@article{salzman_merten_panek_fefer_mondino_westermeyer_gruen_olby_mowat_2023, title={Age-associated changes in electroretinography measures in companion dogs}, volume={6}, ISSN={["1573-2622"]}, url={https://doi.org/10.1007/s10633-023-09938-7}, DOI={10.1007/s10633-023-09938-7}, abstractNote={{"Label"=>"PURPOSE", "NlmCategory"=>"OBJECTIVE"} To determine the association between age and retinal full-field electroretinographic (ERG) measures in companion (pet) dogs, an important translational model species for human neurologic aging. {"Label"=>"METHODS", "NlmCategory"=>"METHODS"} Healthy adult dogs with no significant ophthalmic abnormalities were included. Unilateral full-field light- and dark-adapted electroretinography was performed using a handheld device, with mydriasis and topical anaesthesia. Partial least squares effect screening analysis was performed to determine the effect of age, sex, body weight and use of anxiolytic medication on log-transformed ERG peak times and amplitudes; age and anxiolytic usage had significant effects on multiple ERG outcomes. Mixed model analysis was performed on data from dogs not receiving anxiolytic medications. {"Label"=>"RESULTS", "NlmCategory"=>"RESULTS"} In dogs not receiving anxiolytics, median age was 118 months (interquartile range 72-140 months, n = 77, 44 purebred, 33 mixed breed dogs). Age was significantly associated with prolonged peak times of a-waves (dark-adapted 3 and 10 cds/m {"sup"=>"2"}  flash p < 0.0001) and b-waves (cone flicker p = 0.03, dark-adapted 0.01 cds/m {"sup"=>"2"}  flash p = 0.001). Age was also significantly associated with reduced amplitudes of a-waves (dark-adapted 3 cds/m {"sup"=>"2"}  flash p < 0.0001, 10 cds/m {"sup"=>"2"}  flash p = 0.005) and b-waves (light-adapted 3 cds/m {"sup"=>"2"}  flash p < 0.0001, dark-adapted 0.01 cds/m {"sup"=>"2"}  flash p = 0.0004, 3 cds/m {"sup"=>"2"}  flash p < 0.0001, 10 cds/m {"sup"=>"2"}  flash p = 0.007) and flicker (light-adapted 30 Hz 3 cds/m {"sup"=>"2"}  p = 0.0004). Within the Golden Retriever breed, these trends were matched in a cross-sectional analysis of 6 individuals that received no anxiolytic medication. {"Label"=>"CONCLUSIONS", "NlmCategory"=>"CONCLUSIONS"} Aged companion dogs have slower and reduced amplitude responses in both rod- and cone-mediated ERG. Consideration of anxiolytic medication use should be made when conducting ERG studies in dogs.}, journal={DOCUMENTA OPHTHALMOLOGICA}, author={Salzman, Michele M. and Merten, Natascha and Panek, Wojciech K. and Fefer, Gilad and Mondino, Alejandra and Westermeyer, Hans D. and Gruen, Margaret E. and Olby, Natasha J. and Mowat, Freya M.}, year={2023}, month={Jun} }
 @article{mondino_khan_case_fefer_panek_gruen_olby_2023, title={Winning the race with aging: age-related changes in gait speed and its association with cognitive performance in dogs}, volume={10}, ISSN={["2297-1769"]}, DOI={10.3389/fvets.2023.1150590}, abstractNote={IntroductionIn humans, gait speed is a crucial component in geriatric evaluation since decreasing speed can be a harbinger of cognitive decline and dementia. Aging companion dogs can suffer from age-related mobility impairment, cognitive decline and dementia known as canine cognitive dysfunction syndrome. We hypothesized that there would be an association between gait speed and cognition in aging dogs.}, journal={FRONTIERS IN VETERINARY SCIENCE}, author={Mondino, Alejandra and Khan, Michael and Case, Beth and Fefer, Gilad and Panek, Wojciech K. and Gruen, Margaret E. and Olby, Natasha J.}, year={2023}, month={Jun} }
 @article{fefer_khan_panek_case_gruen_olby_2022, title={Relationship between hearing, cognitive function, and quality of life in aging companion dogs}, volume={8}, ISSN={["1939-1676"]}, url={https://doi.org/10.1111/jvim.16510}, DOI={10.1111/jvim.16510}, abstractNote={Abstract}, journal={JOURNAL OF VETERINARY INTERNAL MEDICINE}, author={Fefer, Gilad and Khan, Michael Z. and Panek, Wojciech K. and Case, Beth and Gruen, Margaret E. and Olby, Natasha J.}, year={2022}, month={Aug} }
