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1.  Cellular iron metabolism in prognosis and therapy of breast cancer 
Critical reviews in oncogenesis  2013;18(5):435-448.
Despite many recent advances, breast cancer remains a clinical challenge. Current issues include improving prognostic evaluation and increasing therapeutic options for women whose tumors are refractory to current frontline therapies. Iron metabolism is frequently disrupted in breast cancer, and may offer an opportunity to address these challenges. Iron enhances breast tumor initiation, growth and metastases. Iron may contribute to breast tumor initiation by promoting redox cycling of estrogen metabolites. Up-regulation of iron import and down-regulation of iron export may enable breast cancer cells to acquire and retain excess iron. Alterations in iron metabolism in macrophages and other cells of the tumor microenvironment may also foster breast tumor growth. Expression of iron metabolic genes in breast tumors is predictive of breast cancer prognosis. Iron chelators and other strategies designed to limit iron may have therapeutic value in breast cancer. The dependence of breast cancer on iron presents rich opportunities for improved prognostic evaluation and therapeutic intervention.
PMCID: PMC3736347  PMID: 23879588
iron; breast cancer; estrogen
2.  FERRITIN H INDUCTION BY HISTONE DEACETYLASE INHIBITORS 
Biochemical pharmacology  2010;80(3):316-324.
Because both iron deficiency and iron excess are deleterious to normal cell function, the intracellular level of iron must be tightly controlled. Ferritin, an iron binding protein, regulates iron balance by storing iron in a bioavailable but non-toxic form. Ferritin protein comprises two subunits: ferritin H, which contains ferroxidase activity, and ferritin L. Here we demonstrate that ferritin H mRNA and protein are induced by histone deacetylase inhibitors (HDAC inhibitors), a promising class of anti-cancer drugs, in cultured human cancer cells. Deletion analysis and EMSA assays reveal that the induction of ferritin H occurs at a transcriptional level via Sp1 and NF-Y binding sites near the transcriptional start site of the human ferritin H promoter. Classically, HDAC inhibitors modulate gene expression by increasing histone acetylation. However, ChIP assays demonstrate that HDAC inhibitors induce ferritin H transcription by increasing NF-Y binding to the ferritin H promoter without changes in histone acetylation. These results identify ferritin H as a new target of HDAC inhibitors, and recruitment of NF-Y as a novel mechanism of action of HDAC inhibitors.
doi:10.1016/j.bcp.2010.04.008
PMCID: PMC2913600  PMID: 20385107
Ferritin H; histone acetylation; chromatin immunoprecipitation; cancer; HDAC inhibitors; transcription
3.  Targeting Cancer Stem Cells with Nanoparticle-Enabled Therapies 
Journal of molecular biomarkers & diagnosis  2012;Suppl 8:10.4172/2155-9929.S8-003.
Emerging evidence suggests that multiple tumor types are sustained by a small population of transformed stem-like cells that have the ability to both self-renew and give rise to non-tumorigenic daughter cells that constitute the bulk of a tumor. These cells, which generally constitute a minority of the overall cancer cell population, are highly resistant to conventional therapies and persist following treatment, leading to disease relapse and the formation of distant metastases. Therapies that disrupt the maintenance and survival of cancer stem cells are the subject of active current investigation. This review discusses recent approaches to the application of nanomedicine to the targeting and elimination of cancer stem cells. Specifically, recent publications in the areas of nanoparticle-enabled drug and nucleic acid delivery and photothermal therapy are addressed.
doi:10.4172/2155-9929.S8-003
PMCID: PMC3875221  PMID: 24383043
Cancer stem cells; Tumor-initiating cells; Drug delivery; Nucleic acid delivery; Targeted; Nanoparticle; Carbon nanotube; Photo thermal therapy; Hyperthermia
4.  Synthetic and natural iron chelators: therapeutic potential and clinical use 
Future medicinal chemistry  2009;1(9):10.4155/fmc.09.121.
