90 results on '"Christopher Albanese"'
Search Results
2. Hypoxia-activated neuropeptide Y/Y5 receptor/RhoA pathway triggers chromosomal instability and bone metastasis in Ewing sarcoma
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Congyi Lu, Akanksha Mahajan, Sung-Hyeok Hong, Susana Galli, Shiya Zhu, Jason U. Tilan, Nouran Abualsaud, Mina Adnani, Stacey Chung, Nada Elmansy, Jasmine Rodgers, Olga Rodriguez, Christopher Albanese, Hongkun Wang, Maureen Regan, Valerie Zgonc, Jan Blancato, Ewa Krawczyk, G. Ian Gallicano, Michael Girgis, Amrita Cheema, Ewa Iżycka-Świeszewska, Luciane R. Cavalli, Svetlana D. Pack, and Joanna Kitlinska
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Science - Abstract
Ewing sarcoma tumour cells frequently metastasize to the bone but the molecular mechanisms governing this process are not well understood. Here, the authors show that neuropeptide Y/Y5 receptor pathway is activated in the hypoxic tumour microenvironment, which results in cytokinesis defects and chromosomal instability, leading to bone invasion.
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- 2022
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3. A novel chemo-phenotypic method identifies mixtures of salpn, vitamin D3, and pesticides involved in the development of colorectal and pancreatic cancer
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Naiem T. Issa, Henri Wathieu, Eric Glasgow, Ivana Peran, Erika Parasido, Tianqi Li, Cynthia M. Simbulan-Rosenthal, Dean Rosenthal, Alexander V. Medvedev, Sergei S. Makarov, Christopher Albanese, Stephen W. Byers, and Sivanesan Dakshanamurthy
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Environmental chemicals ,Mixtures ,Pesticides ,Food additive ,Cancer ,Environmental pollution ,TD172-193.5 ,Environmental sciences ,GE1-350 - Abstract
Environmental chemical (EC) exposures and our interactions with them has significantly increased in the recent decades. Toxicity associated biological characterization of these chemicals is challenging and inefficient, even with available high-throughput technologies. In this report, we describe a novel computational method for characterizing toxicity, associated biological perturbations and disease outcome, called the Chemo-Phenotypic Based Toxicity Measurement (CPTM). CPTM is used to quantify the EC “toxicity score” (Zts), which serves as a holistic metric of potential toxicity and disease outcome. CPTM quantitative toxicity is the measure of chemical features, biological phenotypic effects, and toxicokinetic properties of the ECs. For proof-of-concept, we subject ECs obtained from the Environmental Protection Agency’s (EPA) database to the CPTM. We validated the CPTM toxicity predictions by correlating ‘Zts’ scores with known toxicity effects. We also confirmed the CPTM predictions with in-vitro, and in-vivo experiments. In in-vitro and zebrafish models, we showed that, mixtures of the motor oil and food additive ‘Salpn’ with endogenous nuclear receptor ligands such as Vitamin D3, dysregulated the nuclear receptors and key transcription pathways involved in Colorectal Cancer. Further, in a human patient derived cell organoid model, we found that a mixture of the widely used pesticides ‘Tetramethrin’ and ‘Fenpropathrin’ significantly impacts the population of patient derived pancreatic cancer cells and 3D organoid models to support rapid PDAC disease progression. The CPTM method is, to our knowledge, the first comprehensive toxico-physicochemical, and phenotypic bionetwork-based platform for efficient high-throughput screening of environmental chemical toxicity, mechanisms of action, and connection to disease outcomes.
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- 2022
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4. Magnetic Microdevices for MRI-Based Detection of SARS-CoV-2 Viruses
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Lamar O. Mair, Olivia Hale, Sahar Jafari, Cheng Chen, Oleg Udalov, Roland Probst, Ittai Baum, Anjana Hevaganinge, Elaine Yi Wang, Olga C. Rodriguez, Christopher Albanese, Stanley T. Fricke, and Irving N. Weinberg
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Coronavirus ,COVID ,magnetic microdevices ,MRI ,theranostic ,Computer applications to medicine. Medical informatics ,R858-859.7 ,Medical technology ,R855-855.5 - Abstract
Goal: To develop a micron-scale device that can operate as an MRI-based reporter for the presence of SARS-CoV-2 virus. Methods: Iron rod microdevices were constructed via template-guided synthesis and suspended in phosphate buffered saline (PBS). Heat-inactivated SARS-CoV-2 viruses were added to the samples and imaged with low-field MRI. Results: MRI of microdevices and viruses showed decreased signal intensity at low concentrations of viruses that recovered at higher concentrations. Electron micrographs suggest that reduced MRI intensity may be due to concentration-dependent shielding of water protons from local magnetic inhomogeneities caused by the iron microdevices. Conclusions: The preliminary results presented in this letter provide justification for further studies exploring the potential diagnostic role of magnetic microdevices in assessing the presence and concentration of SARS-CoV-2 viruses.
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- 2020
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5. Opening the Blood Brain Barrier with an Electropermanent Magnet System
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Sahar Jafari, Ittai S. Baum, Oleg G. Udalov, Yichien Lee, Olga Rodriguez, Stanley T. Fricke, Maryam Jafari, Mostafa Amini, Roland Probst, Xinyao Tang, Cheng Chen, David J. Ariando, Anjana Hevaganinge, Lamar O. Mair, Christopher Albanese, and Irving N. Weinberg
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blood brain barrier ,electropermanent magnet ,magnetic resonance imaging ,Pharmacy and materia medica ,RS1-441 - Abstract
Opening the blood brain barrier (BBB) under imaging guidance may be useful for the treatment of many brain disorders. Rapidly applied magnetic fields have the potential to generate electric fields in brain tissue that, if properly timed, may enable safe and effective BBB opening. By tuning magnetic pulses generated by a novel electropermanent magnet (EPM) array, we demonstrate the opening of tight junctions in a BBB model culture in vitro, and show that induced monophasic electrical pulses are more effective than biphasic ones. We confirmed, with in vivo contrast-enhanced MRI, that the BBB can be opened with monophasic pulses. As electropermanent magnets have demonstrated efficacy at tuning B0 fields for magnetic resonance imaging studies, our results suggest the possibility of implementing an EPM-based hybrid theragnostic device that could both image the brain and enhance drug transport across the BBB in a single sitting.
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- 2022
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6. Empagliflozin Treatment Attenuates Hepatic Steatosis by Promoting White Adipose Expansion in Obese TallyHo Mice
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Ryan Kurtz, Andrew Libby, Bryce A. Jones, Komuraiah Myakala, Xiaoxin Wang, Yichien Lee, Grace Knoer, Julia N. Lo Cascio, Michaela McCormack, Grace Nguyen, Elijah N. D. Choos, Olga Rodriguez, Avi Z. Rosenberg, Suman Ranjit, Christopher Albanese, Moshe Levi, Carolyn M. Ecelbarger, and Blythe D. Shepard
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SGLT2 inhibitors ,steatosis ,white adipose ,brown adipose ,TallyHo mouse ,NAFLD ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Sodium-glucose co-transporters (SGLTs) serve to reabsorb glucose in the kidney. Recently, these transporters, mainly SGLT2, have emerged as new therapeutic targets for patients with diabetes and kidney disease; by inhibiting glucose reabsorption, they promote glycosuria, weight loss, and improve glucose tolerance. They have also been linked to cardiac protection and mitigation of liver injury. However, to date, the mechanism(s) by which SGLT2 inhibition promotes systemic improvements is not fully appreciated. Using an obese TallyHo mouse model which recapitulates the human condition of diabetes and nonalcoholic fatty liver disease (NAFLD), we sought to determine how modulation of renal glucose handling impacts liver structure and function. Apart from an attenuation of hyperglycemia, Empagliflozin was found to decrease circulating triglycerides and lipid accumulation in the liver in male TallyHo mice. This correlated with lowered hepatic cholesterol esters. Using in vivo MRI analysis, we further determined that the reduction in hepatic steatosis in male TallyHo mice was associated with an increase in nuchal white fat indicative of “healthy adipose expansion”. Notably, this whitening of the adipose came at the expense of brown adipose tissue. Collectively, these data indicate that the modulation of renal glucose handling has systemic effects and may be useful as a treatment option for NAFLD and steatohepatitis.
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- 2022
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7. Publisher Correction: Hypoxia-activated neuropeptide Y/Y5 receptor/RhoA pathway triggers chromosomal instability and bone metastasis in Ewing sarcoma
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Congyi Lu, Akanksha Mahajan, Sung-Hyeok Hong, Susana Galli, Shiya Zhu, Jason U. Tilan, Nouran Abualsaud, Mina Adnani, Stacey Chung, Nada Elmansy, Jasmine Rodgers, Olga Rodriguez, Christopher Albanese, Hongkun Wang, Maureen Regan, Valerie Zgonc, Jan Blancato, Ewa Krawczyk, G. Ian Gallicano, Michael Girgis, Amrita Cheema, Ewa Iżycka-Świeszewska, Luciane R. Cavalli, Svetlana D. Pack, and Joanna Kitlinska
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Science - Published
- 2022
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8. Combined EphB2 receptor knockdown with radiation decreases cell viability and invasion in medulloblastoma
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Shilpa Bhatia, Kellen Hirsch, Sanjana Bukkapatnam, Nimrah A. Baig, Ayman Oweida, Anastacia Griego, Dylan Calame, Jaspreet Sharma, Andrew Donson, Nicholas Foreman, Christopher Albanese, Sujatha Venkataraman, Rajeev Vibhakar, and Sana D. Karam
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EphB2 ,Radiosensitization ,Medulloblastoma ,Invasion ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Cytology ,QH573-671 - Abstract
Abstract Background Medulloblastoma is one of the most common types of pediatric brain tumor characterized by the subpopulation of cells that exhibit high invasive potential and radioresistant properties. In addition, dysregulated function and signaling by Eph family of receptors have been shown to impart pro-tumorigenic characteristics in this brain malignancy. In the current study, we investigated whether EphB2 knockdown in combination with radiation can alter invasiveness and decrease medulloblastoma tumor growth or viability in vitro. Methods The expression of EphB2 receptor was analyzed by immunohistochemistry and Western blotting. Microarray analysis and mRNA analysis was performed on medulloblastoma patient datasets and compared to the normal cerebellum. The radiosensitization effect following EphB2 knockdown was determined by clonogenic assay in human medulloblastoma cells. Effects of EphB2-siRNA in absence or presence of radiation on cell cycle distribution, cell viability, and invasion were analyzed by flow cytometry, MTT assay, trypan blue exclusion assay, xcelligence system, and Western blotting. Results We observed that EphB2 is expressed in both medulloblastoma cell lines and patient samples and its downregulation sensitized these cells to radiation as evident by decreased clonogenic survival fractions. EphB2 expression was also high across different medulloblastoma subgroups compared to normal cerebellum. The radiosensitization effect observed following EphB2 knockdown was in part mediated by enhanced G2/M cell cycle arrest. We also found that the combined approach of EphB2 knockdown and radiation exposure significantly reduced overall cell viability in medulloblastoma cells compared to control groups. Similar results were obtained in the xcelligence-based invasion assay. Western blot analysis also demonstrated changes in the protein expression of cell proliferation, cell survival, and invasion molecules in the combination group versus others. Conclusions Overall, our findings indicate that specific targeting of EphB2 receptor in combination with radiation may serve as an effective therapeutic strategy in medulloblastoma. Future studies are warranted to test the efficacy of this approach in in vivo preclinical models.
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- 2017
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9. Muscadine grape skin extract inhibits prostate cancer cells by inducing cell-cycle arrest, and decreasing migration through heat shock protein 40
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Diane N. Ignacio, Kimberly D. Mason, Ezra C. Hackett-Morton, Christopher Albanese, Lymor Ringer, William D. Wagner, Paul C. Wang, Michael A. Carducci, Sushant K. Kachhap, Channing J. Paller, Janet Mendonca, Leo Li-Ying Chan, Bo Lin, Diane K. Hartle, Jeffrey E. Green, Collis A. Brown, and Tamaro S. Hudson
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Cancer research ,Cell biology ,Molecular biology ,Science (General) ,Q1-390 ,Social sciences (General) ,H1-99 - Abstract
Previously we demonstrated that muscadine grape skin extract (MSKE), a natural product, significantly inhibited androgen-responsive prostate cancer cell growth by inducing apoptosis through the targeting of survival pathways. However, the therapeutic effect of MSKE on more aggressive androgen-independent prostate cancer remains unknown. This study examined the effects of MSKE treatment in metastatic prostate cancer using complementary PC-3 cells and xenograft model. MSKE significantly inhibited PC-3 human prostate cancer cell tumor growth in vitro and in vivo. The growth-inhibitory effect of MSKE appeared to be through the induction of cell-cycle arrest. This induction was accompanied by a reduction in the protein expression of Hsp40 and cell-cycle regulation proteins, cyclin D1 and NF-kBp65. In addition, MSKE induced p21 expression independent of wild-type p53 induced protein expression. Moreover, we demonstrate that MSKE significantly inhibited cell migration in PC-3 prostate cancer cells. Overall, these results demonstrate that MSKE inhibits prostate tumor growth and migration, and induces cell-cycle arrest by targeting Hsp40 and proteins involved in cell-cycle regulation and proliferation. This suggests that MSKE may also be explored either as a neo-adjuvant or therapeutic for castration resistant prostate cancer.
