Although increasing evidence supports a link between epidermal growth factor receptor (EGFR) signaling and resistance to apoptosis, the mechanism by which the EGFR signaling pathway inhibits apoptosis is not well understood. In this study, we found that epidermal growth factor ( The EGFR 2 signaling pathway plays a key role in the regulation of cell proliferation, survival, and differentiation (1, 2). It has been shown that the level of EGFR is up-regulated in many human tumor tissues. Activation of EGFR signaling has been associated with highly aggressive cancer types and poor responses to therapeutic agents (3-7). Prior preclinical and clinical studies have shown that blocking the EGFR signaling via monoclonal antibodies or inhibition of the EGFR tyrosine kinase with small molecules reduces the growth of breast cancers and sensitizes responses to chemotherapy (8 -10).Recently, we and others have shown that activation of the EGFR signaling pathway leads to the up-regulation of survivin, a member of the inhibitor of apoptosis (IAP) protein family (11)(12)(13)(14). Survivin is broadly expressed in fetal tissues but is undetectable in the most normal adult tissues (15). However, a high level of survivin is found in most common tumor types, including over 70% of human breast cancer tissues at all stages of cancer development (16 -18). It has been shown that in breast cancer cells, levels of survivin expression correlate with susceptibility to apoptosis (17). At present, the mechanism by which this up-regulation of survivin occurs in tumor cells having activated EGFR signaling is not fully understood. Recent studies have suggested, however, that activation of the phosphoinositide 3-kinase (PI3K)/AKT pathway by EGFR signaling causes up-regulation of survivin expression (12, 13). It is still unknown how PI3K/AKT signaling leads to survivin gene transcription.Several studies have shown that under normoxic conditions, activation of EGFR signaling also increases the level of hypoxiainducible factor 1␣ (HIF-1␣) through the PI3K/AKT pathway (19 -21). HIF-1␣, a member of the basic helix-loop-helix-PAS protein family (22) 2 The abbreviations used are: EGFR, epidermal growth factor receptor; IAP, inhibitor of apoptosis; EGF, epidermal growth factor; HIF, hypoxia-inducible factor; Doc, docetaxel; HRE, hypoxia-responsive element; 7-AAD, 7-amino-actinomycin D; PI3K, phosphoinositide 3-kinase; siRNA, small interfering RNA; FBS, fetal bovine serum; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; PE, phycoerythrin; nt, nucleotide(s); MAPK, mitogen-activated protein kinase; VEGF, vascular endothelial growth factor.

Purpose: Cell-surface receptor-targeted magnetic iron oxide nanoparticles provide molecular magnetic resonance imaging contrast agents for improving specificity of the detection of human cancer. Experimental Design:The present study reports the development of a novel targeted iron oxide nanoparticle using a recombinant peptide containing the amino-terminal fragment of urokinasetype plasminogen activator (uPA) conjugated to magnetic iron oxide nanoparticles amino-terminal fragment conjugated-iron oxide (ATF-IO).This nanoparticle targets uPA receptor, which is overexpressed in breast cancer tissues. Results: ATF-IO nanoparticles are able to specifically bind to and be internalized by uPA receptor^expressing tumor cells. Systemic delivery of ATF-IO nanoparticles into mice bearing s.c. and i.p. mammary tumors leads to the accumulation of the particles in tumors, generating a strong magnetic resonance imaging contrast detectable by a clinical magnetic resonance imaging scanner at a field strength of 3 tesla. Target specificity of ATF-IO nanoparticles showed by in vivo magnetic resonance imaging is further confirmed by near-IR fluorescence imaging of the mammary tumors using near-IR dye-labeled amino-terminal fragment peptides conjugated to iron oxide nanoparticles. Furthermore, mice administered ATF-IO nanoparticles exhibit lower uptake of the particles in the liver and spleen compared with those receiving nontargeted iron oxide nanoparticles. Conclusions: Our results suggest that uPA receptor^targeted ATF-IO nanoparticles have potential as molecularly targeted, dual modality imaging agents for in vivo imaging of breast cancer.Breast cancer is the most common type of cancer and the second leading cause of cancer-related death among women. Novel approaches for the detection of primary and metastatic breast cancers are urgently needed to increase the survival of patients. A promising strategy to improve the specificity and sensitivity of cancer imaging is to use biomarker target -specific imaging probes (1 -3) for image-based diagnosis and treatment monitoring. Currently, targeted radionuclide probes have been used for cancer detection by positron emission tomography or single photon emission tomography (2, 4, 5). Although nuclear imaging modalities show a high sensitivity, they lack good resolution and anatomic localization of the tumor lesion and require complicated and expensive radiochemistry. In addition, the half-life of the radiotracer often limits the ability for dynamic and time-resolved imaging and may not be able to capture the biomarker-targeting agent to reach and accumulate in the tumor. Magnetic resonance imaging offers a high spatial resolution and three-dimensional anatomic details and has been widely used in clinical oncology imaging. Recently, breast magnetic resonance imaging was recommended by the American Cancer Society as a screening approach, adjunct to mammography, for the early detection of breast cancer in women at high risk for this disease (6). Although breast cancer magnetic reson...