Iron-chelation therapy has its origins in the treatment of iron-overload syndromes. For many years, the standard for this purpose has been deferoxamine. Recently, considerable progress has been made in identifying synthetic chelators with improved pharmacologic properties relative to deferoxamine. Most notable are deferasirox (Exjade®) and deferiprone (Ferriprox®), which are now available clinically. In addition to treatment of iron overload, there is an emerging role for iron chelators in the treatment of diseases characterized by oxidative stress, including cardiovascular disease, atherosclerosis, neurodegenerative diseases and cancer. While iron is not regarded as the underlying cause of these diseases, it does play an important role in disease progression, either through promotion of cellular growth and proliferation or through participation in redox reactions that catalyze the formation of reactive oxygen species and increase oxidative stress. Thus, iron chelators may be of therapeutic benefit in many of these conditions. Phytochemicals, many of which bind iron, may also owe some of their beneficial properties to iron chelation. This review will focus on the advances in iron-chelation therapy for the treatment of iron-overload disease and cancer, as well as neurodegenerative and chronic inflammatory diseases. Established and novel iron chelators will be discussed, as well as the emerging role of dietary plant polyphenols that effectively modulate iron biochemistry.
doi:10.4155/fmc.09.121
PMCID: PMC3821171  PMID: 21425984
5.  Ferroportin and Iron Regulation in Breast Cancer Progression and Prognosis 
Science translational medicine  2010;2(43):43ra56.
Ferroportin and hepcidin are critical proteins for the regulation of systemic iron homeostasis. Ferroportin is the only known mechanism for export of intracellular non–heme-associated iron; its stability is regulated by the hormone hepcidin. Although ferroportin profoundly affects concentrations of intracellular iron in tissues important for systemic iron absorption and trafficking, ferroportin concentrations in breast cancer and their influence on growth and prognosis have not been examined. We demonstrate here that both ferroportin and hepcidin are expressed in cultured human breast epithelial cells and that hepcidin regulates ferroportin in these cells. Further, ferroportin protein is substantially reduced in breast cancer cells compared to nonmalignant breast epithelial cells; ferroportin protein abundance correlates with metabolically available iron. Ferroportin protein is also present in normal human mammary tissue and markedly decreased in breast cancer tissue, with the highest degree of anaplasia associated with lowest ferroportin expression. Transfection of breast cancer cells with ferroportin significantly reduces their growth after orthotopic implantation in the mouse mammary fat pad. Gene expression profiles in breast cancers from >800 women reveal that decreased ferroportin gene expression is associated with a significant reduction in metastasis-free and disease-specific survival that is independent of other breast cancer risk factors. High ferroportin and low hepcidin gene expression identifies an extremely favorable cohort of breast cancer patients who have a 10-year survival of >90%. Ferroportin is a pivotal protein in breast biology and a strong and independent predictor of prognosis in breast cancer.
doi:10.1126/scisignal.3001127
PMCID: PMC3734848  PMID: 20686179
6.  Photothermal Response of Human and Murine Cancer Cells to Multiwalled Carbon Nanotubes after Laser Irradiation 
Cancer research  2010;70(23):9855-9864.
This study demonstrates the capability of multiwalled carbon nanotubes (MWNTs) coupled with laser irradiation to enhance treatment of cancer cells through enhanced and more controlled thermal deposition, increased tumor injury, and diminished heat shock protein (HSP) expression. We also explored the potential promise of MWNTs as drug delivery agents by observing the degree of intracellular uptake of these nanoparticles. To determine the heat generation capability of MWNTs, the absorption spectra and temperature rise during heating were measured. Higher optical absorption was observed for MWNTs in water compared with water alone. For identical laser parameters, MWNT-containing samples produced a significantly greater temperature elevation compared to samples treated with laser alone. Human prostate cancer (PC3) and murine renal carcinoma (RENCA) cells were irradiated with a 1,064-nm laser with an irradiance of 15.3 W/cm2 for 2 heating durations (1.5 and 5 minutes) alone or in combination with MWNT inclusion. Cytotoxicity and HSP expression following laser heating was used to determine the efficacy of laser treatment alone or in combination with MWNTs. No toxicity was observed for MWNTs alone. Inclusion of MWNTs dramatically decreased cell viability and HSP expression when combined with laser irradiation. MWNT cell internalization was measured using fluorescence and transmission electron microscopy following incubation of MWNTs with cells. With increasing incubation duration, a greater number of MWNTs were observed in cellular vacuoles and nuclei. These findings offer an initial proof of concept for the application of MWNTs in cancer therapy.