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- 2019
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10. 3367 A Mouse Model of APOE Genotype in Chemotherapy Related Cognitive Impairment
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Tamar Demby, G. William Rebeck, Christopher Albanese, Olga C. Rodriguez, Yichien Lee, and Jeanne Mandelblatt
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Medicine - Abstract
OBJECTIVES/SPECIFIC AIMS: Chemotherapy-related cognitive impairment (CRCI) affects 15-35% of breast cancer survivors and constitutes a significant challenge for survivor quality of life. Among older breast cancer survivors who received chemotherapy treatment, carriers of at least one ɛ4 allele of the APOE gene, which encodes apolipoprotein E, are at higher risk for developing CRCI than non-carriers. APOE4 is well characterized as the strongest genetic risk factor for Alzheimer’s disease, but how it contributes to CRCI is not yet understood, and no animal models of APOE genotype and CRCI have yet been established. To better understand how APOE4 acts as a risk factor for CRCI, we used APOE targeted replacement (TR) mice to develop a model of its effects on cognition following treatment with doxorubicin, a chemotherapy drug commonly used in breast cancer treatment. METHODS/STUDY POPULATION: Twelve-to-thirteen month old APOE3 and APOE4 targeted replacement mice expressing human APOE3 or human APOE4 under control of the endogenous murine promoter were treated with 10 mg/kg doxorubicin or equivolume saline given via two IP injections spaced one week apart. One week post-treatment, mice were tested using Open Field and Elevated Zero apparatuses to assess baseline locomotive activity and anxiety and exploratory behaviors. Five weeks post-treatment, mice were assessed using the Barnes Maze over four days of training trials and one 72 hour memory probe. RESULTS/ANTICIPATED RESULTS: We found no differences in Open Field and Elevated Zero behavior, indicating limited influence of doxorubicin treatment on locomotive and anxiety behaviors in both genotypes. During Barnes Maze training, APOE4 mice treated with doxorubicin showed increased latency compared to untreated APOE4 mice as well as treated and untreated APOE3 mice, indicating deficiencies in spatial learning. In APOE3 mice, no differences in performance were seen between doxorubicin-treated and untreated mice (n = 15-16/group, p
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- 2019
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11. An intrinsically disordered region of the acetyltransferase p300 with similarity to prion-like domains plays a role in aggregation.
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Alexander Kirilyuk, Mika Shimoji, Jason Catania, Geetaram Sahu, Nagarajan Pattabiraman, Antonio Giordano, Christopher Albanese, Italo Mocchetti, Jeffrey A Toretsky, Vladimir N Uversky, and Maria Laura Avantaggiati
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Medicine ,Science - Abstract
Several human diseases including neurodegenerative disorders and cancer are associated with abnormal accumulation and aggregation of misfolded proteins. Proteins with high tendency to aggregate include the p53 gene product, TAU and alpha synuclein. The potential toxicity of aberrantly folded proteins is limited via their transport into intracellular sub-compartments, the aggresomes, where misfolded proteins are stored or cleared via autophagy. We have identified a region of the acetyltransferase p300 that is highly disordered and displays similarities with prion-like domains. We show that this region is encoded as an alternative spliced variant independently of the acetyltransferase domain, and provides an interaction interface for various misfolded proteins, promoting their aggregation. p300 enhances aggregation of TAU and of p53 and is a component of cellular aggregates in both tissue culture cells and in alpha-synuclein positive Lewy bodies of patients affected by Parkinson disease. Down-regulation of p300 impairs aggresome formation and enhances cytotoxicity induced by misfolded protein stress. These data unravel a novel activity of p300, offer new insights into the function of disordered domains and implicate p300 in pathological aggregation that occurs in neurodegeneration and cancer.
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- 2012
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12. Molecular Parameters Promoting High Relaxivity in Cluster–Nanocarrier Magnetic Resonance Imaging Contrast Agents
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Trevor Lyons, Chloe Kekedjian, Priscilla Glaser, C. André Ohlin, Rudi van Eldik, Olga Rodriguez, Christopher Albanese, Edward Van Keuren, and Sarah L. Stoll
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General Materials Science - Abstract
We have investigated the mechanism of relaxivity for two magnetic resonance imaging contrast agents that both employ a cluster-nanocarrier design. The first system termed Mn
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- 2022
13. Supplementary Methods from The Canonical NF-κB Pathway Governs Mammary Tumorigenesis in Transgenic Mice and Tumor Stem Cell Expansion
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Richard G. Pestell, Christopher Albanese, Michael P. Lisanti, David Joyce, L. Andrew Shirley, Sanjay Katiyar, Wen-Shuz Yeow, Xuanmao Jiao, John Ojeifo, Xiaoming Ju, Andrew A. Quong, Nicole E. Willmarth, Mathew C. Casimiro, Toshiyuki Sakamaki, and Manran Liu
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Supplementary Methods from The Canonical NF-κB Pathway Governs Mammary Tumorigenesis in Transgenic Mice and Tumor Stem Cell Expansion
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- 2023
14. Supplementary Tables 1-2 from The Canonical NF-κB Pathway Governs Mammary Tumorigenesis in Transgenic Mice and Tumor Stem Cell Expansion
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Richard G. Pestell, Christopher Albanese, Michael P. Lisanti, David Joyce, L. Andrew Shirley, Sanjay Katiyar, Wen-Shuz Yeow, Xuanmao Jiao, John Ojeifo, Xiaoming Ju, Andrew A. Quong, Nicole E. Willmarth, Mathew C. Casimiro, Toshiyuki Sakamaki, and Manran Liu
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Supplementary Tables 1-2 from The Canonical NF-κB Pathway Governs Mammary Tumorigenesis in Transgenic Mice and Tumor Stem Cell Expansion
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- 2023
15. Supplementary Figure Legends 1-5 from The Canonical NF-κB Pathway Governs Mammary Tumorigenesis in Transgenic Mice and Tumor Stem Cell Expansion
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Richard G. Pestell, Christopher Albanese, Michael P. Lisanti, David Joyce, L. Andrew Shirley, Sanjay Katiyar, Wen-Shuz Yeow, Xuanmao Jiao, John Ojeifo, Xiaoming Ju, Andrew A. Quong, Nicole E. Willmarth, Mathew C. Casimiro, Toshiyuki Sakamaki, and Manran Liu
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Supplementary Figure Legends 1-5 from The Canonical NF-κB Pathway Governs Mammary Tumorigenesis in Transgenic Mice and Tumor Stem Cell Expansion
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- 2023
16. Supplementary Figures 1-5 from The Canonical NF-κB Pathway Governs Mammary Tumorigenesis in Transgenic Mice and Tumor Stem Cell Expansion
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Richard G. Pestell, Christopher Albanese, Michael P. Lisanti, David Joyce, L. Andrew Shirley, Sanjay Katiyar, Wen-Shuz Yeow, Xuanmao Jiao, John Ojeifo, Xiaoming Ju, Andrew A. Quong, Nicole E. Willmarth, Mathew C. Casimiro, Toshiyuki Sakamaki, and Manran Liu
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Supplementary Figures 1-5 from The Canonical NF-κB Pathway Governs Mammary Tumorigenesis in Transgenic Mice and Tumor Stem Cell Expansion
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- 2023
17. Paramagnetic Mn8Fe4-co-Polystyrene Nanobeads as a Potential T1–T2 Multimodal Magnetic Resonance Imaging Contrast Agent with In Vivo Studies
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Sarah L. Stoll, Trevor Lyons, Tatjana Paunesku, Brendan Kerwin, Gayle E. Woloschak, Yichien Lee, Erika Parasido, Luxi Li, Olga Rodriguez, Edward Van Keuren, Vidumin Dahanayake, Christopher Albanese, and Evan Maxey
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Miniemulsion ,chemistry.chemical_compound ,Biodistribution ,Nuclear magnetic resonance ,Materials science ,chemistry ,In vivo ,MRI contrast agent ,Fluorescence microscope ,General Materials Science ,Polystyrene ,Preclinical imaging ,Hydrophobe - Abstract
In developing a cluster-nanocarrier design, as a magnetic resonance imaging contrast agent, we have investigated the enhanced relaxivity of a manganese and iron-oxo cluster grafted within a porous polystyrene nanobead with increased relaxivity due to a higher surface area. The synthesis of the cluster-nanocarrier for the cluster Mn8Fe4O12(O2CC6H4CH═CH2)16(H2O)4, cross-linked with polystyrene (the nanocarrier), under miniemulsion conditions is described. By including a branched hydrophobe, iso-octane, the resulting nanobeads are porous and ∼70 nm in diameter. The increased surface area of the nanobeads compared to nonporous nanobeads leads to an enhancement in relaxivity; r1 increases from 3.8 to 5.2 ± 0.1 mM-1 s-1, and r2 increases from 11.9 to 50.1 ± 4.8 mM-1 s-1, at 9.4 teslas, strengthening the potential for T1 and T2 imaging. Several metrics were used to assess stability, and the porosity produced no reduction in metal stability. Synchrotron X-ray fluorescence microscopy was used to demonstrate that the nanobeads remain intact in vivo. In depth, physicochemical characteristics were determined, including extensive pharmacokinetics, in vivo imaging, and systemic biodistribution analysis.
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- 2021
18. Abstract PR018: Neuropeptide Y as a metastatic factor
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Mina Adnani, Sung-Hyeok Hong, Susana Galli, Akanksha Mahajan, Nouran Abualsaud, Lindsay Caprio, Jason U. Tilan, Olga Rodriguez, Hingkun Wang, Christopher Albanese, Luciane R. Cavalli, and Joanna Kitlinska
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Cancer Research ,Oncology - Abstract
Although neuropeptide Y (NPY) is known mainly as a sympathetic neurotransmitter, growing evidence indicates its role in tumor biology. Previous studies from our laboratory and other groups suggested associations of high expression of NPY and its Y5 receptor (Y5R) with invasive and metastatic phenotypes of various tumor types; yet the direct evidence for the metastatic activity was lacking. Our recent work began to fill this gap. Using Ewing sarcoma (ES) as a model of NPY-rich tumor, we identified the NPY/Y5R axis as a crucial pathway responsible for hypoxia-induced ES bone metastasis. This osseous dissemination was driven by hypoxia-dependent over-activation of the NPY/Y5R/RhoA pathway, which led to cytokinesis defects and formation of the aneuploid ES cell population with high propensity to bone metastasis. Here, we sought to determine the impact of the Y5R signaling on overall, hypoxia-independent metastatic capabilities of ES cells. To this end, a doxycycline-inducible CRIPSR/Cas9 system was used to knockout Y5R in ES orthotopic xenografts and test its impact on metastasis and cell migration assessed by a transwell assay. The frequency of the NPY5R gene modifications was determined by sequencing and confirmed by immunohistochemistry. FISH was used to identify NPY5R gene gains in ES xenografts. RhoA activity was measured by immunocytochemistry and pull-down assay. As expected, ES/Y5R-sgRNA primary tumors in doxycycline-treated mice consisted of a heterogeneous ES cell population with variable Y5R levels. In contrast, metastases developing from these xenografts were primarily initiated by ES clones with an intact NPY5R gene. The frequency of NPY5R gene modifications in metastases from the doxycycline-treated group was markedly reduced, as compared to the primary tumors. No metastases arising from ES clones lacking intact NPY5R gene were detected. Similarly, metastasis from wild type ES xenografts was associated with a selection of clones with the NPY5R gene gain that was present in a small percent of the parental cells. Subsequent in vitro assays implicated Y5R-dependent ES cell motility driven by the activation of a key cytoskeleton regulator, RhoA, as the mechanism underlying the metastatic effects of NPY. The above results, along with our previously published data, provide direct evidence for the crucial role of the NPY/Y5R axis in metastasis. We have shown that under basal conditions the NPY/Y5R/RhoA axis promotes tumor cell motility and overall cancer cell dissemination, while over-activation of this pathway under hypoxic conditions leads to genomic instability and bone metastasis. While our study focused on ES due to its high endogenous expression of NPY and its receptors, our findings may be relevant to other malignancies rich in NPY and Y5R, such as neuroblastoma, breast and prostate cancer. Given availability of the FDA approved Y5R antagonist, NPY/Y5R pathway may be a promising target for therapies preventing cancer progression. Yet, further research is required to establish effectiveness of such pharmacological interventions. Citation Format: Mina Adnani, Sung-Hyeok Hong, Susana Galli, Akanksha Mahajan, Nouran Abualsaud, Lindsay Caprio, Jason U. Tilan, Olga Rodriguez, Hingkun Wang, Christopher Albanese, Luciane R. Cavalli, Joanna Kitlinska. Neuropeptide Y as a metastatic factor [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr PR018.
