Superparamagnetic iron oxide nanoparticles have recently been developed as T2 contrast agents for magnetic resonance imaging. Here we report the dependence of the phase relaxivity, r2, on the particle shape. We show that the size dependence of the relaxivity for spherical particles can be generalized to spheroidal particles. In addition, we show that the saturation of relaxivity above a certain size observed in spherical particles does not occur in the spheroidal particles investigated.
Abstract Introduction. A distinctive feature of cancer cells is the implementation of the synthesis of fatty acids (FA), (lipogenesis), which is instead suppressed in most normal adult tissues. Because metabolites produced via lipogenesis provide redox potential and influence the activity of enzymes involved in transcription regulation, by turning on this pathway tumor cells might enable metabolic and transcriptional adjustments necessary for survival in various stress conditions. A still unanswered question is whether oncogenes expressed in human tumors directly favor the shift towards lipogenesis and, if so, whether this has consequences for proliferation or for therapy. The initial goal of this study was to identify metabolic gene targets regulated by tumor-derived mutant forms of the p53 gene product, whose role in metabolism is currently unknown. Results. We found that p53 mutants enhance the expression levels of the mitochondria citrate transporter, CIC. CIC is central to lipogenesis as it scaffolds citrate from the mitochondria to the cytosol, yielding acetyl-CoA, in turn necessary for fatty acid synthesis. Data extracted from gene expression databases, confirmed a strong association between high levels of CIC mRNA and p53 mutant-expressing human tumors, suggesting that up-regulation of CIC is a molecular signature for p53 mutations. CIC up-regulation is also a negative prognostic factor, and a predictor of tumor recurrence, thus mirroring the negative prognostic value of p53 mutant positive tumors. We show that the CIC promoter is transcriptionally up-regulated by mutant p53, via a unique mechanism that involves p53 mutant binding to FOXO-1- and to p53-consensus elements contained therein, as well as a physical interaction between these two proteins. Importantly, while in glucose-deprived cells CIC promoter activity is physiologically shut down, p53 mutants maintain higher levels of CIC transcription in these conditions. This is in contrast with wild-type p53 that suppresses CIC transcription. Furthermore, we demonstrate that inhibition of CIC with a siRNA, or blocking export of citrate to the cytoplasm with a CIC inhibitor, lowers fatty acid levels and impairs survival of p53-mutant tumors. This effect is not seen in pseudo-normal or tumor cells that have a wild-type p53 gene, again suggesting specificity for mutant p53. Additional experiments indicate that by promoting cytoplasmic export of citrate, elevated CIC levels might hamper mitochondrial pathways of energy production. Conclusions. We have identified the first metabolic signature gene regulated by p53 mutants, CIC, and shown that some tumors expressing these proteins depend upon CIC up-regulation and FA synthesis for survival especially in metabolic stress conditions. Furthermore, we have identified strategies for targeting CIC activity, thus opening new opportunities for the treatment of p53 positive tumors. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 66.