 @article{fefer_panek_khan_singer_westermeyer_mowat_murdoch_case_olby_gruen_2022, title={Use of Cognitive Testing, Questionnaires, and Plasma Biomarkers to Quantify Cognitive Impairment in an Aging Pet Dog Population}, volume={87}, ISSN={["1875-8908"]}, DOI={10.3233/JAD-215562}, abstractNote={Background: Aging dogs may suffer from canine cognitive dysfunction syndrome (CCDS), a condition in which cognitive decline is associated with amyloid pathology and cortical atrophy. Presumptive diagnosis is made through physical examination, exclusion of systemic/metabolic conditions, and completion of screening questionnaires by owners. Objective: This study aimed to determine whether cognitive function could be quantified in aging pet dogs, and to correlate cognitive testing with validated questionnaires and plasma neurofilament light chain (pNfL) concentration. Methods: Thirty-nine dogs from fifteen breeds were recruited (9.3 to 15.3 years). Owners completed the Canine Dementia Scale (CADES) and Canine Cognitive Dysfunction Rating scale (CCDR). Executive control and social cues were tested, and pNfL was measured with single molecule array assay. Comparisons were made between cognitive testing scores, CADES, CCDR scores, and pNfL. Results: CADES scoring classified five dogs as severe CCDS, six as moderate, ten as mild, and eighteen as normal. CCDR identified seven dogs at risk of CCDS and thirty-two as normal. Cognitive testing was possible in the majority of dogs, although severely affected dogs were unable to learn tasks. CADES score correlated with sustained attention duration (r = –0.47, p = 0.002), inhibitory control (r = –0.51, p = 0.002), detour (r = –0.43, p = 0.001), and pNfL (r = 0.41, p = 0.025). Concentration of pNfL correlated with inhibitory control (r = –0.7, p≤0.001). The CCDR scale correlated with performance on inhibitory control (r = –0.46, p = 0.005). Conclusion: Our findings suggest that a multi-dimensional approach using a combination of questionnaires, specific cognitive tests, and pNfL concentration can be used to quantify cognitive decline in aging pet dogs.}, number={3}, journal={JOURNAL OF ALZHEIMERS DISEASE}, author={Fefer, Gilad and Panek, Wojciech K. and Khan, Michael Z. and Singer, Matthew and Westermeyer, Hans D. and Mowat, Freya M. and Murdoch, David M. and Case, Beth and Olby, Natasha J. and Gruen, Margaret E.}, year={2022}, pages={1367–1378} }
 @article{hebel_panek_ruszkowski_nabzdyk_niedzielski_pituch_jackson_kielbowicz_pomorska-mol_2021, title={Computed tomography findings in a cohort of 169 dogs with elbow dysplasia-a retrospective study}, volume={17}, ISSN={["1746-6148"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85114341520&partnerID=MN8TOARS}, DOI={10.1186/s12917-021-02997-5}, abstractNote={Abstract}, number={1}, journal={BMC VETERINARY RESEARCH}, author={Hebel, Mateusz and Panek, Wojciech K. and Ruszkowski, Jakub J. and Nabzdyk, Maria and Niedzielski, Dariusz and Pituch, Katarzyna C. and Jackson, Aaron M. and Kielbowicz, Maciej and Pomorska-Mol, Malgorzata}, year={2021}, month={Sep} }
 @article{panek_murdoch_gruen_mowat_marek_olby_2021, title={Plasma Amyloid Beta Concentrations in Aged and Cognitively Impaired Pet Dogs}, volume={58}, ISSN={["1559-1182"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85091529286&partnerID=MN8TOARS}, DOI={10.1007/s12035-020-02140-9}, abstractNote={Longevity-associated neurological disorders have been observed across human and canine aging populations. Alzheimer's disease (AD) and canine cognitive dysfunction syndrome (CDS) represent comparable diseases affecting both species as they age. Translational diagnostic and therapeutic research is needed for these incurable diseases. The amyloid β (Aβ) peptide family are AD-associated peptides with identical amino acid sequences between dogs and humans. Plasma Aβ42 concentration increases with age and decreases with AD in humans, and cerebrospinal fluid (CSF) concentration decreases in AD and correlates inversely with the amyloid load within the brain. Similarly, CSF Aβ42 concentrations decrease in dogs with CDS but there is limited and conflicting information on plasma Aβ42 concentrations in aging dogs and dogs with CDS. We measured plasma concentrations of Aβ42 and Aβ40 with an ultrasensitive single-molecule array assay (SIMOA) in a population of healthy aging dogs of different life stages (n = 36) and dogs affected with CDS (n = 11). In addition, the ratio of Aβ42/β40 was calculated. The mean plasma concentrations of Aβ42 and Aβ40 increased significantly with age (r2 = 0.27, p = 0.001; and r2 = 0.42, p < 0.001, respectively) and with life stage: puppy/junior group (0.43-2 years): 1.23 ± 0.95 and 38.26 ± 49.43 pg/mL; adult/mature group (2.1-9 years): 10.99 ± 5.45 and 131.05 ± 80.17 pg/mL; geriatric/senior group (9.3-14.5 years): 18.65 ± 16.65 and 192.88 ± 146.38 pg/mL, respectively. Concentrations of Aβ42 and Aβ40 in dogs with CDS (11.0-15.6 years) were significantly lower than age-matched healthy dogs at 11.61 ± 6.39 and 150.23 ± 98.2 pg/mL (p = 0.0048 and p = 0.001), respectively. Our findings suggest the dynamics of canine plasma amyloid concentrations are analogous to that found in aging humans with and without AD.}, number={2}, journal={MOLECULAR NEUROBIOLOGY}, author={Panek, Wojciech K. and Murdoch, David M. and Gruen, Margaret E. and Mowat, Freya M. and Marek, Robert D. and Olby, Natasha J.}, year={2021}, month={Feb}, pages={483–489} }