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- 2023
19. A novel chemo-phenotypic method identifies mixtures of salpn, vitamin D3, and pesticides involved in the development of colorectal and pancreatic cancer
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Naiem T. Issa, Henri Wathieu, Eric Glasgow, Ivana Peran, Erika Parasido, Tianqi Li, Cynthia M. Simbulan-Rosenthal, Dean Rosenthal, Alexander V. Medvedev, Sergei S. Makarov, Christopher Albanese, Stephen W. Byers, and Sivanesan Dakshanamurthy
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Pancreatic Neoplasms ,Health, Toxicology and Mutagenesis ,Public Health, Environmental and Occupational Health ,Animals ,Humans ,General Medicine ,Pesticides ,Colorectal Neoplasms ,Pollution ,Zebrafish ,Cholecalciferol - Abstract
Environmental chemical (EC) exposures and our interactions with them has significantly increased in the recent decades. Toxicity associated biological characterization of these chemicals is challenging and inefficient, even with available high-throughput technologies. In this report, we describe a novel computational method for characterizing toxicity, associated biological perturbations and disease outcome, called the Chemo-Phenotypic Based Toxicity Measurement (CPTM). CPTM is used to quantify the EC "toxicity score" (Z
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- 2021
20. Paramagnetic Mn
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Vidumin, Dahanayake, Trevor, Lyons, Brendan, Kerwin, Olga, Rodriguez, Christopher, Albanese, Erika, Parasido, Yichien, Lee, Edward Van, Keuren, Luxi, Li, Evan, Maxey, Tatjana, Paunesku, Gayle, Woloschak, and Sarah L, Stoll
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Manganese ,Mice, Inbred BALB C ,Cell Membrane Permeability ,Cell Survival ,Iron ,Contrast Media ,Spectrometry, X-Ray Emission ,Biocompatible Materials ,Magnetic Resonance Imaging ,Multimodal Imaging ,Cross-Linking Reagents ,Cell Line, Tumor ,Organometallic Compounds ,Animals ,Humans ,Nanoparticles ,Polystyrenes ,Tissue Distribution ,Porosity - Abstract
In developing a cluster-nanocarrier design, as a magnetic resonance imaging contrast agent, we have investigated the enhanced relaxivity of a manganese and iron-oxo cluster grafted within a porous polystyrene nanobead with increased relaxivity due to a higher surface area. The synthesis of the cluster-nanocarrier for the cluster Mn
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- 2021
21. EphB4 and ephrinB2 act in opposition in the head and neck tumor microenvironment
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Shilpa Bhatia, Diemmy Nguyen, Laurel B. Darragh, Benjamin Van Court, Jaspreet Sharma, Michael W. Knitz, Miles Piper, Sanjana Bukkapatnam, Jacob Gadwa, Thomas E. Bickett, Shiv Bhuvane, Sophia Corbo, Brian Wu, Yichien Lee, Mayumi Fujita, Molishree Joshi, Lynn E. Heasley, Robert L. Ferris, Olga Rodriguez, Christopher Albanese, Mohit Kapoor, Elena B. Pasquale, and Sana D. Karam
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Mice ,Multidisciplinary ,Head and Neck Neoplasms ,Squamous Cell Carcinoma of Head and Neck ,Receptor, EphB4 ,Tumor Microenvironment ,General Physics and Astronomy ,Animals ,Ephrin-B2 ,General Chemistry ,General Biochemistry, Genetics and Molecular Biology - Abstract
Differential outcomes of EphB4-ephrinB2 signaling offers formidable challenge for the development of cancer therapeutics. Here, we interrogate the effects of targeting EphB4 and ephrinB2 in head and neck squamous cell carcinoma (HNSCC) and within its microenvironment using genetically engineered mice, recombinant constructs, pharmacologic agonists and antagonists. We observe that manipulating the EphB4 intracellular domain on cancer cells accelerates tumor growth and angiogenesis. EphB4 cancer cell loss also triggers compensatory upregulation of EphA4 and T regulatory cells (Tregs) influx and their targeting results in reversal of accelerated tumor growth mediated by EphB4 knockdown. EphrinB2 knockout on cancer cells and vasculature, on the other hand, results in maximal tumor reduction and vascular normalization. We report that EphB4 agonism provides no additional anti-tumoral benefit in the absence of ephrinB2. These results identify ephrinB2 as a tumor promoter and its receptor, EphB4, as a tumor suppressor in HNSCC, presenting opportunities for rational drug design.
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- 2021
22. Magnetic Microdevices for MRI-Based Detection of SARS-CoV-2 Viruses
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Sahar Jafari, Stanley T. Fricke, Elaine Yi Wang, Roland Probst, Olga Rodriguez, O. G. Udalov, Anjana Hevaganinge, Irving N. Weinberg, Lamar O. Mair, Ittai Baum, Christopher Albanese, Olivia Hale, and Cheng Chen
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2019-20 coronavirus outbreak ,Materials science ,medicine.diagnostic_test ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,viruses ,theranostic ,Phosphate buffered saline ,Computer applications to medicine. Medical informatics ,R858-859.7 ,Magnetic resonance imaging ,Article ,magnetic microdevices ,Coronavirus ,Electron micrographs ,medicine ,Medical technology ,Signal intensity ,R855-855.5 ,Volume concentration ,Biomedical engineering ,COVID ,MRI - Abstract
Goal: To develop a micron-scale device that can operate as an MRI-based reporter for the presence of SARS-CoV-2 virus. Methods: Iron rod microdevices were constructed via template-guided synthesis and suspended in phosphate buffered saline (PBS). Heat-inactivated SARS-CoV-2 viruses were added to the samples and imaged with low-field MRI. Results: MRI of microdevices and viruses showed decreased signal intensity at low concentrations of viruses that recovered at higher concentrations. Electron micrographs suggest that reduced MRI intensity may be due to concentration-dependent shielding of water protons from local magnetic inhomogeneities caused by the iron microdevices. Conclusions: The preliminary results presented in this letter provide justification for further studies exploring the potential diagnostic role of magnetic microdevices in assessing the presence and concentration of SARS-CoV-2 viruses.
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- 2020
23. Paramagnetic Clusters of Mn3(O2CCH3)6(Bpy)2 in Polyacrylamide Nanobeads as a New Design Approach to a T1–T2 Multimodal Magnetic Resonance Imaging Contrast Agent
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Chanon Pornrungroj, Christopher Albanese, Sarah L. Stoll, Trevor Lyons, Jeffery A. Bertke, Vidumin Dahanayake, Yichien Lee, David Lah, William J. Hickling, Olga Rodriguez, Erika Parasido, Edward Van Keuren, and Michele Pablico-Lansigan
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Materials science ,medicine.diagnostic_test ,media_common.quotation_subject ,Polyacrylamide ,Magnetic resonance imaging ,02 engineering and technology ,010402 general chemistry ,021001 nanoscience & nanotechnology ,01 natural sciences ,0104 chemical sciences ,Paramagnetism ,chemistry.chemical_compound ,Nuclear magnetic resonance ,chemistry ,medicine ,Contrast (vision) ,General Materials Science ,0210 nano-technology ,media_common - Abstract
There is an increasing need for gadolinium-free magnetic resonance imaging (MRI) contrast agents, particularly for patients suffering from chronic kidney disease. Using a cluster–nanocarrier combin...
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- 2019
24. Human ex vivo 3D bone model recapitulates osteocyte response to metastatic prostate cancer
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Woo Y. Lee, Jenny Zilberberg, Poornema Ramasundaram, Ciaran Mannion, Lucas Tricoli, Saba Choudhary, Eugenia Dziopa, Christopher Albanese, and Yair D Kissin
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0301 basic medicine ,Fibroblast growth factor 23 ,Male ,Cell Survival ,Fluorescent Antibody Technique ,Gene Expression ,lcsh:Medicine ,Bone Neoplasms ,Biology ,Bone tissue ,Osteocytes ,Article ,Metastasis ,03 medical and health sciences ,chemistry.chemical_compound ,Prostate cancer ,0302 clinical medicine ,Imaging, Three-Dimensional ,Cell Line, Tumor ,medicine ,Biomarkers, Tumor ,Humans ,lcsh:Science ,Wnt Signaling Pathway ,Multidisciplinary ,Osteoblasts ,lcsh:R ,Wnt signaling pathway ,Prostatic Neoplasms ,medicine.disease ,Immunohistochemistry ,3. Good health ,Fibroblast Growth Factor-23 ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,030220 oncology & carcinogenesis ,Osteocyte ,Cancer research ,Sclerostin ,lcsh:Q ,Ex vivo - Abstract
Prostate cancer (PCa) is the second leading cause of cancer deaths among American men. Unfortunately, there is no cure once the tumor is established within the bone niche. Although osteocytes are master regulators of bone homeostasis and remodeling, their role in supporting PCa metastases remains poorly defined. This is largely due to a lack of suitable ex vivo models capable of recapitulating the physiological behavior of primary osteocytes. To address this need, we integrated an engineered bone tissue model formed by 3D-networked primary human osteocytes, with conditionally reprogrammed (CR) primary human PCa cells. CR PCa cells induced a significant increase in the expression of fibroblast growth factor 23 (FGF23) by osteocytes. The expression of the Wnt inhibitors sclerostin and dickkopf-1 (Dkk-1), exhibited contrasting trends, where sclerostin decreased while Dkk-1 increased. Furthermore, alkaline phosphatase (ALP) was induced with a concomitant increase in mineralization, consistent with the predominantly osteoblastic PCa-bone metastasis niche seen in patients. Lastly, we confirmed that traditional 2D culture failed to reproduce these key responses, making the use of our ex vivo engineered human 3D bone tissue an ideal platform for modeling PCa-bone interactions.
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- 2018
25. Optical and magnetic resonance imaging approaches for investigating the tumour microenvironment: state-of-the-art review and future trends
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L.L. del Mercato, Stanley T. Fricke, Yichien Lee, Marta Cavo, Olga Rodriguez, Saumya Prasad, Erika Parasido, Giuseppe Gigli, Anil Chandra, Christopher Albanese, Eliana D'Amone, Prasad S., Chandra A., Cavo M., Parasido E., Fricke S., Lee Y., D'Amone E., Gigli G., Albanese C., Rodriguez O., and Del Mercato L.L.