doi:10.1158/0008-5472.CAN-10-0250
PMCID: PMC3699181  PMID: 21098701
7.  Hybrid 2D Nanomaterials as Dual-mode Contrast Agents in Cellular Imaging 
doi:10.1002/adma.201200706
PMCID: PMC3395317  PMID: 22573478
hybrid materials; imaging techniques; magnetic resonance imaging; luminescence; graphene oxide
8.  Application of circuit simulation method for differential modeling of TIM-2 iron uptake and metabolism in mouse kidney cells 
Circuit simulation is a powerful methodology to generate differential mathematical models. Due to its highly accurate modeling capability, circuit simulation can be used to investigate interactions between the parts and processes of a cellular system. Circuit simulation has become a core technology for the field of electrical engineering, but its application in biology has not yet been fully realized. As a case study for evaluating the more advanced features of a circuit simulation tool called Advanced Design System (ADS), we collected and modeled laboratory data for iron metabolism in mouse kidney cells for a H ferritin (HFt) receptor, T cell immunoglobulin and mucin domain-2 (TIM-2). The internal controlling parameters of TIM-2 associated iron metabolism were extracted and the ratios of iron movement among cellular compartments were quantified by ADS. The differential model processed by circuit simulation demonstrated a capability to identify variables and predict outcomes that could not be readily measured by in vitro experiments. For example, an initial rate of uptake of iron-loaded HFt (Fe-HFt) was 2.17 pmol per million cells. TIM-2 binding probability with Fe-HFt was 16.6%. An average of 8.5 min was required for the complex of TIM-2 and Fe-HFt to form an endosome. The endosome containing HFt lasted roughly 2 h. At the end of endocytosis, about 28% HFt remained intact and the rest was degraded. Iron released from degraded HFt was in the labile iron pool (LIP) and stimulated the generation of endogenous HFt for new storage. Both experimental data and the model showed that TIM-2 was not involved in the process of iron export. The extracted internal controlling parameters successfully captured the complexity of TIM-2 pathway and the use of circuit simulation-based modeling across a wider range of cellular systems is the next step for validating the significance and utility of this method.
doi:10.3389/fphys.2013.00136
PMCID: PMC3675319  PMID: 23761763
circuit simulator; export; ferritin; iron; model; storage; TIM-2; uptake
9.  The Resistance of Breast Cancer Stem Cells to Conventional Hyperthermia and their Sensitivity to Nanoparticle-mediated Photothermal Therapy 
Biomaterials  2012;33(10):2961-2970.
Breast tumors contain a small population of tumor initiating stem-like cells, termed breast cancer stem cells (BCSCs). These cells, which are refractory to chemotherapy and radiotherapy, are thought to persist following treatment and drive tumor recurrence. We examined whether BCSCs are similarly resistant to hyperthermic therapy, and whether nanoparticles could be used to overcome this resistance. Using a model of triple-negative breast cancer stem cells, we show that BCSCs are markedly resistant to traditional hyperthermia and become enriched in the surviving cell population following treatment. In contrast, BCSCs are sensitive to nanotube-mediated thermal treatment and lose their long-term proliferative capacity after nanotube-mediated thermal therapy. Moreover, use of this therapy in vivo promotes complete tumor regression and long-term survival of mice bearing cancer stem cell-driven breast tumors. Mechanistically, nanotube thermal therapy promotes rapid membrane permeabilization and necrosis of BCSCs. These data suggest that nanotube-mediated thermal treatment can simultaneously eliminate both the differentiated cells that constitute the bulk of a tumor and the BCSCs that drive tumor growth and recurrence.
doi:10.1016/j.biomaterials.2011.12.052
PMCID: PMC3286596  PMID: 22245557
10.  An Iron Regulatory Gene Signature Predicts Outcome in Breast Cancer 
Cancer research  2011;71(21):6728-6737.