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
// Lucas Tricoli 1, 4 , Aisha Naeem 1 , Erika Parasido 1 , John P. Mikhaiel 1 , Muhammad Umer Choudhry 1 , Deborah L. Berry 1 , Iman A. Abdelgawad 2 , Richard J. Lee 3 , Adam S. Feldman 3 , Chukwuemeka Ihemelandu 1 , Maria Avantaggiati 1 , Deepak Kumar 4 , Stephen Byers 1 , Rosa Gallagher 5 , Julia Wulfkuhle 5 , Emanuel Petricoin 5 , Olga Rodriguez 1, 6 and Chris Albanese 1, 6 1 Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA 2 National Cancer Institute of Egypt, Cairo, Egypt 3 Massachusetts General Hospital Cancer Center, Boston, MA, USA 4 Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, Durham, NC, USA 5 Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA 6 Preclinical Imaging Research Laboratory, Georgetown University Medical Center, Washington, DC, USA Correspondence to: Chris Albanese, email: albanese@georgetown.edu Keywords: prostate; cancer; primary tissue; reprogrammed cells; androgen Received: October 26, 2017 Accepted: November 02, 2017 Published: December 18, 2017 ABSTRACT The inability to propagate human prostate epithelial cells indefinitely has historically presented a serious impediment to prostate cancer research. The conditionally reprogrammed cell (CRC) approach uses the combination of irradiated J2 mouse fibroblasts and a Rho kinase inhibitor such as Y27632 to support the continuous culture of cells derived from most epithelial tissues, including the prostate. Due to their rapid establishment and overall ease of use, CRCs are now widely used in a variety of basic and preclinical settings. In addition, CRCs were successfully used to clinically treat respiratory papillomatosis. Although both normal and tumor-derived prostate CRCs have been used to study the basic biology of prostate cancer and to test new therapies, certain limitations exist. We have previously reported that prostate CRCs form functional prostate glands when implanted under the mouse renal capsule. However in conventional culture, the prostate CRCs exist in an adult stem-like, transient amplifying state and consequently do not adequately recapitulate several important features of a differentiated prostate epithelium. To address these limitations, we previously described a transwell dish-based model that supported the culturing of prostate CRCs and the collection of cells and cell extracts for molecular and genetic analyses. Using normal and tumor-derived prostate CRCs, we describe the combined effects of the multi-dimensional transwell platform and defined culture media on prostate cellular proliferation, differentiation and signaling.
The integrated mouse mammary tumor virus (MMTV) promoter has provided an excellent model system with which to study the impact of steroid hormones on transcriptional activation in the context of a defined chromatin structure. The hormone response element (HRE) of this promoter is positioned on a phased nucleosome which becomes remodeled in response to steroids. One possible mechanism of chromatin remodeling by steroid receptors could involve recruitment of coactivators which alter the histone acetylation status of the HRE nucleosome. To examine how the androgen receptor (AR) influences transcription and chromatin remodeling and to assess whether changes in histone acetylation are involved in these effects, we determined whether the specific histone deacetylase inhibitor trichostatin A (TSA) influenced basal- and androgen-mediated transcriptional activation of the integrated MMTV promoter in the mouse L-cell fibroblast cell line 29+. These cells harbor the MMTV promoter integrated in the genome and express only one steroid hormone receptor subtype, i.e., the AR. Surprisingly, we found that treatment of the cells with TSA alone had virtually no effect on transcription and chromatin remodeling of the MMTV promoter nor on AR levels. However, pretreatment with TSA augmented the DHT effects on all three parameters. These results suggest that histone acetylation changes at the MMTV B nucleosome per se are not alone sufficient to induce chromatin remodeling and subsequent induction of MMTV transcription. Rather, the histone deacetylase inhibitor TSA exerts a portion of its effect on MMTV chromatin remodeling and transcriptional activation indirectly through increases in AR levels.
Peroxisome proliferator-activated receptorδ (PPARδ) regulates a multiplicity of physiological processes associated with glucose and lipid metabolism, inflammation, and proliferation. One or more of these processes likely create risk factors associated with the ability of PPARδ agonists to promote tumorigenesis in some organs. In the present study, we describe a new gastric tumor mouse model that is dependent on the potent and highly selective PPARδ agonist GW501516 following carcinogen administration. The progression of gastric tumorigenesis was rapid as determined by magnetic resonance imaging and resulted in highly metastatic squamous cell carcinomas of the forestomach within two months. Tumorigenesis was associated with gene expression signatures indicative of cell adhesion, invasion, inflammation, and metabolism. Increased PPARδ expression in tumors correlated with increased PDK1, Akt, β-catenin, and S100A9 expression. The rapid development of metastatic gastric tumors in this model will be useful for evaluating preventive and therapeutic interventions in this disease.