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Nanostructure ,Fluorescent Dye ,02 engineering and technology ,01 natural sciences ,fluorescence microscopy ,Neoplasms ,Tumor Microenvironment ,General Materials Science ,medicine.diagnostic_test ,Optical Imaging ,State of the art review ,Hydrogen-Ion Concentration ,021001 nanoscience & nanotechnology ,Magnetic Resonance Imaging ,3. Good health ,optical sensing ,Acidosi ,Metalloporphyrin ,Mechanics of Materials ,Positron emission tomography ,Acidosis ,0210 nano-technology ,Human ,Tumour heterogeneity ,Metalloporphyrins ,FOS: Physical sciences ,Bioengineering ,010402 general chemistry ,Optical imaging ,Optical sensing ,Medical imaging ,medicine ,Animals ,Humans ,Electrical and Electronic Engineering ,Fluorescent Dyes ,business.industry ,Animal ,Mechanical Engineering ,Critical factors ,Magnetic resonance imaging ,General Chemistry ,Physics - Medical Physics ,Nanostructures ,0104 chemical sciences ,Neoplasm ,Tumor Hypoxia ,Medical Physics (physics.med-ph) ,sense organs ,business ,Neuroscience - Abstract
The tumour microenvironment (TME) strongly influences tumorigenesis and metastasis. Two of the most characterized properties of the TME are acidosis and hypoxia, both of which are considered hallmarks of tumours as well as critical factors in response to anticancer treatments. Currently, various imaging approaches exist to measure acidosis and hypoxia in the TME, including magnetic resonance imaging (MRI), positron emission tomography and optical imaging. In this review, we will focus on the latest fluorescent-based methods for optical sensing of cell metabolism and MRI as diagnostic imaging tools applied both in vitro and in vivo. The primary emphasis will be on describing the current and future uses of systems that can measure intra- and extra-cellular pH and oxygen changes at high spatial and temporal resolution. In addition, the suitability of these approaches for mapping tumour heterogeneity, and assessing response or failure to therapeutics will also be covered., Comment: 36 pages, 13 figures
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- 2021
26. Clinicopathologic and prognostic significance of LGR5, a cancer stem cell marker in patients with colorectal cancer
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Christopher Albanese, Erika Parasido, Olga Rodriguez, Deborah L. Berry, Krysta Chaldekas, Chukwuemeka Ihemelandu, Brent T. Harris, and Aisha Naeem
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Oncology ,medicine.medical_specialty ,Colorectal cancer ,overall survival ,colorectal cancer ,03 medical and health sciences ,LGR5 ,0302 clinical medicine ,Cancer stem cell ,Internal medicine ,medicine ,Overall survival ,Receptor ,cancer stem cell marker ,030304 developmental biology ,0303 health sciences ,Tissue microarray ,tissue microarray ,business.industry ,Gastroenterology ,biomarkers ,medicine.disease ,metastatic ,3. Good health ,030220 oncology & carcinogenesis ,immunohistochemistry ,Cohort ,Immunohistochemistry ,business ,Leucine-rich repeat-containing G-protein-coupled receptor 5 ,tumor stage ,Research Article - Abstract
Aim: To analyze the clinicopathologic and prognostic significance of Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5), a cancer stem cell marker expression in a cohort of colorectal cancer patients (CRC). Patients & methods: A total of 76 formalin-fixed paraffin-embedded tissue blocks of primary or metastatic tumors from 49 CRC patients were collected for duration 2009–2015. LGR5 expression was assessed through immunohistochemical staining of a tissue microarray. Results: LGR5 was significantly over expressed in CRC tissue samples and found to be a statistically significant independent prognostic marker for an improved overall survival. Conclusion: LGR5 expression was higher in colorectal cancer than in normal tissue. LGR5 was an independent prognostic marker for better clinical outcomes and might be used as a potential therapeutic target in CRCs.
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- 2020
27. A Mouse Model of Chemotherapy-Related Cognitive Impairments Integrating the Risk Factors of Aging and APOE4 Genotype
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G. William Rebeck, Olga Rodriguez, Christopher Albanese, Jeanne S. Mandelblatt, Yichien Lee, Tamar C. Demby, and Camryn W. McCarthy
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Oncology ,Apolipoprotein E ,medicine.medical_specialty ,Aging ,medicine.medical_treatment ,Apolipoprotein E4 ,Apolipoprotein E3 ,Spatial Learning ,Grey matter ,Anxiety ,Open field ,Article ,03 medical and health sciences ,Behavioral Neuroscience ,Mice ,0302 clinical medicine ,Cognition ,Chemotherapy-Related Cognitive Impairment ,Risk Factors ,Internal medicine ,medicine ,Animals ,Doxorubicin ,Fear conditioning ,Gene Knock-In Techniques ,030304 developmental biology ,Spatial Memory ,0303 health sciences ,Chemotherapy ,Antibiotics, Antineoplastic ,Behavior, Animal ,business.industry ,Prepulse Inhibition ,Brain ,Organ Size ,Magnetic Resonance Imaging ,Barnes maze ,Disease Models, Animal ,medicine.anatomical_structure ,Exploratory Behavior ,Female ,business ,Open Field Test ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Some cancer survivors experience marked cognitive impairment, referred to as cancer-related cognitive impairment (CRCI). CRCI has been linked to the genetic factor APOE4, the strongest genetic risk factor for Alzheimer’s disease (AD). We used APOE knock-in mice to test whether the relationship between APOE4 and CRCI can be demonstrated in a mouse model, to identify associations of chemotherapy with behavioural and structural correlates of cognition, and to test whether chemotherapy affects markers of AD. Twelve-month old C57BL/6 J female APOE3 (n = 30) and APOE4 (n = 31) knock-in mice were randomized to treatment with either doxorubicin (10 mg/kg) or saline. Behavioural assays at 2–21 weeks-post exposure included open field maze, elevated zero maze, pre-pulse inhibition, Barnes maze, and fear conditioning. Ex-vivo magnetic resonance imaging was used to determine regional volume differences at 31–35 weeks-post exposure, and tissue sections were analyzed for markers of AD pathogenesis. Minimal toxicities were observed in the aged mice after doxorubicin exposure. In the Barnes maze assay, APOE3 mice did not exhibit impairment in spatial learning after doxorubicin treatment, but APOE4 mice demonstrated significant impairments in both the initial identification of the escape hole and the latency to full escape at 6 weeks post-exposure. Both APOE3 and APOE4 mice treated with doxorubicin showed impairment of spatial memory. Grey matter volume in the frontal cortex decreased in APOE4 mice treated with doxorubicin vs. APOE3 mice. This study demonstrates cognitive impairments in aged APOE4 knock-in mice after doxorubicin treatment and establishes this system as a novel and powerful model of CRCI.
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- 2020
28. Abstract 1577: Gene expression studies using microgel embedded pancreatic cancer spheroids
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Anil Chandra, Christopher Albanese, Enza Lonardo, Saumya Prasad, Erika Parasido, and Loretta L. del Mercato
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0303 health sciences ,Cancer Research ,Stromal cell ,business.industry ,Biology ,Precision medicine ,medicine.disease ,3. Good health ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Pancreatic cancer ,Cancer cell ,Gene expression ,medicine ,Cancer research ,Personalized medicine ,business ,Pancreas ,030304 developmental biology - Abstract
Pancreatic ductal adenocarcinoma (PDAC) is known to be one of the deadliest cancers due to its late diagnosis and faster metastasis rate1. Thus, the time required to test the patient-derived cancer cells against different therapeutics becomes extremely crucial. Gene expression analysis using real-time PCR is vital, typically when designing patient-specific therapeutics. 2D tumor models do not represent the true picture of the tumor in vivo. In order to perform these gene expression studies, robust 3D cancer models are required2. The traditional techniques of generating cancer spheroids using U-bottom wells and hanging drop methods are effective but are limited by scalability as well as the limitations associated with the traditional organoid architecture. Gene expression studies of spheroids under different combinations of drug treatment thus requires many well defined and easy to handle spheroids. Here, we are trying to perform real-time PCR studies to access the gene expression changes on MIA PaCa-2 microgel based spheroids generated using co-axial droplet microfluidics with or without stromal cells. This 3D platform will enable gene expression studies in miniature co-culture tumor models. In addition, PCR and single-cell sequencing analyses will define the gene expression changes in the recently described conditionally reprogramed, patient-derived, primary PDAC cultures3. The establishment and analysis of this 3D model is fast, reproducible and can be easily scaled to enable high-throughput screening, thereby providing an opportunity to design patient-specific precision medicine. The research leading to these results received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement No 759959, ERC-StG “INTERCELLMED”). References: (1) Adamska, A.; Domenichini, A.; Falasca, M. Pancreatic Ductal Adenocarcinoma: Current and Evolving Therapies. Int. J. Mol. Sci. 2017, 18 (7). (2) Moreira, L.; Bakir, B.; Chatterji, P.; Dantes, Z.; Reichert, M.; Rustgi, A. K. Pancreas 3D Organoids: Current and Future Aspects as a Research Platform for Personalized Medicine in Pancreatic Cancer. Cell. Mol. Gastroenterol. Hepatol. 2018, 5 (3), 289-298. (3) Parasido, E.; Avetian, G. S.; Naeem, A.; Graham, G.; Pishvaian, M.; Glasgow, E.; Mudambi, S.; Lee, Y.; Ihemelandu, C.; Choudhry, M.; et al. The Sustained Induction of C-MYC Drives Nab-Paclitaxel Resistance in Primary Pancreatic Ductal Carcinoma Cells. Mol. Cancer Res. 2019, 17 (9), 1815-1827. Citation Format: Saumya Prasad, Anil Chandra, Enza Lonardo, Erika Parasido, Christopher Albanese, Loretta L. del Mercato. Gene expression studies using microgel embedded pancreatic cancer spheroids [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1577.
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- 2020
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29. Morphological and functional characteristics of aging kidneys based on two‐photon microscopy in vivo
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Avi Z. Rosenberg, Parnaz Daneshpajouhnejad, Suman Ranjit, Christopher Albanese, Yu Chen, Hengchang Guo, Qinggong Tang, Peter M. Andrews, Hannah Horng, Hui Li, Moshe Levi, Shulian Wu, and Yi Liu
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Aging ,Pathology ,medicine.medical_specialty ,H&E stain ,General Physics and Astronomy ,Renal function ,Kidney ,01 natural sciences ,General Biochemistry, Genetics and Molecular Biology ,010309 optics ,In vivo ,0103 physical sciences ,medicine ,Animals ,General Materials Science ,Microscopy ,Chemistry ,010401 analytical chemistry ,General Engineering ,General Chemistry ,medicine.disease ,Kidney Transplantation ,Rats ,0104 chemical sciences ,Transplantation ,Autofluorescence ,medicine.anatomical_structure ,Homeostasis ,Kidney disease - Abstract
Age-related kidney disease, which is chronic and naturally occurring, is a general term for a set of heterogeneous disorders affecting kidney structures and characterized by a decline in renal function. Age-related renal insufficiency has important implications with regard to body homeostasis, drug toxicity and renal transplantation. In our study, two-photon microscopy was used to image kidney morphological and functional characteristics in an age-related rat model in vivo. The changes in morphology are analyzed based on autofluorescence and Hoechst 33342 labeling in rats with different ages. Structural parameters including renal tubular diameter, cell nuclei density, size and shape are studied and compared with Hematoxylin and Eosin histological analysis. Functional characteristics, such as blood flow, and glomerular filtration rate are studied with high-molecular weight (MW) 500-kDa dextran-fluorescein and low-MW 10-kDa dextran-rhodamine. Results indicate that morphology changes significantly and functional characteristics deteriorate with age. These parameters are potential indicators for evaluating age-related renal morphology and function changes. Combined analyses of these parameters could provide a quantitative, novel method for monitoring kidney diseases and/or therapeutic effects of kidney drugs.
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- 2019
30. Knockdown of microRNA-214-3p Promotes Tumor Growth and Epithelial-Mesenchymal Transition in Prostate Cancer
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S.D. Kim, Leslimar Rios-Colon, Yahui Li, Deepak Kumar, Sean P. Collins, Christopher Albanese, Simeng Suy, Gagan Deep, Nikia Smith, Patrice Cagle, Suryakant K. Niture, and Timothy O. Adekoya
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Cancer Research ,Gene knockdown ,microRNA ,biology ,Cell growth ,EMT ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RNA sequencing ,Vimentin ,prostate cancer ,medicine.disease_cause ,Article ,CRISPR/Cas9 ,Oncology ,biology.protein ,medicine ,Cancer research ,Anoikis ,Epithelial–mesenchymal transition ,PTK6 ,Carcinogenesis ,RC254-282 - Abstract
Simple Summary Prostate Cancer is the second leading cause of cancer-related deaths in the United States. In this study, we analyzed a molecule known as a microRNA, which regulates the expression of genes. microRNAs are involved in processes related to cancer onset and progression. Abnormal expression of microRNAs can promote prostate cancer. This study showed that knockdown of microRNA miR-214-3p enhanced the progression and of prostate cancer. In addition, miR-214 regulated the expression of many genes. These results are useful to better understand the function of miR-214-3p in prostate cancer and can be a useful target in the treatment of the disease. Abstract Abnormal expression of microRNA miR-214-3p (miR-214) is associated with multiple cancers. In this study, we assessed the effects of CRISPR/Cas9 mediated miR-214 depletion in prostate cancer (PCa) cells and the underlying mechanisms. Knockdown of miR-214 promoted PCa cell proliferation, invasion, migration, epithelial-mesenchymal transition (EMT), and increased resistance to anoikis, a key feature of PCa cells that undergo metastasis. The reintroduction of miR-214 in miR-214 knockdown cells reversed these effects and significantly suppressed cell proliferation, migration, and invasion. These in vitro studies are consistent with the role of miR-214 as a tumor suppressor. Moreover, miR-214 knockout increased tumor growth in PCa xenografts in nude mice supporting its anti-oncogenic role in PCa. Knockdown of miR-214 increased the expression of its target protein, Protein Tyrosine Kinase 6 (PTK6), a kinase shown to promote oncogenic signaling and tumorigenesis in PCa. In addition, miR-214 modulated EMT as exhibited by differential regulation of E-Cadherin, N-Cadherin, and Vimentin both in vitro and in vivo. RNA-seq analysis of miR-214 knockdown cells revealed altered gene expression related to PCa tumor growth pathways, including EMT and metastasis. Collectively, our findings reveal that miR-214 is a key regulator of PCa oncogenesis and is a potential novel therapeutic target for the treatment of the disease.