Changes in iron regulation characterize the malignant state. However, the pathways that effect these changes and their specific impact on prognosis remain poorly understood. We capitalized on publicly available microarray datasets comprising 674 breast cancer cases to systematically investigate how expression of genes related to iron metabolism is linked to breast cancer prognosis. Of 61 genes involved in iron regulation, 49% were statistically significantly associated with distant metastasis-free survival (DMFS). Cases were divided into test and training cohorts and the supervised principal component method was used to stratify cases into risk groups. Optimal risk stratification was achieved with a model comprising 16 genes, which we term the iron regulatory gene signature (IRGS). Multivariable analysis revealed that the IRGS contributes information not captured by conventional prognostic indicators (hazard ratio 1.61; 95% CI 1.16–2.24; p=0.004). The IRGS successfully stratified homogeneously treated patients, including ER+ patients treated with tamoxifen monotherapy, both with (p=0.006) and without (p=0.03) lymph node metastases. To test whether multiple pathways were embedded within the IRGS, we evaluated the performance of two gene dyads with known roles in iron biology in ER+ patients treated with tamoxifen monotherapy (n=371). For both dyads, gene combinations that minimized intracellular iron content (anti-import: TFRCLow/HFEHigh; or pro-export: FPHigh/HAMPLow) were associated with favorable prognosis (p<0.005). Although the clinical utility of the IRGS will require further evaluation, its ability to both identify high risk patients within traditionally low risk groups and low risk patients within high risk groups has the potential to affect therapeutic decision-making.
doi:10.1158/0008-5472.CAN-11-1870
PMCID: PMC3206152  PMID: 21875943
11.  Determinants of the Thrombogenic Potential of Multiwalled Carbon Nanotubes 
Biomaterials  2011;32(26):5970-5978.
Multiwalled carbon nanotubes (MWCNTs) are cylindrical tubes of graphitic carbon with unique physical and electrical properties. MWCNTs are being explored for a variety of diagnostic and therapeutic applications. Successful biomedical application of MWCNTs will require compatibility with normal circulatory components, including constituents of the hemostatic cascades. In this manuscript, we compare the thrombotic activity of MWCNTs in vitro and in vivo. We also assess the influence of functionalization of MWCNTs on thrombotic activity. In vitro, MWCNT activate the intrinsic pathway of coagulation as measured by activated partial thromboplastin time (aPTT) assays. Functionalization by amidation or carboxylation enhances this procoagulant activity. Mechanistic studies demonstrate that MWCNTs enhance propagation of the intrinsic pathway via a non-classical mechanism strongly dependent on factor IX. MWCNTs preferentially associate with factor IXa and may provide a platform for its activation. In addition to their effects on the coagulation cascade, MWCNTs activate platelets in vitro, with amidated MWCNTs exhibiting greater platelet activation than carboxylated or pristine MWCNTs. However, contrasting trends are obtained in vivo, where functionalization tends to diminish rather than enhance pro-coagulant activity. Thus, following systemic injection of MWCNTs in mice, pristine MWCNTs decreased platelet counts, increased vWF, and increased D-dimers. In contrast, carboxylated MWCNTS exhibited little procoagulant tendency in vivo, eliciting only a mild and transient decrease in platelets. Amidated MWCNTs elicited no statistically significant change in platelet count. Further, neither carboxylated nor amidated MWCNTs increased vWF or D-dimers in mouse plasma. We conclude that the pro-coagulant tendencies of MWCNTs observed in vitro are not necessarily recapitulated in vivo. Further, functionalization can markedly attenuate the procoagulant activity of MWCNTs in vivo. This work will inform the rational development of biocompatible MWCNTs for systemic delivery.
doi:10.1016/j.biomaterials.2011.04.059
PMCID: PMC3130101  PMID: 21663954
blood; blood compatibility; clotting; nanoparticle; platelet activation; thrombosis
12.  Differential gene expression in normal and transformed human mammary epithelial cells in response to oxidative stress 
Free radical biology & medicine  2011;50(11):1565-1574.
Oxidative stress plays a key role in breast carcinogenesis. To investigate whether normal and malignant breast epithelial cells differ in their responses to oxidative stress, we examined the global gene expression profiles of three cell types, representing cancer progression from a normal to a malignant stage, under oxidative stress. Normal human mammary epithelial cells (HMEC), an immortalized cell line (HMLER-1), and a tumorigenic cell line (HMLER-5), were exposed to increased levels of reactive oxygen species (ROS) by treatment with glucose oxidase. Functional analysis of the metabolic pathways enriched with differentially expressed genes demonstrates that normal and malignant breast epithelial cells diverge substantially in their response to oxidative stress. While normal cells exhibit the up-regulation of antioxidant mechanisms, cancer cells are unresponsive to the ROS insult. However, the gene expression response of normal HMEC cells under oxidative stress is comparable to that of the malignant cells under normal conditions, indicating that altered redox status is persistent in breast cancer cells, which makes them resistant to increased generation of ROS. This study discusses some of the possible adaptation mechanisms of breast cancer cells under persistent oxidative stress that differentiate them from the response to acute oxidative stress in normal mammary epithelial cells.
doi:10.1016/j.freeradbiomed.2011.03.002
PMCID: PMC3119600  PMID: 21397008
Oxidative stress; breast cancer; human mammary epithelial cells; microarrays; glucose oxidase; GluOx
13.  Ironing Out Cancer 
Cancer research  2011;71(5):1511-1514.
