 70% complete remission rate in AML patients. 1 Treatment with drugs such as anthracyclines, however, is associated with severe side effects such as myelosuppression and dose-limiting cardiotoxicity and a high incidence of relapse. 2 Relapsed disease is frequently refractory to chemotherapy and exhibits multidrug resistance (MDR). 3 A potential means of treating AML is by targeted drug delivery through liposomes. Liposomal delivery of drugs has been shown to extend their systemic circulation time, reduce dose-limiting toxicity, and overcome MDR. [4][5][6][7] Liposomal anthracyclines have reached clinical use for the treatment of Kaposi sarcoma 5 and are in clinical trial for solid tumors and leukemias. [8][9][10][11][12][13][14] Liposomal delivery has also been shown to increase anthracycline cytotoxicity in tumor cells exhibiting MDR. 6,7,[15][16][17] The efficacy of liposomal drugs can potentially be further enhanced by selective targeting to tumor cells through a cell surface molecule that is differentially expressed on tumor cells. 18,19 The folate receptor (FR) is a promising target because of its narrow tissue specificity, its overexpression in malignant tissues, and its ability to bind and internalize folic acid conjugates. Of the 3 human folate receptor isoforms, 20-22 2 (FR-␣ and FR-␤) are attached to the cell surface through a glycosyl-phosphatidylinositol (GPI) membrane anchor, 20,23 whereas the third (FR-␥) is constitutively secreted. 24 The expression of FR-␣ in normal tissues is restricted to certain epithelial cells, where it is inaccessible by the circulation. 25,26 FR-␣ is found to be amplified in many epitheliallineage human tumors, including approximately 90% of ovarian carcinomas. [26][27][28][29] A wide variety of experimental therapies, 30 including drug-loaded liposomes, 31-34 have successfully targeted FR-␣ selectively in gynecologic and other tumors. The expression of FR-␤ in normal tissues is restricted to placenta and hematopoietic cells, where it is expressed in the myelomonocytic lineage and is particularly elevated during neutrophil maturation or during monocyte or macrophage activation. 29,35,36 FR-␤ is also known to be expressed in chronic myelogenous leukemia (CML) and in AML. 22,37,38 FR-␤ from membrane preparations from CML and ...

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The utility of the folate receptor (FR) type A, in a broad range of targeted therapies and as a diagnostic serum marker in cancer, is confounded by its variable tumor expression levels. FR-A, its mRNA and its promoter activity were coordinately up-regulated by the glucocorticoid receptor (GR) agonist, dexamethasone. Optimal promoter activation which occurred at <50 nmol/L dexamethasone was inhibited by the GR antagonist, RU486, and was enhanced by coactivators, supporting GR mediation of the dexamethasone effect. The dexamethasone response of the FR-A promoter progressed even after dexamethasone was withdrawn, but this delayed effect required prior de novo protein synthesis indicating an indirect regulation. The dexamethasone effect was mediated by the G/C-rich (Sp1 binding) element in the core P4 promoter and was optimal in the proper initiator context without associated changes in the complement of major Sp family proteins. Histone deacetylase (HDAC) inhibitors potentiated dexamethasone induction of FR-A independent of changes in GR levels. Dexamethasone/HDAC inhibitor treatment did not cause de novo FR-A expression in a variety of receptornegative cells. In a murine HeLa cell tumor xenograft model, dexamethasone treatment increased both tumor-associated and serum FR-A. The results support the concept of increasing FR-A expression selectively in the receptor-positive tumors by brief treatment with a nontoxic dose of a GR agonist, alone or in combination with a well-tolerated HDAC inhibitor, to increase the efficacy of various FR-A-dependent therapeutic and diagnostic applications. They also offer a new paradigm for cancer diagnosis and combination therapy that includes altering a marker or a target protein expression using general transcription modulators. (Cancer Res 2005; 65(10): 4431-41)

In this paper, we consider an inverse source problem for elliptic partial differential equations with Dirichlet and Neumann boundary data. The unknown source term is to be determined from additional boundary conditions. Unlike the existing methods found in the literature, which usually use some of the boundary conditions to form a boundary value problem for the elliptic partial differential equation and the remaining boundary conditions in the objective functional for optimization to determine the source term, the novel method that we propose here has coupled complex boundary conditions. We use a complex elliptic partial differential equation with a Robin boundary condition coupling the Dirichlet and Neumann boundary data, and optimize with respect to the imaginary part of the solution in the domain to determine the source term. Then, on the basis of the complex boundary value problem, Tikhonov regularization is used to obtain a stable approximate source function and the finite element method is used for discretization. Theoretical analysis is given for both the continuous model and the discrete model. Several numerical examples are provided to show the usefulness of the proposed coupled complex boundary method.

We report the synthesis of single-crystal La0.67Sr0.33MnO3 (LSMO) freestanding films with different crystal orientations. By using pulsed laser deposition, water soluble perovskite-like sacrificial layers Sr3Al2O6 (SAO) followed by LSMO films are grown on differently oriented SrTiO3 substrates. Freestanding LSMO films with different orientations are obtained by etching the SAO in pure water. All the freestanding films show room-temperature ferromagnetism and metallicity, independent of the crystal orientation. Intriguingly, the Curie temperature (TC) of the freestanding films is increased due to strain relaxation after releasing from the substrates. Our results provide an additional degree of freedom to tailor the properties of freestanding perovskite oxide heterostructures by crystal orientation and an opportunity to further integrate different oriented films together.

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