 @article{kanojia_panek_cordero_fares_xiao_savchuk_kumar_xiao_pituch_miska_et al._2020, title={BET inhibition increases βIII-tubulin expression and sensitizes metastatic breast cancer in the brain to vinorelbine}, volume={12}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85089984516&partnerID=MN8TOARS}, DOI={10.1126/SCITRANSLMED.AAX2879}, abstractNote={Combination of BET inhibitor and vinorelbine improves survival in preclinical models of brain metastases.}, number={558}, journal={Science Translational Medicine}, publisher={American Association for the Advancement of Science (AAAS)}, author={Kanojia, Deepak and Panek, Wojciech K. and Cordero, Alex and Fares, Jawad and Xiao, Annie and Savchuk, Solomiia and Kumar, Krishan and Xiao, Ting and Pituch, Katarzyna C. and Miska, Jason and et al.}, year={2020} }
 @article{rashidi_miska_lee-chang_kanojia_panek_lopez-rosas_zhang_han_xiao_pituch_et al._2020, title={GCN2 is essential for CD8<sup>+</sup> T cell survival and function in murine models of malignant glioma}, volume={69}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85076745407&partnerID=MN8TOARS}, DOI={10.1007/s00262-019-02441-6}, abstractNote={Amino acid deprivation is a strategy that malignancies utilize to blunt anti-tumor T-cell immune responses. It has been proposed that amino acid insufficiency in T-cells is detected by GCN2 kinase, which through phosphorylation of EIF2α, shuts down global protein synthesis leading to T-cell arrest. The role of this amino acid stress sensor in the context of malignant brain tumors has not yet been studied, and may elucidate important insights into the mechanisms of T-cell survival in this harsh environment. Using animal models of glioblastoma and animals with deficiency in GCN2, we explored the importance of this pathway in T-cell function within brain tumors. Our results show that GCN2 deficiency limited CD8+ T-cell activation and expression of cytotoxic markers in two separate murine models of glioblastoma in vivo. Importantly, adoptive transfer of antigen-specific T-cells from GCN2 KO mice did not control tumor burden as well as wild-type CD8+ T-cells. Our in vitro and in vivo data demonstrated that reduction in amino acid availability caused GCN2 deficient CD8+ T-cells to become rapidly necrotic. Mechanistically, reduced CD8+ T-cell activation and necrosis was due to a disruption in TCR signaling, as we observed reductions in PKCθ and phoshpo-PKCθ on CD8+ T-cells from GCN2 KO mice in the absence of tryptophan. Validating these observations, treatment of wild-type CD8+ T-cells with a downstream inhibitor of GCN2 activation also triggered necrosis of CD8+ T-cells in the absence of tryptophan. In conclusion, our data demonstrate the vital importance of intact GCN2 signaling on CD8+ T-cell function and survival in glioblastoma.}, number={1}, journal={Cancer Immunology, Immunotherapy}, author={Rashidi, A. and Miska, J. and Lee-Chang, C. and Kanojia, D. and Panek, W.K. and Lopez-Rosas, A. and Zhang, P. and Han, Y. and Xiao, T. and Pituch, K.C. and et al.}, year={2020}, pages={81–94} }
 @article{panek_gruen_murdoch_marek_stachel_mowat_saker_olby_2020, title={Plasma Neurofilament Light Chain as a Translational Biomarker of Aging and Neurodegeneration in Dogs}, volume={57}, ISSN={["1559-1182"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85085898712&partnerID=MN8TOARS}, DOI={10.1007/s12035-020-01951-0}, abstractNote={Age is a primary risk factor for multiple comorbidities including neurodegenerative diseases. Pet dogs and humans represent two populations that have experienced a significant increase in average life expectancy over the last century. A higher prevalence of age-related neurodegenerative diseases has been observed across both species, and human diseases, such as Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS), have