New insights into the roles of proteins that regulate cellular iron in cancer growth, angiogenesis, and metastasis have recently emerged. Discoveries of the roles of ferroportin, hepcidin, Lcn2, and members of the STEAP and IRP families in cancer have provided specificity and molecular definition to the role of iron homeostasis in cancer growth and metastasis. A number of studies directly support a role of these proteins in modifying bio-available iron, while other studies suggest that at least some of their effects are independent of their role in iron biology.
doi:10.1158/0008-5472.CAN-10-3614
PMCID: PMC3079335  PMID: 21363917
14.  Development of iron-containing multiwalled carbon nanotubes for MR-guided laser-induced thermotherapy 
Nanomedicine (London, England)  2011;6(8):1341-1352.
Aims
To test iron-containing multiwalled carbon nanotubes (MWCNTs) as bifunctional nanomaterials for imaging and thermal ablation of tumors.
Materials & Methods
MWCNTs entrapping iron were synthesized by chemical vapor deposition. The T2-weighted contrast enhancement properties of MWCNTs containing increasing amounts of iron were determined in vitro. Suspensions of these particles were injected into tumor-bearing mice and tracked longitudinally over 7 days by MRI. Heat-generating abilities of these nanomaterials following exposure to near infrared (NIR) laser irradiation was determined in vitro and in vivo.
Results
The magnetic resonance contrast properties of carbon nanotubes were directly related to their iron content. Iron-containing nanotubes were functional T2-weighted contrast agents in vitro and could be imaged in vivo long-term following injection. Iron content of nanotubes did not affect their ability to generate thermoablative temperatures following exposure to NIR and significant tumor regression was observed in mice treated with MWCNTs and NIR laser irradiation.
Conclusion
These data demonstrate that iron-containing MWCNTs are functional T2-weighted contrast agents and efficient mediators of tumor-specific thermal ablation in vivo.
doi:10.2217/nnm.11.37
PMCID: PMC3197747  PMID: 21506687
cancer; contrast agent; in vivo; laser; MRI; nanotube; T2; thermal therapy
15.  Iron Uptake Mediated by Binding of H-Ferritin to the TIM-2 Receptor in Mouse Cells 
PLoS ONE  2011;6(8):e23800.
Ferritin binds specifically and saturably to a variety of cell types, and recently several ferritin receptors have been cloned. TIM-2 is a specific receptor for H ferritin (HFt) in the mouse. TIM-2 is a member of the T cell immunoglobulin and mucin domain containing (TIM) protein family and plays an important role in immunity. The expression of TIM-2 outside of the immune system indicates that this receptor may have broader roles. We tested whether ferritin binding to TIM-2 can serve as an iron delivery mechanism. TIM-2 was transfected into normal (TCMK-1) mouse kidney cells, where it was appropriately expressed on the cell surface. HFt was labeled with 55Fe and 55Fe-HFt was incubated with TIM-2 positive cells or controls. 55Fe-HFt uptake was observed only in TIM-2 positive cells. HFt uptake was also seen in A20 B cells, which express endogenous TIM-2. TIM-2 levels were not increased by iron chelation. Uptake of 55Fe-HFt was specific and temperature-dependent. HFt taken up by TIM-2 positive cells transited through the endosome and eventually entered a lysosomal compartment, distinguishing the HFt pathway from that of transferrin, the classical vehicle for cellular iron delivery. Iron delivered following binding of HFt to TIM-2 entered the cytosol and became metabolically available, resulting in increased levels of endogenous intracellular ferritin. We conclude that TIM-2 can function as an iron uptake pathway.
doi:10.1371/journal.pone.0023800
PMCID: PMC3158792  PMID: 21886823
16.  Serum Ferritin: Past, Present and Future 
Biochimica et biophysica acta  2010;1800(8):760-769.