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- 2021
31. Skilled reach training enhances robotic gait training to restore overground locomotion following spinal cord injury in rats
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Nathan D. Neckel, Olga Rodriguez, Yichien Lee, Christopher Albanese, Haining Dai, and John Hanckel
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Cellular activity ,medicine.medical_specialty ,education ,Motor Activity ,Article ,Task (project management) ,Behavioral Neuroscience ,Task specificity ,Physical medicine and rehabilitation ,Gait training ,Animals ,Humans ,Medicine ,Spinal cord injury ,Gait Disorders, Neurologic ,Spinal Cord Injuries ,Behavior, Animal ,business.industry ,Neurological Rehabilitation ,Training (meteorology) ,Robotics ,medicine.disease ,Rats ,Disease Models, Animal ,Diffusion Tensor Imaging ,medicine.anatomical_structure ,Relay network ,Forelimb ,business ,human activities - Abstract
Rehabilitative training has been shown to improve motor function following spinal cord injury (SCI). Unfortunately, these gains are primarily task specific; where reach training only improves reaching, step training only improves stepping and stand training only improves standing. More troublesome is the tendency that the improvement in a trained task often comes at the expense of an untrained task. However, the task specificity of training does not preclude the benefits of combined rehabilitative training. Here we show that robot assisted gait training alone can partially reduce the deficits in unassisted overground locomotion following a C4/5 overhemisection injury in rats. When robot-assisted gait training is done in conjunction with skilled forelimb training, we observe a much greater level of recovery of unassisted overground locomotion. In order to provide reach training that would not interfere with our robotic gait training schedule, we prompted rats to increase the use of their forelimbs by replacing the standard overhead feeder with a custom made, deep welled hopper that dispensed nutritionally equivalent small milled pellets. We speculate that the increase in recovery from combined training is due to a more robust interneuronal relay network around the injury site. in vivo manganese-enhanced magnetic resonance imaging of the spinal cord indicated that there was no increase in the cellular activity, however ex vivo diffusion tensor imaging (DTI) suggested an increase in collateralization around the injury site in rats that received both reach training and robot assisted gait training.
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- 2021
32. Paramagnetic Clusters of Mn
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Vidumin, Dahanayake, Chanon, Pornrungroj, Michele, Pablico-Lansigan, William J, Hickling, Trevor, Lyons, David, Lah, Yichien, Lee, Erika, Parasido, Jeffery A, Bertke, Christopher, Albanese, Olga, Rodriguez, Edward, Van Keuren, and Sarah L, Stoll
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Gadolinium DTPA ,Manganese ,Acrylic Resins ,Contrast Media ,Mice, Nude ,Neoplasms, Experimental ,Magnetic Resonance Imaging ,Multimodal Imaging ,Article ,Mice ,PC-3 Cells ,Animals ,Humans ,Nanoparticles - Abstract
There is an increasing need for gadolinium-free magnetic resonance imaging (MRI) contrast agents, particularly for patients suffering from chronic kidney disease. Using a cluster–nanocarrier combination, we have identified a novel approach to the design of biomedical nanomaterials and report here the criteria for the cluster and the nanocarrier and the advantages of this combination. We have investigated the relaxivity of the following manganese oxo clusters: the parent cluster Mn(3)(O(2)CCH(3))(6)(Bpy)(2) (1) where Bpy = 2,2′-bipyridine and three new analogs, Mn(3)(O(2)CC(6)H(4)CH=CH(2))(6)(Bpy)(2) (2), Mn(3)(O(2)CC(CH(3))=CH(2))(6)(Bpy)(2) (3), and Mn(3)O(O(2)CCH(3))(6)(Pyr)(2) (4) where Pyr = pyridine. The parent cluster, Mn(3)(O(2)CCH(3))(6)(Bpy)(2) (1), had impressive relaxivity (r(1) = 6.9 mM(−1) s(−1), r(2) = 125 mM(−1) s(−1)) and was found to be the most amenable for the synthesis of cluster-nanocarrier nanobeads. Using the inverse miniemulsion polymerization technique (1) in combination with the hydrophilic monomer acrylamide, we synthesized nanobeads (~125 nm diameter) with homogeneously dispersed clusters within the polyacrylamide matrix (termed Mn(3)Bpy-PAm). The nanobeads were surface-modified by co-polymerization with an amine-functionalized monomer. This enabled various postsynthetic modifications, for example, to attach a near-IR dye, Cyanine7, as well as a targeting agent. When evaluated as a potential multimodal MRI contrast agent, high relaxivity and contrast were observed with r(1) = 54.4 mM(−1) s(−1) and r(2) = 144 mM(−1) s(−1), surpassing T(1) relaxivity of clinically used Gd-DTPA chelates as well as comparable T(2) relaxivity to iron oxide microspheres. Physicochemical properties, cellular uptake, and impacts on cell viability were also investigated.
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- 2019
33. Analogs of the novel phytohormone, strigolactone, trigger apoptosis and synergize with PARP inhibitors by inducing DNA damage and inhibiting DNA repair
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Keli Agama, Yves Pommier, Ronit I. Yarden, Jennifer Lapier, Hinanit Koltai, Christopher Albanese, Michael P. Croglio, Lucas Tricoli, Victor S. Wang, Jeannine R. LaRocque, Cristina Prandi, Colin P. Ryan, Emma Artuso, Jamie P. Schlarbaum, Yu Chen, Yaron Dayani, and Jefferson M. Haake
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0301 basic medicine ,Genome instability ,Programmed cell death ,DNA Repair ,DNA damage ,DNA repair ,Poly ADP ribose polymerase ,small molecule ,RAD51 ,Apoptosis ,Poly(ADP-ribose) Polymerase Inhibitors ,Biology ,Poly (ADP-Ribose) Polymerase Inhibitor ,Homology directed repair ,Lactones ,03 medical and health sciences ,0302 clinical medicine ,Plant Growth Regulators ,Neoplasms ,Tumor Cells, Cultured ,Humans ,strigolactone ,Phosphorylation ,PARP inhibitors ,Cell Proliferation ,integumentary system ,Homology-directed repair ,Small molecule ,Strigolactone ,Oncology ,Drug Synergism ,Cell biology ,homology-directed repair ,030104 developmental biology ,Biochemistry ,030220 oncology & carcinogenesis ,Drug Therapy, Combination ,Research Paper ,DNA Damage - Abstract
Strigolactones are a novel class of plant hormones produced in roots that regulate shoot and root development. We previously reported that strigolactone analogs (SLs) induce G2/M cell cycle arrest and apoptosis in a variety of human cancer cells and inhibit tumor growth of human breast cancer xenografts in mice. SLs had no significant influences on non-transformed cells. Here we report for the first time that SLs induce DNA damage in the form of DNA double-strand breaks (DSBs) and activate the DNA damage response signaling by inducing phosphorylation of ATM, ATR and DNA-PKcs and co-localization of the DNA damage signaling protein, 53BP1, with γH2AX nuclear foci. We further report that in addition to DSBs induction, SLs simultaneously impair DSBs repair, mostly homology-directed repair (HDR) and to a lesser extent non-homologous end joining (NHEJ). In response to SLs, RAD51, the homologous DSB repair protein, is ubiquitinated and targeted for proteasomal degradation and it fails to co-localize with γH2AX foci. Interestingly, SLs synergize with DNA damaging agents-based therapeutics. The combination of PARP inhibitors and SLs showed an especially potent synergy, but only in BRCA1-proficient cells. No synergy was observed between SLs and PARP inhibitors in BRCA1-deficient cells, supporting a role for SLs in HDR impairment. Together, our data suggest that SLs increase genome instability and cell death by a unique mechanism of inducing DNA damage and inhibiting DNA repair.
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- 2016
34. Abstract 2967: Microgel-based in vitro tumoroid platform for real time assessment of drug sensitivity and resistance
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Anil Chandra, Enza Lonardo, Erika Parasido, Loretta L. del Mercato, Adriano Barra, Francesco Alemanno, Christopher Albanese, and Saumya Prasad
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Cancer Research ,Cell type ,Stromal cell ,Chemistry ,Spheroid ,Cancer ,medicine.disease ,Oncology ,Cell culture ,In vivo ,Cancer cell ,Cancer research ,medicine ,Cancer-Associated Fibroblasts - Abstract
While 3D cell cultures have been used as suitable representatives of in vivo conditions compared to 2D systems, scalability and flexibility in designing such platforms has been a major challenge1. Micron-sized 3D culture platforms offer the possibility of high throughput analysis, however major challenges exist with respect to their overall design. Technical obstacles include difficulties in supporting multiple cell types (e.g. co-cultures of cancer associated fibroblasts (CAFs) and tumor cells) as well as enabling monitoring of important parameters, such as proliferation and metabolism, in real time. Our 3D co-culture systems are based on pancreatic ductal adenocarcinoma (PDAC) spheroid models in microgels, generated by coaxial droplet microfluidics. This allows for co-culturing of cancer cells with the supporting cell types that constitute the major portion of the actual tumor. Initial optimization experiments utilized co-culture of commercial pancreatic cancer cell lines such, as L3.6pl cells, and stromal CAFs. In addition to optimizing the 3D microcultures using commercial PDAC cell lines, we are also modifying the system to take advantage of patient-matched CAFs and conditionally reprogrammed (CR) primary PDAC cells. Both drug sensitive and isogenic nab-paclitaxel resistant PDAC CR cells will be used, as recently published2. Our preliminary data showed that our platform supports rapid generation of numerous identical spheroids inside the microgel. Using microscopy under different treatment conditions (e.g the presence/absence of drugs) we can quantify spheroid growth. In addition, spatio-temporal mapping of the microenvironmental parameters such as dissolved O2, pH and K+ during growth is performed by time lapse fluorescence microscopy using fluorescent silica microparticles embedded in the matrix. This process will yield an in-depth understanding of the kinetics of growth and associated biochemical and metabolic activity for each cell type (e.g. CAF and PDAC) under different treatment conditions. Our T3D platform offers a rapid, quantifiable assessment of the behavior of patient-derived cells in providing additional details related to the changing microenvironment and may advance our understanding of treatment response and failures. The research leading to these results received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement No 759959, ERC-StG “INTERCELLMED”). Reference (1) Nunes et al. Biotechnol. Bioeng. 2019, 116 (1), 206-226. (2) Parasido et al. Mol. Cancer Res. 2019, 17 (9), 1815-1827. Citation Format: Anil Chandra, Saumya Prasad, Francesco Alemanno, Adriano Barra, Enza Lonardo, Erika Parasido, Christopher Albanese, Loretta L. del Mercato. Microgel-based in vitro tumoroid platform for real time assessment of drug sensitivity and resistance [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2967.