Recent reports have highlighted greater complexity, plasticity and functional diversity of mononuclear phagocytes (MPCs), including monocytes, macrophages and dendritic cells (DCs), in our organs, than previously understood. The functions and origins of MPCs resident within healthy organs, especially in the kidney, are less well understood, while studies suggest they play roles in disease states distinct from recruited monocytes. We developed an unbiased approach using flow cytometry to analyze MPCs residing in the normal mouse kidney, and identified five discrete subpopulations according to CD11b/CD11c expression as well as F4/80, CD103, CD14, CD16 and CD64 expression. In addition to distinct marker profiles, these subpopulations have different lineages and expression of genes involved in tissue homeostasis, including angiogenesis. Among them, the CD11bint CD11cint F4/80hi subpopulation notably exhibited high capacity to produce a representative anti-inflammatory cytokine, IL-10. Each subpopulation had different degrees of both macrophage (phagocytosis) and DC (antigen presentation) capacities, with a tendency to promote differentiation of regulatory T cells, while two of these showed expression of transcription factors reported to be highly expressed by classical DCs, and proclivity to exit the kidney following stimulation with LPS. In summary, resident kidney MPCs comprise discrete subpopulations, which cannot be simply classified into the conventional entities, and they produce anti-inflammatory and tissue-homeostatic factors to differing degrees.

It is appreciated far and wide that increased and regular consumption of fruits and vegetables is linked with noteworthy anticancer benefits. Extensively consumed as a spice in foods and beverages worldwide, ginger (Zingiber officinale Roscoe) is an excellent source of several bioactive phenolics, including non-volatile pungent compounds such as gingerols, paradols, shogaols and gingerones. Ginger has been known to display anti-inflammatory, antioxidant and antiproliferative activities, indicating its promising role as a chemopreventive agent. Here, we show that whole ginger extract (GE) exerts significant growth-inhibitory and death-inductory effects in a spectrum of prostate cancer cells. Comprehensive studies have confirmed that GE perturbed cell-cycle progression, impaired reproductive capacity, modulated cell-cycle and apoptosis regulatory molecules and induced a caspase-driven, mitochondrially mediated apoptosis in human prostate cancer cells. Remarkably, daily oral feeding of 100 mg/kg body weight of GE inhibited growth and progression of PC-3 xenografts by approximately 56 % in nude mice, as shown by measurements of tumour volume. Tumour tissue from GE-treated mice showed reduced proliferation index and widespread apoptosis compared with controls, as determined by immunoblotting and immunohistochemical methods. Most importantly, GE did not exert any detectable toxicity in normal, rapidly dividing tissues such as gut and bone marrow. To the best of our knowledge, this is the first report to demonstrate the in vitro and in vivo anticancer activity of whole GE for the management of prostate cancer.

Reversible acetylation of Tat is critical for its transactivation activity toward HIV-1 transcription. However, the enzymes involved in the acetylation/deacetylation cycles have not been fully characterized. In this study, by yeast two-hybrid assay, we have discovered the histone deacetylase HDAC6 to be a binding partner of Tat. Our data show that HDAC6 interacts with Tat in the cytoplasm in a microtubule-dependent manner. In addition, HDAC6 deacetylates Tat at Lys-28 and thereby suppresses Tatmediated transactivation of the HIV-1 promoter. Inactivation of HDAC6 promotes the interaction of Tat with cyclin T1 and leads to an increase in Tat transactivation activity. These findings establish HDAC6 as a Tat deacetylase and support a model in which Lys-28 deacetylation decreases Tat transactivation activity through affecting the ability of Tat to form a ribonucleoprotein complex with cyclin T1 and the transactivation-responsive RNA.