Background
Serum ferritin was discovered in the 1930’s, and was developed as a clinical test in the 1970’s. Many diseases are associated with iron overload or iron deficiency. Serum ferritin is widely used in diagnosing and monitoring these diseases.
Scope of Review
In this chapter, we discuss the role of serum ferritin in physiological and pathological processes and its use as a clinical tool.
Major Conclusions
Although many aspects of the fundamental biology of serum ferritin remain surprisingly unclear, a growing number of roles have been attributed to extracellular ferritin, including newly described roles in iron delivery, angiogenesis, inflammation, immunity, signaling and cancer.
General Significance
Serum ferritin remains a clinically useful tool. Further studies on the biology of this protein may provide new biological insights.
doi:10.1016/j.bbagen.2010.03.011
PMCID: PMC2893236  PMID: 20304033
17.  Bioinformatics tools for cancer metabolomics 
Metabolomics  2011;7(3):329-343.
It is well known that significant metabolic change take place as cells are transformed from normal to malignant. This review focuses on the use of different bioinformatics tools in cancer metabolomics studies. The article begins by describing different metabolomics technologies and data generation techniques. Overview of the data pre-processing techniques is provided and multivariate data analysis techniques are discussed and illustrated with case studies, including principal component analysis, clustering techniques, self-organizing maps, partial least squares, and discriminant function analysis. Also included is a discussion of available software packages.
doi:10.1007/s11306-010-0270-3
PMCID: PMC3155682  PMID: 21949492
Metabolomics; Cancer; Metabolite profiling; NMR; Mass spectrometry; Bioinformatics
18.  A Systems Biology View of Cancer 
Biochimica et biophysica acta  2009;1796(2):129-139.
SUMMARY
In order to understand how a cancer cell is functionally different from a normal cell it is necessary to assess the complex network of pathways involving gene regulation, signaling, and cell metabolism, and the alterations in its dynamics caused by the several different types of mutations leading to malignancy. Since the network is typically complex, with multiple connections between pathways and important feedback loops, it is crucial to represent it in the form of a computational model that can be used for a rigorous analysis. This is the approach of systems biology, made possible by new –omics data generation technologies. The goal of this review is to illustrate this approach and its utility for our understanding of cancer. After a discussion of recent progress using a network-centric approach, three case studies related to diagnostics, therapy, and drug development are presented in detail. They focus on breast cancer, B cell lymphomas, and colorectal cancer. The discussion is centered on key mathematical and computational tools common to a systems biology approach.
doi:10.1016/j.bbcan.2009.06.001
PMCID: PMC2782452  PMID: 19505535
systems biology; cancer; mathematical modeling
19.  Loss of heterozygosity and SOSTDC1 in adult and pediatric renal tumors 
Background
Deletions within the short arm of chromosome 7 are observed in approximately 25% of adult and 10% of Wilms pediatric renal tumors. Within Wilms tumors, the region of interest has been delineated to a 2-Mb minimal region that includes ten known genes. Two of these ten candidate genes, SOSTDC1 and MEOX2, are particularly relevant to tumor development and maintenance. This finding, coupled with evidence that SOSTDC1 is frequently downregulated in adult renal cancer and regulates both Wingless-Int (Wnt)- and bone morphogenetic protein (BMP)-induced signaling, points to a role for SOSTDC1 as a potential tumor suppressor.
Methods
To investigate this hypothesis, we interrogated the Oncomine database to examine the SOSTDC1 levels in adult renal clear cell tumors and pediatric Wilms tumors. We then performed single nucleotide polymorphism (SNP) and sequencing analyses of SOSTDC1 in 25 pediatric and 36 adult renal tumors. Immunohistochemical staining of patient samples was utilized to examine the impact of SOSTDC1 genetic aberrations on SOSTDC1 protein levels and signaling.
Results
Within the Oncomine database, we found that SOSTDC1 levels were reduced in adult renal clear cell tumors and pediatric Wilms tumors. Through SNP and sequencing analyses of 25 Wilms tumors, we identified four with loss of heterozygosity (LOH) at 7p and three that affected SOSTDC1. Of 36 adult renal cancers, we found five with LOH at 7p, two of which affected SOSTDC1. Immunohistochemical analysis of SOSTDC1 protein levels within these tumors did not reveal a relationship between these instances of SOSTDC1 LOH and SOSTDC1 protein levels. Moreover, we could not discern any impact of these genetic alterations on Wnt signaling as measured by altered beta-catenin levels or localization.