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- 2020
35. Pan-cancer analysis to identify a novel class of glucocorticoid and androgen receptor antagonists with potent anti-tumor activity
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Michael Graner, Neil D. Theise, Dimple Chakravarty, Kevin O. Lillehei, Anthony Fringuello, Sujit S. Nair, Christopher Albanese, Ashutosh K. Tewari, Erika Parasido, and Philip D. Tatman
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Antitumor activity ,Cancer Research ,Pan cancer ,business.industry ,Cancer ,medicine.disease_cause ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,medicine ,Cancer research ,Androgen Receptor Antagonists ,Carcinogenesis ,business ,Glucocorticoid ,030215 immunology ,medicine.drug - Abstract
e15663 Background: Large public cancer databases have allowed identification of novel mechanisms of oncogenesis and development of pharmacotherapies targeting these pathways. Examples are the androgen receptor (AR) and glucocorticoid receptor (GR). The Cancer Genome Atlas (TCGA) shows these receptors to have significantly increased expression over matched, normal tissue in several cancer types including: glioblastoma (AR and GR tumor-to-tissue ratios: AR = 6.53, GR = 1.42), low-grade gliomas (AR = 5.08, GR = 1.8), kidney clear cell carcinoma (AR = 1.89, GR = 1.82), kidney papillary cell carcinoma (AR = 3.64, GR = 1.2), and pancreatic adenocarcinoma (AR = 3.77, GR = 3.31). Methods: To investigate the therapeutic potential of targeting these receptors, we produced a series of analogues from a known GR inhibitor that all have the ability to target both the GR and the AR. Of these, PT150 is a clinical stage small molecule and PT157 is a preclinical stage small molecule. We began investigating the potential of these compounds to inhibit tumor growth using the NIH 60 cell lines panel with follow up in vitro testing and validation in clinically derived samples and established cell lines, including some cancers not include in the NIH 60 cell line panel or TCGA. Results: NIH 60 panel disclosed sensitivity towards gliomas, pancreatic cancer, and prostate cancer. For brain tumors, we investigated the effects of these inhibitors on glioblastoma, meningioma, and brain metastases. One analogue in particular, PT157, was able to significantly reduce cell viability after three days in culture in a dose dependent manor for each of the three tumor types and do so at a dose that is safely achievable in humans. Dose-dependent effects of PT150 and PT157 were observed in both androgen dependent and independent prostate cell lines, reducing viability of LNCaP, 22RV1 and DU145 cells. Similar data were also achieved in an in vitro pancreatic cancer model. Using patient-derived, primary pancreatic ductal adenocarcinoma (PDAC) cells, we found that both PT150 and PT157 were effective as monotherapies, inducing cell death in a dose dependent manner. In addition, both PT150 and PT157 significantly increased nab-paclitaxel sensitivity in nab-paclitaxel-resistant isogenic PDAC cells. Based on these in vitro data, we have begun pre-clinical experiments using in vivo mouse models. Conclusions: Our work has identified previously undescribed mechanisms of oncogenesis in several cancer types, as well as an efficacious class of novel compounds with the potential to inhibit them.
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- 2020
36. The mitochondrial citrate carrier, SLC25A1, drives stemness and therapy resistance in non-small cell lung cancer
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Aykut Üren, Martin S Ongkeko, Garrett T. Graham, Erika Parasido, Christopher Albanese, Rami Mosaoa, Kyu Ah Kim, Harvey R. Fernandez, Rebecca B. Riggins, Simone Pacini, Amrita K. Cheema, Shreyas M Gadre, Iacopo Petrini, Mingjun Tan, Giuseppe Giaccone, Habtom W. Ressom, Yu-Wen Zhang, Maria Laura Avantaggiati, Rency S. Varghese, and Mikell Paige
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0301 basic medicine ,Lung Neoplasms ,Anion Transport Proteins ,Mice, Nude ,Organic Anion Transporters ,Oxidative phosphorylation ,Article ,Cell Line ,Mitochondrial Proteins ,03 medical and health sciences ,Cancer stem cell ,Carcinoma, Non-Small-Cell Lung ,medicine ,Animals ,Humans ,Epidermal growth factor receptor ,Lung cancer ,Protein Kinase Inhibitors ,Molecular Biology ,EGFR inhibitors ,Cisplatin ,Mice, Inbred BALB C ,Cell Biology ,biology ,medicine.disease ,Phenotype ,Mitochondria ,Neoplasm Proteins ,3. Good health ,030104 developmental biology ,Drug Resistance, Neoplasm ,Cell culture ,Neoplastic Stem Cells ,Cancer research ,biology.protein ,Female ,medicine.drug - Abstract
Therapy resistance represents a clinical challenge for advanced non-small cell lung cancer (NSCLC), which still remains an incurable disease. There is growing evidence that cancer-initiating or cancer stem cells (CSCs) provide a reservoir of slow-growing dormant populations of cells with tumor-initiating and unlimited self-renewal ability that are left behind by conventional therapies reigniting post-therapy relapse and metastatic dissemination. The metabolic pathways required for the expansion of CSCs are incompletely defined, but their understanding will likely open new therapeutic opportunities. We show here that lung CSCs rely upon oxidative phosphorylation for energy production and survival through the activity of the mitochondrial citrate transporter, SLC25A1. We demonstrate that SLC25A1 plays a key role in maintaining the mitochondrial pool of citrate and redox balance in CSCs, whereas its inhibition leads to reactive oxygen species build-up thereby inhibiting the self-renewal capability of CSCs. Moreover, in different patient-derived tumors, resistance to cisplatin or to epidermal growth factor receptor (EGFR) inhibitor treatment is acquired through SLC25A1-mediated implementation of mitochondrial activity and induction of a stemness phenotype. Hence, a newly identified specific SLC25A1 inhibitor is synthetic lethal with cisplatin or with EGFR inhibitor co-treatment and restores antitumor responses to these agents in vitro and in animal models. These data have potential clinical implications in that they unravel a metabolic vulnerability of drug-resistant lung CSCs, identify a novel SLC25A1 inhibitor and, lastly, provide the first line of evidence that drugs, which block SLC25A1 activity, when employed in combination with selected conventional antitumor agents, lead to a therapeutic benefit.
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- 2018
37. Cyclin-Dependent Kinase Inhibitors and the Treatment of Gastrointestinal Cancers
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Sameh Mikhail, Michael J. Pishvaian, and Christopher Albanese
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Kinase ,Cell Cycle ,Cancer ,Antineoplastic Agents ,Cell cycle ,Biology ,medicine.disease ,medicine.disease_cause ,Bioinformatics ,Molecular diagnostics ,Cyclin-Dependent Kinases ,Article ,Cyclin-Dependent Kinase Inhibitors ,Pathology and Forensic Medicine ,Cell Transformation, Neoplastic ,Stomach Neoplasms ,Cyclin-dependent kinase ,medicine ,biology.protein ,Animals ,Humans ,Carcinogenesis ,Protein Kinase Inhibitors ,Cyclin - Abstract
The cell cycle is a highly conserved and tightly regulated biological system that controls cellular proliferation and differentiation. The cell cycle regulatory proteins, which include the cyclins, the cyclin-dependent kinases (CDKs), and the CDK inhibitors, are critical for the proper temporal and spatial regulation of cellular proliferation. Conversely, alterations in cell cycle regulatory proteins, leading to the loss of normal cell-cycle control, are a hallmark of many cancers, including gastrointestinal cancers. Accordingly, overexpression of CDKs and cyclins and by contrast loss of CDK inhibitors, are all linked to gastrointestinal cancers and are often associated with less favorable prognoses and outcomes. Because of the importance that the cell cycle regulatory proteins play in tumorigenesis, currently there is a broad spectrum of cell-cycle inhibitors under development that, as a group, hold promise as effective cancer treatments. In support of this approach to cancer treatment, the growing availability of molecular diagnostics techniques may help in identifying patients who have driving abnormalities in the cell-cycle machinery and are thus more likely to respond to cell-cycle inhibitors. In this review, we discuss the prevalence of cell-cycle abnormalities in patients with gastrointestinal cancers and provide a preclinical and clinical overview of new agents that target cell-cycle abnormalities with a special emphasis on gastrointestinal cancers.
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- 2015
38. The Effects of Particle Shape and Size on T2 Relaxation in Magnetic Resonance Imaging
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Olga Rodriguez, York Jn, Christopher Albanese, Ackun-Farmmer M, Le Yc, and Van Keuren E
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Materials science ,Superparamagnetic iron oxide nanoparticles ,medicine.diagnostic_test ,Condensed matter physics ,Biomedical Engineering ,Pharmaceutical Science ,Medicine (miscellaneous) ,Bioengineering ,Magnetic resonance imaging ,Nuclear magnetic resonance ,T2 relaxation ,T2 contrast ,embryonic structures ,medicine ,General Materials Science ,Saturation (magnetic) ,Size dependence - Abstract
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.
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- 2014
39. HPV positive neuroendocrine cervical cancer cells are dependent on Myc but not E6/E7 viral oncogenes
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Nancy Palechor-Ceron, Xuefeng Liu, Ewa Krawczyk, Thomas Ried, Jan Blancato, Siddartha Paul, Seema Agarwal, Richard Schlegel, Bassem R. Haddad, Naidong Wang, Danny Wangsa, Tung Wei Hou, Faris Alkhilaiwi, Christopher Albanese, Hang Yuan, Shuang Fang, Dan Zhou, Yukari Usuda, Maura L. Gillison, Sujata Choudhary, Yun Ling Zheng, David E. Symer, Aleksandra Dakic, and Dan P. Hartmann
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0301 basic medicine ,Papillomavirus E7 Proteins ,Cell ,Viral Oncogene ,Uterine Cervical Neoplasms ,Biology ,Models, Biological ,Article ,Proto-Oncogene Proteins c-myc ,Fusion gene ,Mice ,03 medical and health sciences ,Tumor Cells, Cultured ,medicine ,Animals ,In Situ Hybridization, Fluorescence ,Cell Proliferation ,Recombination, Genetic ,Human papillomavirus 16 ,Gene knockdown ,Multidisciplinary ,Oncogene ,Cell growth ,Oncogene Proteins, Viral ,medicine.disease ,Primary tumor ,Repressor Proteins ,Cell Transformation, Neoplastic ,030104 developmental biology ,medicine.anatomical_structure ,Cell culture ,Karyotyping ,Cancer research ,Female ,Gene Fusion - Abstract
Using conditional cell reprogramming, we generated a stable cell culture of an extremely rare and aggressive neuroendocrine cervical cancer. The cultured cells contained HPV-16, formed colonies in soft agar and rapidly produced tumors in immunodeficient mice. The HPV-16 genome was integrated adjacent to the Myc gene, both of which were amplified 40-fold. Analysis of RNA transcripts detected fusion of the HPV/Myc genes, arising from apparent microhomologous recombination. Spectral karyotyping (SKY) and fluorescent-in-situ hybridization (FISH) demonstrated coordinate localization and translocation of the amplified Myc and HPV genes on chromosomes 8 and 21. Similar to the primary tumor, tumor cell cultures expressed very high levels of the Myc protein and, in contrast to all other HPV-positive cervical cancer cell lines, they harbored a gain-of-function mutation in p53 (R273C). Unexpectedly, viral oncogene knockdown had no effect on the growth of the cells, but it did inhibit the proliferation of a conventional HPV-16 positive cervical cancer cell line. Knockdown of Myc, but not the mutant p53, significantly inhibited tumor cell proliferation. On the basis of these data, we propose that the primary driver of transformation in this aggressive cervical cancer is not HPV oncogene expression but rather the overexpression of Myc.
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- 2017
40. Conditional reprogramming and long-term expansion of normal and tumor cells from human biospecimens
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Christopher Albanese, Thomas N. Darling, Seema Agarwal, Anatoly Dritschilo, Nancy Palechor-Ceron, Rajesh L. Thangapazham, Sujata Choudhury, Scott H. Randell, Ewa Krawczyk, Richard Schlegel, Hang Yuan, Tung-Wei Hou, Jie Lu, Frank A. Suprynowicz, Yun-Ling Zheng, Praathibha Sripadhan, Bhaskar Kallakury, Vera Simic, Xuefeng Liu, Chen Chen, Olga A. Timofeeva, Aleksandra Dakic, and Dean G. Tang
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0301 basic medicine ,Pyridines ,Biology ,Regenerative medicine ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Tissue culture ,Mice ,Neoplasms ,Animals ,Humans ,Protein Kinase Inhibitors ,rho-Associated Kinases ,Drug discovery ,Feeder Cells ,Fibroblasts ,Cellular Reprogramming ,Amides ,In vitro ,Coculture Techniques ,Cell biology ,Rats ,Gene expression profiling ,030104 developmental biology ,Cell Transformation, Neoplastic ,Cell culture ,Immunology ,Cryopreserved Tissue ,Reprogramming - Abstract
Historically, it has been difficult to propagate cells in vitro that are derived directly from human tumors or healthy tissue. However, in vitro preclinical models are essential tools for both the study of basic cancer biology and the promotion of translational research, including drug discovery and drug target identification. This protocol describes conditional reprogramming (CR), which involves coculture of irradiated mouse fibroblast feeder cells with normal and tumor human epithelial cells in the presence of a Rho kinase inhibitor (Y-27632). CR cells can be used for various applications, including regenerative medicine, drug sensitivity testing, gene expression profiling and xenograft studies. The method requires a pathologist to differentiate healthy tissue from tumor tissue, and basic tissue culture skills. The protocol can be used with cells derived from both fresh and cryopreserved tissue samples. As approximately 1 million cells can be generated in 7 d, the technique is directly applicable to diagnostic and predictive medicine. Moreover, the epithelial cells can be propagated indefinitely in vitro, yet retain the capacity to become fully differentiated when placed into conditions that mimic their natural environment.