Abstract Epidemiological and experimental studies suggest that psychosocial stress contributes to cancer development and progression. Yet, the mechanism of this phenomenon is not clear. The goal of our study was to test whether the sympathetic neurotransmitter neuropeptide Y (NPY), which is up-regulated in chronic stress and acts as an angiogenic and growth factor, mediates this process. To this end, wild type (WT) and NPY knockout (NPY KO) mice were treated with a chemical carcinogen, 7,12 dimethylbenz[a]anthracene (DMBA), in the presence of medroxyprogesterone acetate (MPA). To isolate NPY-dependent effects of stress, DMBA/MPA-treated WT and NPY KO mice were subjected to chronic stress (daily cold exposure) for two weeks in the following groups: 1) Control; 2) Early stress during DMBA administration to establish its effect on tumor initiation; 3) Late stress applied when tumors were detectable to determine its effect on their progression. Tumorigenic processes were assessed by monitoring mammary tumor growth, periodical MRI imaging and histopathology of tumor tissues. DMBA/MPA treatment resulted in various neoplastic changes: lymphoma/leukemia (Leu), uterine hemangiomas and angiosarcomas, folliculomas and mammary tumors. The following differences were observed: 1) Under basal conditions, lack of NPY resulted in reduced incidence of Leu and a protective effect on mammary tumor formation (reduced frequency and increased latency) in NPY KO mice suggesting its role in development of these malignancies; 2) early stress increased incidence of uterine angiosarcomas in an NPY-dependent manner. In contrast, a stress-induced increase in frequency of Leu and ovarian folliculoma was observed only in NPY KO mice suggesting that this effect may be mediated by catecholamines (CA), which are excessively released in the absence of an inhibitor of their secretion such as NPY. Surprisingly, early stress had a protective effect on mammary tumor formation that was observed in both WT and NPY KO mice suggesting an NPY-independent mechanism; 3) Late stress accelerated the progression of Leu in an NPY-independent manner. A similar phenomenon was observed in uterine angiosarcomas induced in WT mice, while late stress in NPY KO mice caused their complete regression. These results may be explained by a growth inhibitory effect of CA excessively released in stressed animals devoid of NPY. Lastly, in mammary tumors, stress increased tumor vascularization and proliferation in an NPY-dependent manner. In summary, our data demonstrate potent and differential effects of NPY and other stress mediators on tumor development and progression. These results lay a foundation for further, more comprehensive and mechanistic studies on the effects of stress on particular tumor types. This, in turn, may open new therapeutic and perhaps also preventative avenues for cancer patients, as well as identify populations at risk. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-186. doi:1538-7445.AM2012-LB-186
<div>Abstract<p>Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with limited and, very often, ineffective medical and surgical therapeutic options. The treatment of patients with advanced unresectable PDAC is restricted to systemic chemotherapy, a therapeutic intervention to which most eventually develop resistance. Recently, nab-paclitaxel (n-PTX) has been added to the arsenal of first-line therapies, and the combination of gemcitabine and n-PTX has modestly prolonged median overall survival. However, patients almost invariably succumb to the disease, and little is known about the mechanisms underlying n-PTX resistance. Using the conditionally reprogrammed (CR) cell approach, we established and verified continuously growing cell cultures from treatment-naïve patients with PDAC. To study the mechanisms of primary drug resistance, nab-paclitaxel–resistant (n-PTX-R) cells were generated from primary cultures and drug resistance was verified <i>in vivo</i>, both in zebrafish and in athymic nude mouse xenograft models. Molecular analyses identified the sustained induction of <i>c-MYC</i> in the n-PTX-R cells. Depletion of c-MYC restored n-PTX sensitivity, as did treatment with either the MEK inhibitor, trametinib, or a small-molecule activator of protein phosphatase 2a.</p>Implications:<p>The strategies we have devised, including the patient-derived primary cells and the unique, drug-resistant isogenic cells, are rapid and easily applied <i>in vitro</i> and <i>in vivo</i> platforms to better understand the mechanisms of drug resistance and for defining effective therapeutic options on a patient by patient basis.</p></div>