Conclusions
This study shows that genetic aberrations near SOSTDC1 are not uncommon in renal cancer, and occur in adult as well as pediatric renal tumors. These observations of SOSTDC1 LOH, however, did not correspond with changes in SOSTDC1 protein levels or signaling regulation. Although our conclusions are limited by sample size, we suggest that an alternative mechanism such as epigenetic silencing of SOSTDC1 may be a key contributor to the reduced SOSTDC1 mRNA and protein levels observed in renal cancer.
doi:10.1186/1756-9966-29-147
PMCID: PMC3002326  PMID: 21080955
20.  A General Map of Iron Metabolism and Tissue-specific Subnetworks 
Molecular bioSystems  2009;5(5):422-443.
Iron is required for survival of mammalian cells. Recently, understanding of iron metabolism and trafficking has increased dramatically, revealing a complex, interacting network largely unknown just a few years ago. This provides an excellent model for systems biology development and analysis. The first step in such an analysis is the construction of a structural network of iron metabolism, which we present here. This network was created using CellDesigner version 3.5.2 and includes reactions occurring in mammalian cells of numerous tissue types. The iron metabolic network contains 151 chemical species and 107 reactions and transport steps. Starting from this general model, we construct iron networks for specific tissues and cells that are fundamental to maintaining body iron homeostasis. We include subnetworks for cells of the intestine and liver, tissues important in iron uptake and storage, respectively; as well as the reticulocyte and macrophage, key cells in iron utilization and recycling. The addition of kinetic information to our structural network will permit the simulation of iron metabolism in different tissues as well as in health and disease.
doi:10.1039/b816714c
PMCID: PMC2680238  PMID: 19381358
iron; liver; macrophage; reactive oxygen species; red blood cells
21.  Ferritin for the Clinician 
Blood reviews  2008;23(3):95-104.
Ferritin, a major iron storage protein, is essential to iron homeostasis and is involved in a wide range of physiologic and pathologic processes. In clinical medicine, ferritin is predominantly utilized as a serum marker of total body iron stores. In cases of iron deficiency and overload, serum ferritin serves a critical role in both diagnosis and management. Elevated serum and tissue ferritin are linked to coronary artery disease, malignancy, and poor outcomes following stem cell transplantation. Ferritin is directly implicated in less common but potentially devastating human diseases including sideroblastic anemias, neurodegenerative disorders, and hemophagocytic syndrome. Additionally, recent research describes novel functions of ferritin independent of iron storage.
doi:10.1016/j.blre.2008.08.001
PMCID: PMC2717717  PMID: 18835072
ferritin; iron
22.  Preparation of Disubstituted Phenyl Propargyl Alcohols, their Use in Oxathiolene Oxide Synthesis, and Evaluation of the Oxathiolene Oxide Products as Anticarcinogenic Enzyme Inducers 
Letters in organic chemistry  2009;6(3):242-251.
A number of alkynols have been prepared by Sonogoshira coupling of propargyl alcohol to disubstituted aromatic halides. Chelation controlled addition of organometallic nucleophiles to these alkynols was then affected followed by the addition of sulfur dioxide. This methodology was used to prepare a number of oxathiolene oxides which have been screened as NQO1 (quinone oxidoreductase) inducers.
doi:10.2174/157017809787893064
PMCID: PMC2768303  PMID: 19865593
Alkynol synthesis; cancer chemoprevention; sulfur heterocycle synthesis; NQO1
23.  The transplant iron score as a predictor of stem cell transplant survival 
Recent studies have suggested that the presence of iron overload prior to stem cell transplantation is associated with decreased survival. Within these studies, the criteria used to define iron overload have varied considerably. Given the lack of consensus regarding the definition of iron overload in the transplant setting, we sought to methodically examine iron status among transplant patients. We studied 78 consecutive patients at risk for transfusion-related iron overload (diagnoses included AML, ALL, MDS, and aplastic anemia) who received either autologous or allogeneic stem cell transplant. Multiple measures of iron status were collected prior to transplantation and examined for their association with survival. Using this data, three potentially prognostic iron measures were identified and incorporated into a rational and unified scoring system. The resulting Transplant Iron Score assigns a point for each of the following variables: (1) greater than 25 red cell units transfused prior to transplantation; (2) serum ferritin > 1000 ng/ml; and (3) a semi-quantitative bone marrow iron stain of 6+. In our cohort, the score (range 0 to 3) was more closely associated with survival than any available single iron parameter. In multivariate analysis, we observed an independent effect of iron overload on transplant survival (p = 0.01) primarily attributable to an increase in early treatment-related deaths (p = 0.02) and lethal infections. In subgroup analysis, the predictive power of the iron score was most pronounced among allogeneic transplant patients, where a high score (≥ 2) was associated with a 50% absolute decrease in survival at one year. In summary, our results lend further credence to the notion that iron overload prior to transplant is detrimental and suggest iron overload may predispose to a higher rate of lethal infections.