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- 2017
41. Abstract 667: A mouse model of APOE to define effects of doxorubicin on cognition
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Tamar C. Demby, Yichien Lee, Olga Rodriguez, Christopher Albanese, Jeanne Mandelblatt, and G. William Rebeck
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Cancer Research ,Oncology - Abstract
The purpose of this study was to establish the effects of Apolipoprotein E (APOE) genotype on cognitive function following doxorubicin treatment in a mouse model. Chemotherapy treatment can lead to cognitive impairment in cancer survivors, and, in older breast cancer survivors, APOE4 carriers have been shown to have higher risk for these impairments. Though APOE4 genotype is known as the strongest genetic risk factor for late-onset Alzheimer’s Disease compared to the APOE2 and APOE3 alleles, its effects on cognitive outcomes following treatment with common breast cancer chemotherapeutics are not yet well characterized. One year old female mice with targeted replacement of human APOE3 or APOE4 under control of the endogenous murine promoter were treated with 10 mg/kg doxorubicin or saline. Five weeks following treatment, spatial learning and memory was tested using the Barnes Maze. In APOE3 mice, doxorubicin treatment left spatial learning and memory intact. In APOE4 mice, doxorubicin treatment lead to impairment in spatial learning over the four days of training. This represents a promising model for studying the mechanisms behind cognitive impairment following doxorubicin treatment in a genetically vulnerable population. Citation Format: Tamar C. Demby, Yichien Lee, Olga Rodriguez, Christopher Albanese, Jeanne Mandelblatt, G. William Rebeck. A mouse model of APOE to define effects of doxorubicin on cognition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 667.
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- 2019
42. Abstract 1283: Targeting c-MYC and MAPK pathway to overcome pancreatic cancer drug resistance
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Goutham Narla, Christopher Albanese, Jordan M. Winter, Jonathan R. Brody, Eric Glasgow, Eric Londin, Michael J. Pishvaian, Erika M. Parasido, George S. Avetian, and Stephen W. Byers
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MAPK/ERK pathway ,Cancer Research ,Stromal cell ,business.industry ,Cancer ,Drug resistance ,medicine.disease ,Oncology ,In vivo ,Cell culture ,Pancreatic cancer ,Cancer research ,Medicine ,Gene silencing ,business - Abstract
Background: Acquired resistance to systemic chemotherapy is the main complication in pancreatic ductal adenocarcinoma (PDAC) treatment. Although there are studies focused on gemcitabine resistance mechanisms, our understanding of the mechanisms of nab-paclitaxel (n-PTX) treatment failure remains extremely limited. To enhance the use of properly powered patient-derived platforms, we adopted the conditionally reprogrammed (CR) cell culture technique in order to develop both parental and nab-PTX-resistant cells. The CR approach allowed us to identify the critical role of c-MYC and ERK in the PDAC drug response. Small molecule activators of PP2A (SMAPS) have showed activity in inhibiting lung KRAS-mutant tumor growth. We used SMAPS as new therapeutic agents in PDAC, for its ability to alter c-MYC activity through PP2A dysregulation and enhance PDAC sensitivity to n-PTX. Methods: Long-term cultures of PDAC CRs were established from treatment-naive PDAC patients’ biopsies, and used to generate drug-resistant cells. Zebrafish and mouse model were used to test the cells’ ability to form tumors and to verify the drug resistance in vivo. Molecular analyses were used to characterize the drug-resistant cells and to identify key pathways involved in the drug resistance evolution. Genomic and chemical alterations of the key proteins were used to confirm the involvement in the drug resistance mechanism. We regulated the expression of c-MYC and ERK using SMAPS as a new targeting agent and trametenib to verify the direct correlation between c-MYC and ERK and the drug resistance mechanism. Results: Using the credentialed KRAS-mutant CR cultures, we generated n-PTX-resistant cell lines. The parental and nab-PTX resistant cells were subjected to subcutaneous injections in nude mice, and formed tumors in 2-3 weeks. Histological evaluation showed that the CRs self-assembled into ductal structures, surrounded by a desmoplastic stromal microenvironment that faithfully recapitulates human PDAC. Resistant profiles were verified both in mouse and Zebrafish model. RNA microarrays identified a sustained induction of a pro-inflammatory pathway leading to c-MYC overexpression. c-MYC silencing and overexpression confirmed the role of c-MYCin the evolution of nab-PTX resistance. Treatment of the resistant CRs with either trametenib or with SMAPS resulted in enhanced sensitivity to nab-PTX. We furtherverified that the enhanced sensitivity was commensurate with a reduction in p-Erk and c-Myc. Conclusion: The CR methodology addresses the need for a reliable method for generating primary cell lines on a single patient basis. The ability to rapidly model in vitro, and verify in vivo, that the overexpression of c-MYC contributes to the development of n-PTX resistance is a significant advancement in the field. Our data showed that SMAPs or trametanib overcome a significant component of the n-PTX resistance providing new hope for refractory PDAC. Citation Format: Erika Maria Parasido, George S. Avetian, Jonathan Brody, Jordan Winter, Eric Londin, Michael Pishvaian, Eric Glasgow, Stephen Byers, Goutham Narla, Christopher Albanese. Targeting c-MYC and MAPK pathway to overcome pancreatic cancer drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1283.
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- 2019
43. 3367 A Mouse Model of APOE Genotype in Chemotherapy Related Cognitive Impairment
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G. William Rebeck, Jeanne S. Mandelblatt, Yichien Lee, Olga Rodriguez, Tamar Demby, and Christopher Albanese
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Oncology ,Apolipoprotein E ,Chemotherapy ,medicine.medical_specialty ,education.field_of_study ,business.industry ,medicine.medical_treatment ,Population ,General Medicine ,Basic/Translational Science/Team Science ,medicine.disease ,Open field ,Barnes maze ,Breast cancer ,Internal medicine ,medicine ,Population study ,Risk factor ,business ,education - Abstract
OBJECTIVES/SPECIFIC AIMS: Chemotherapy-related cognitive impairment (CRCI) affects 15-35% of breast cancer survivors and constitutes a significant challenge for survivor quality of life. Among older breast cancer survivors who received chemotherapy treatment, carriers of at least one ɛ4 allele of the APOE gene, which encodes apolipoprotein E, are at higher risk for developing CRCI than non-carriers. APOE4 is well characterized as the strongest genetic risk factor for Alzheimer’s disease, but how it contributes to CRCI is not yet understood, and no animal models of APOE genotype and CRCI have yet been established. To better understand how APOE4 acts as a risk factor for CRCI, we used APOE targeted replacement (TR) mice to develop a model of its effects on cognition following treatment with doxorubicin, a chemotherapy drug commonly used in breast cancer treatment. METHODS/STUDY POPULATION: Twelve-to-thirteen month old APOE3 and APOE4 targeted replacement mice expressing human APOE3 or human APOE4 under control of the endogenous murine promoter were treated with 10 mg/kg doxorubicin or equivolume saline given via two IP injections spaced one week apart. One week post-treatment, mice were tested using Open Field and Elevated Zero apparatuses to assess baseline locomotive activity and anxiety and exploratory behaviors. Five weeks post-treatment, mice were assessed using the Barnes Maze over four days of training trials and one 72 hour memory probe. RESULTS/ANTICIPATED RESULTS: We found no differences in Open Field and Elevated Zero behavior, indicating limited influence of doxorubicin treatment on locomotive and anxiety behaviors in both genotypes. During Barnes Maze training, APOE4 mice treated with doxorubicin showed increased latency compared to untreated APOE4 mice as well as treated and untreated APOE3 mice, indicating deficiencies in spatial learning. In APOE3 mice, no differences in performance were seen between doxorubicin-treated and untreated mice (n = 15-16/group, p
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- 2019
44. Radiation Induces Diffusible Feeder Cell Factor(s) That Cooperate with ROCK Inhibitor to Conditionally Reprogram and Immortalize Epithelial Cells
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Tsion Z. Minas, Michael D. Johnson, Frank A. Suprynowicz, Aleksandra Dakic, Nancy Palechor-Ceron, Geeta Upadhyay, Christopher Albanese, Xuefeng Liu, Richard Schlegel, and Vera Simic
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Keratinocytes ,Male ,Telomerase ,Apoptosis ,Biology ,Article ,Pathology and Forensic Medicine ,Mice ,Conditioned medium ,Animals ,Humans ,Rho-associated protein kinase ,Cell Line, Transformed ,integumentary system ,Feeder Cells ,Cell Differentiation ,3T3 Cells ,Cell biology ,Feeder Cell ,Rho kinase inhibitor ,Gamma Rays ,Culture Media, Conditioned ,embryonic structures ,Intercellular Signaling Peptides and Proteins ,sense organs ,Reprogramming ,Immortalised cell line - Abstract
Both feeder cells and Rho kinase inhibition are required for the conditional reprogramming and immortalization of human epithelial cells. In the present study, we demonstrated that the Rho kinase inhibitor Y-27632, significantly suppresses keratinocyte differentiation and extends life span in serum-containing medium but does not lead to immortalization in the absence of feeder cells. Using Transwell culture plates, we further demonstrated that physical contact between the feeder cells and keratinocytes is not required for inducing immortalization and, more importantly, that irradiation of the feeder cells is required for this induction. Consistent with these experiments, conditioned medium was shown to induce and maintain conditionally immortalized cells, which was accompanied by increased telomerase expression. The activity of conditioned medium directly correlated with radiation-induced apoptosis of the feeder cells. Thus, the induction of conditionally reprogrammed cells is mediated by a combination of Y-27632 and a diffusible factor (or factors) released by apoptotic feeder cells.
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- 2013
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45. Use of Reprogrammed Cells to Identify Therapy for Respiratory Papillomatosis
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Aziza T. Shad, Bhaskar Kallakury, Nazaneen N. Grant, Richard Schlegel, Andrew Ju, Yvonne M. Carter, Michael Bazylewicz, Christopher Albanese, Dan Zhou, Jennifer A. Woo, Anatoly Dritschilo, Xuefeng Liu, Scott N. Myers, Jingang Wang, and Hang Yuan
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Male ,Pathology ,medicine.medical_specialty ,Lung Neoplasms ,Gene Expression ,Antineoplastic Agents ,Genome, Viral ,Hydroxamic Acids ,Article ,Young Adult ,Gene duplication ,Parenchyma ,Tumor Cells, Cultured ,medicine ,Humans ,RNA, Messenger ,Laryngeal Neoplasms ,Lung ,Respiratory Tract Infections ,Cells, Cultured ,Vorinostat ,Oncogene ,Human papillomavirus 11 ,business.industry ,Papillomavirus Infections ,General Medicine ,medicine.anatomical_structure ,Cell culture ,DNA, Viral ,Mutation ,RNA, Viral ,Recurrent Respiratory Papillomatosis ,business ,Reprogramming ,Chemosensitivity assay - Abstract
A patient with a 20-year history of recurrent respiratory papillomatosis had progressive, bilateral tumor invasion of the lung parenchyma. We used conditional reprogramming to generate cell cultures from the patient's normal and tumorous lung tissue. Analysis revealed that the laryngeal tumor cells contained a wild-type 7.9-kb human papillomavirus virus type 11 (HPV-11) genome, whereas the pulmonary tumor cells contained a 10.4-kb genome. The increased size of the latter viral genome was due to duplication of the promoter and oncogene regions. Chemosensitivity testing identified vorinostat as a potential therapeutic agent. At 3 months after treatment initiation, tumor sizes had stabilized, with durable effects at 15 months.
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- 2012
46. The Canonical NF-κB Pathway Governs Mammary Tumorigenesis in Transgenic Mice and Tumor Stem Cell Expansion
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Christopher Albanese, Xuanmao Jiao, Manran Liu, Mathew C. Casimiro, Nicole E. Willmarth, David A. Joyce, L. Andrew Shirley, Andrew A. Quong, Michael P. Lisanti, Sanjay Katiyar, Richard G. Pestell, John O. Ojeifo, Xiaoming Ju, Toshiyuki Sakamaki, and Wen Shuz Yeow
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Homeobox protein NANOG ,Genetically modified mouse ,Cancer Research ,Epithelial-Mesenchymal Transition ,Receptor, ErbB-2 ,Transgene ,Mice, Transgenic ,Cell Growth Processes ,Biology ,Transfection ,Stem cell marker ,Article ,Mice ,NF-KappaB Inhibitor alpha ,SOX2 ,Animals ,Epithelial–mesenchymal transition ,NF-kappa B ,Mammary Neoplasms, Experimental ,Epithelial Cells ,Molecular biology ,Cell Transformation, Neoplastic ,Oncology ,Tumor progression ,Neoplastic Stem Cells ,Cancer research ,Female ,I-kappa B Proteins ,Stem cell ,Reactive Oxygen Species - Abstract
The role of mammary epithelial cell (MEC) NF-κB in tumor progression in vivo is unknown, as murine NF-κB components and kinases either are required for murine survival or interfere with normal mammary gland development. As NF-κB inhibitors block both tumor-associated macrophages (TAM) and MEC NF-κB, the importance of MEC NF-κB to tumor progression in vivo remained to be determined. Herein, an MEC-targeted inducible transgenic inhibitor of NF-κB (IκBαSR) was developed in ErbB2 mammary oncomice. Inducible suppression of NF-κB in the adult mammary epithelium delayed the onset and number of new tumors. Within similar sized breast tumors, TAM and tumor neoangiogenesis was reduced. Coculture experiments demonstrated MEC NF-κB enhanced TAM recruitment. Genome-wide expression and proteomic analysis showed that IκBαSR inhibited tumor stem cell pathways. IκBαSR inhibited breast tumor stem cell markers in transgenic tumors, reduced stem cell expansion in vitro, and repressed expression of Nanog and Sox2 in vivo and in vitro. MEC NF-κB contributes to mammary tumorigenesis. As we show that NF-κB contributes to expansion of breast tumor stem cells and heterotypic signals that enhance TAM and vasculogenesis, these processes may contribute to NF-κB–dependent mammary tumorigenesis. Cancer Res; 70(24); 10464–73. ©2010 AACR.
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- 2010
47. Abstract 1083A: An ex vivo 3D bone metastasis model for prostate cancer
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Eugenia Dziopa, Yair D Kissin, Saba Choudhary, Christopher Albanese, Cirian Mannion, Erika Parasido, Woo Y. Lee, and Jenny Zilberberg
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Cancer Research ,Prostate cancer ,Oncology ,business.industry ,Cancer research ,Medicine ,Bone metastasis ,business ,medicine.disease ,Ex vivo - Abstract
Introduction: Bone is the preferred site for prostate cancer (PCa) metastases and there is virtually no cure once the tumor is established within this niche. The development of therapeutic strategies against metastatic PCa has been limited by the lack of an all-human preclinical model to: (1) study PCa-bone interactions under physiologically relevant three dimensional (3D) microenvironments, (2) understand how these interactions result in the development of drug resistance, and (3) explore paradigm-changing precision medicine concepts. Methods: Conditionally reprogrammed primary PCa cells (CR-PCa, derived from a lymph node metastatic site) were integrated with our ex vivo human 3D bone tissue platform, as a transformative approach for modeling tumor behavior at the bone niche. The 3D bone tissue was engineered using primary osteoblastic (OSB) cells from human bone samples. These cells were biomimetically assembly with biphasic calcium phosphate microbeads (BCPm) in perfusion microfluidic culture devices. BCPm were used to replicate the 3D cellular network of OSTs in human bone. This 3D tissue model was successfully used to support the osteocytic differentiation of primary human OSB cells within the BCPm structure, while maintaining a single cell layer of osteoblasts on the surface of the 3D tissue resembling the bone endosteum. Results: Integration of the 3D bone tissue with CR-PCa cells resulted in a compromised endosteal layer after only 4 days of coculture, with more apoptotic OSTs in the tissues with CR-PCa vs. no PCa cells controls (P Conclusions: Our model recapitulates: (1) an OSB monolayer closely resembling the endosteum at the bone/ bone marrow interface, (2) the complex microphysiological features and functions of 3D-networked OSTs, and (3) the interactions of primary PCa cells with osteoblasts and OSTs. Citation Format: Jenny Zilberberg, Saba Choudhary, Eugenia Dziopa, Cirian Mannion, Yair Kissin, Erika Parasido, Christopher Albanese, Woo Lee. An ex vivo 3D bone metastasis model for prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1083A.
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- 2018
48. Abstract 4073: Using patient-derived PDAC cells to understand c-MYC involvement in the drug resistance mechanisms of pancreatic cancer
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Jordan M. Winter, Jonathan R. Brody, Eric Glasgow, Eric Londin, Michael J. Pishvaian, Erika M. Parasido, Christopher Albanese, George S. Avetian, and Stephen W. Byers
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Cancer Research ,Microarray ,Cell ,Cancer ,Drug resistance ,Biology ,medicine.disease ,digestive system diseases ,medicine.anatomical_structure ,Oncology ,In vivo ,Tumor progression ,Pancreatic cancer ,Cancer research ,medicine ,Immunohistochemistry - Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease that is typically incurable due to acquired resistance to systemic chemotherapy. A deeper understanding of the mechanisms involving drug resistance is needed to improve patient outcomes. Commercially available PDAC cell lines are the most used model in research but do not accurately recapitulate a given patient's tumor. Using the conditional reprogrammed cell (CRC) technique, we established patient-specific cell lines and created nab-paclitaxel (nab-PTX)-resistant clones, which allowed us to better study resistance mechanisms. In many cancers, c-MYC has a known function in tumor progression, and recent studies suggest that the c-MYC pathway is involved in PDAC. However, the role of c-MYC in the mechanisms leading to nab-PTX resistance has not been extensively explored. Methods: Biopsies were collected from treatment-naive PDAC patients, and long-term cultures of PDAC CRCs were established. The PDAC origin of the cell lines was validated with genomic analysis. The IC50s for nab-PTX were calculated and used to generate drug-resistant clones. The Zebrafish model was used to verify the drug resistance in vivo, while subcutaneous injections of the parental and drug-resistant CRCs in nude mice were performed to test the cells' ability to form tumors. Exome sequencing, microarray, and Western blotting analyses were used to characterize and compare the parental lines with the drug-resistant clones and to identify key pathways involved in the evolution of drug resistance. Results: We established KRAS-mutant primary cell lines from PDAC patients' biopsies. Using 2 parental lines, we generated 5 nab-PTX-resistant clones, with IC50s up to 800 times greater than those of the matched parents; resistant profiles were verified in Zebrafish. Subcutaneous injections in nude mice showed the CRCs' ability to form tumors that recapitulate human PDAC. A greater metastatic phenotype was observed in the tumors derived from the resistant clones. RNA microarrays, comparing the parental cells with the resistant clones, identified a possible resistance mechanism involving the induction of a pro-inflammatory pathway leading to c-MYC overexpression. Western blotting, as well as immunocytochemical and immunohistochemical staining, performed on the CRCs and CRC-PDX-derived samples confirmed the role of c-MYC overexpression in the evolution of nab-PTX resistance. Conclusion: The conditional reprogrammed cell (CRC) methodology addresses the need for a reliable method for generating primary cell lines on a single patient basis. The ability to rapidly model in vitro, and verify in vivo, that the overexpression of c-MYC contributes to the development of nab-PTX resistance is a significant advancement in the field and provides a platform for discovery of more effective treatment of refractory PDAC. Citation Format: George S. Avetian, Erika M. Parasido, Jonathan Brody, Jordan Winter, Eric Londin, Michael Pishvaian, Eric Glasgow, Stephen Byers, Christopher Albanese. Using patient-derived PDAC cells to understand c-MYC involvement in the drug resistance mechanisms of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4073.
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- 2018
49. Abstract 342: Strigolactone analogues show potential as new combination therapy agents against pancreatic cancer
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Christopher Albanese, Erika Parasido, Matthew D. Park, Jefferson M. Haake, and Ronit I. Yarden
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Cancer Research ,Oncology ,Combination therapy ,business.industry ,Pancreatic cancer ,medicine ,Cancer research ,Strigolactone ,medicine.disease ,business - Abstract
There is an increasing appreciation for combination therapy of antineoplastic drugs that target key pathways often through a synergistic effect, reducing the chance for tumor growth, self-renewal of cancer stem cell (CSC), spread of metastasis and drug resistance. The combination of DNA repair impairment and DNA damage was shown to be a successful approach. Previously, we had shown that strigolactone (SLs; synthetic analogues, SLAs), a novel class of phytohormones, causes DNA double strand breaks (DSBs) and inhibits breast and osteosarcoma cancer cells and CSC viability. Here, we tested whether SLAs inhibit the growth of pancreatic ductal adenocarcinoma (PDAC) cells and stem cells and whether SLAs sensitize the effects of Gemcitabine (Gemzar), the most commonly prescribed drug for PDAC patients. We show that SLAs induce DSBs in different PDAC cells and the combination of SLAs with Gemcitabine significantly increases apoptosis when compared to PDAC cells treated with Gemcitabine alone. This additive effect is independent of BRCA2 expression, which suggests that SLAs are effective at impairing multiple repair mechanisms and is suitable in combination with multiple DNA damaging agents. Interestingly, we show that SLAs sensitize patient-derived Gemcitabine non-responsive, PDAC Conditionally-Reprogrammed Cells (CRCs) to Gemcitabine, reducing their overall viability by more than 30%. Accordingly, the SLA- Gemcitabine combination has a significant impact on tumorsphere (CSCs) growth outcome. These findings demonstrate the potential for a novel drug combination of SLAs and Gemcitabine and underscore the potential of SLAs for multiple highly valuable translational applications regarding alternative therapies to combat cancer. Citation Format: Matthew D. Park, Jefferson M. Haake, Erika Parasido, Christopher Albanese, Ronit I. Yarden. Strigolactone analogues show potential as new combination therapy agents against pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 342.
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- 2018
50. Restoration of DNA-binding and growth-suppressive activity of mutant forms of p53 via a PCAF-mediated acetylation pathway
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Vamsi K. Kolukula, Jason Catania, Adolf Graessmann, Michael J. Pishvaian, Christopher Albanese, Daniel L. Stoler, Chad D. Knights, Geetaram Sahu, Ricardo E. Perez, Maria Laura Avantaggiati, and Vasily Ogryzko
- Subjects
Programmed cell death ,Physiology ,Clinical Biochemistry ,Mutant ,Biology ,medicine.disease_cause ,Article ,Mice ,chemistry.chemical_compound ,Cell Line, Tumor ,medicine ,Animals ,Humans ,p300-CBP Transcription Factors ,Loss function ,Cell Proliferation ,Mutation ,Promoter ,DNA ,Cell Biology ,Chromatin ,chemistry ,PCAF ,Acetylation ,Cancer research ,Tumor Suppressor Protein p53 ,Colorectal Neoplasms ,Protein Binding - Abstract
Tumor-derived mutant forms of p53 compromise its DNA binding, transcriptional, and growth regulatory activity in a manner that is dependent upon the cell-type and the type of mutation. Given the high frequency of p53 mutations in human tumors, reactivation of the p53 pathway has been widely proposed as beneficial for cancer therapy. In support of this possibility p53 mutants possess a certain degree of conformational flexibility that allows for re-induction of function by a number of structurally different artificial compounds or by short peptides. This raises the question of whether physiological pathways for p53 mutant reactivation also exist and can be exploited therapeutically. The activity of wild-type p53 is modulated by various acetyl-transferases and deacetylases, but whether acetylation influences signaling by p53 mutant is still unknown. Here, we show that the PCAF acetyl-transferase is down-regulated in tumors harboring p53 mutants, where its re-expression leads to p53 acetylation and to cell death. Furthermore, acetylation restores the DNA-binding ability of p53 mutants in vitro and expression of PCAF, or treatment with deacetylase inhibitors, promotes their binding to p53-regulated promoters and transcriptional activity in vivo. These data suggest that PCAF-mediated acetylation rescues activity of at least a set of p53 mutations. Therefore, we propose that dis-regulation of PCAF activity is a pre-requisite for p53 mutant loss of function and for the oncogenic potential acquired by neoplastic cells expressing these proteins. Our findings offer a new rationale for therapeutic targeting of PCAF activity in tumors harboring oncogenic versions of p53.
- Published
- 2010
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