doi:10.1186/1756-8722-2-44
PMCID: PMC2770452  PMID: 19852846
24.  N-Picolyl Derivatives of Kemp’s Triamine as Potential Antitumor Agents: A Preliminary Investigation 
Journal of medicinal chemistry  2005;48(25):7993-7999.
Pre-organized tripodal ligands such as the N-picolyl derivatives of cis,cis-1,3,5-triamino-cis,cis-1,3,5-trimethylcyclohexane (Kemp’s triamine) were prepared as analogs to N,N’,N”- tris(2-pyridylmethyl)-cis,cis-1,3,5-triaminocyclohexane (tachpyr) in hopes of enhancing the rate of formation and stability of the metal complexes. A tricyclic bisaminal was formed via the reduction of the Schiff base while the tri(picolyl) derivative was synthesized via reductive amination of pyridine carboxaldehyde. Their cytotoxicities to the HeLa cell line were evaluated and directly compared to tachpyr and N,N’,N”- tris(2-pyridylmethyl)-tris(2-aminoethyl)amine (trenpyr). Results indicate that N,N’,N”-tris(2-pyridylmethyl)-cis,cis-1,3,5-triamino-cis,cis-1,3,5-trimethylcyclohexane (Kemp’s pyr) exhibits cytotoxic activity against the HeLa cancer cell line comparable to tachpyr (IC50 ~ 8.0 µM). Both Kemp’s pyr and tachpyr show higher cytotoxic activity over the aliphatic analogue of trenpyr (IC50 ~ 14 µM) suggesting that the major contributor to the activity is the ligand’s ability to form a stable and tight complex and that the equatorial/axial equilibrium impacting the complex formation for the cyclohexane-based ligands is not significant.
doi:10.1021/jm050724r
PMCID: PMC2597376  PMID: 16335923
25.  A Human Bone Morphogenetic Protein Antagonist Is Down-Regulated in Renal Cancer 
Molecular Biology of the Cell  2008;19(2):457-464.
We analyzed expression of candidate genes encoding cell surface or secreted proteins in normal kidney and kidney cancer. This screen identified a bone morphogenetic protein (BMP) antagonist, SOSTDC1 (sclerostin domain–containing-1) as down-regulated in kidney tumors. To confirm screening results, we probed cDNA dot blots with SOSTDC1. The SOSTDC1 message was decreased in 20/20 kidney tumors compared with normal kidney tissue. Immunohistochemistry confirmed significant decrease of SOSTDC1 protein in clear cell renal carcinomas relative to normal proximal renal tubule cells (p < 0.001). Expression of SOSTDC1 was not decreased in papillary and chromophobe kidney tumors. SOSTDC1 was abundantly expressed in podocytes, distal tubules, and transitional epithelia of the normal kidney. Transfection experiments demonstrated that SOSTDC1 is secreted and binds to neighboring cells and/or the extracellular matrix. SOSTDC1 suppresses both BMP-7–induced phosphorylation of R-Smads-1, -5, and -8 and Wnt-3a signaling. Restoration of SOSTDC1 in renal clear carcinoma cells profoundly suppresses proliferation. Collectively, these results demonstrate that SOSTDC1 is expressed in the human kidney and decreased in renal clear cell carcinoma. Because SOSTDC1 suppresses proliferation of renal carcinoma cells, restoration of SOSTDC1 signaling may represent a novel target in treatment of renal clear cell carcinoma.
doi:10.1091/mbc.E07-05-0433
PMCID: PMC2230586  PMID: 18032587

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