canine analogs, canine cognitive dysfunction (CCD), and degenerative myelopathy (DM) respectively. In humans, protein biomarkers have proved useful in the prediction and diagnosis of neurodegeneration. Molecular signatures of many proteins are highly conserved across species. In this study, we explored the potential of the neuronal cytoskeletal protein neurofilament light chain (NfL) as a biomarker of neuro-aging in dogs using an ultrasensitive single-molecule array assay to measure plasma concentrations. Healthy dogs of different ages and dogs affected with CCD and DM were evaluated. The mean plasma NfL concentrations in the different age groups of the healthy population were as follows: 4.55 ± 1.70 pg/mL in puppy/junior group (0.43–2 years), 13.51 ± 6.8 pg/mL in adult/mature group (2.1–9 years), and 47.1 ± 12.68 pg/mL in geriatric/senior group (9.3–14.5 years). Concentrations in dogs with DM (7.5–12.6 years) and CCD (11.0–15.6 years) were 84.17 ± 53.57 pg/mL and 100.73 ± 83.72 pg/mL, respectively. Plasma NfL increases in an age-dependent manner and is significantly elevated in dogs diagnosed with neurodegenerative disease. This work identified plasma NfL as a key clinical index of neuro-aging and neurodegeneration in pet dogs. Our findings mirror recent reports from human neurodegenerative diseases.}, number={7}, journal={MOLECULAR NEUROBIOLOGY}, author={Panek, Wojciech K. and Gruen, Margaret E. and Murdoch, David M. and Marek, Robert D. and Stachel, Alexandra F. and Mowat, Freya M. and Saker, Korinn E. and Olby, Natasha J.}, year={2020}, month={Jul}, pages={3143–3149} }
 @article{cordero_kanojia_miska_panek_xiao_han_bonamici_zhou_xiao_wu_et al._2019, title={FABP7 is a key metabolic regulator in HER2+ breast cancer brain metastasis}, volume={38}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85069432262&partnerID=MN8TOARS}, DOI={10.1038/s41388-019-0893-4}, abstractNote={Overexpression of human epidermal growth factor receptor 2 (HER2) in breast cancer patients is associated with increased incidence of breast cancer brain metastases (BCBM), but the mechanisms underlying this phenomenon remain unclear. Here, to identify brain-predominant genes critical for the establishment of BCBM, we conducted an in silico screening analysis and identified that increased levels of fatty acid-binding protein 7 (FABP7) correlate with a lower survival and higher incidence of brain metastases in breast cancer patients. We validated these findings using HER2+ BCBM cells compared with parental breast cancer cells. Importantly, through knockdown and overexpression assays, we characterized the role of FABP7 in the BCBM process in vitro and in vivo. Our results uncover a key role of FABP7 in metabolic reprogramming of HER2 + breast cancer cells, supporting a glycolytic phenotype and storage of lipid droplets that enable their adaptation and survival in the brain microenvironment. In addition, FABP7 is shown to be required for upregulation of key metastatic genes and pathways, such as integrins-Src and VEGFA, and for the growth of HER2+ breast cancer cells in the brain microenvironment in vivo. Together, our results support FABP7 as a potential target for the treatment of HER2+ BCBM.}, number={37}, journal={Oncogene}, author={Cordero, A. and Kanojia, D. and Miska, J. and Panek, W.K. and Xiao, A. and Han, Y. and Bonamici, N. and Zhou, W. and Xiao, T. and Wu, M. and et al.}, year={2019}, pages={6445–6460} }
 @article{miska_lee-chang_rashidi_muroski_chang_lopez-rosas_zhang_panek_cordero_han_et al._2019, title={HIF-1α Is a Metabolic Switch between Glycolytic-Driven Migration and Oxidative Phosphorylation-Driven Immunosuppression of Tregs in Glioblastoma}, volume={27}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85063509097&partnerID=MN8TOARS}, DOI={10.1016/j.celrep.2019.03.029}, abstractNote={The mechanisms by which regulatory T cells (Tregs) migrate to and function within the hypoxic tumor microenvironment are unclear. Our studies indicate that specific ablation of hypoxia-inducible factor 1α (HIF-1α) in Tregs results in enhanced CD8+ T cell suppression versus wild-type Tregs under hypoxia, due to increased pyruvate import into the mitochondria. Importantly, HIF-1α-deficient Tregs are minimally affected by the inhibition of lipid oxidation, a fuel that is critical for Treg metabolism in tumors. Under hypoxia, HIF-1α directs glucose away from mitochondria, leaving Tregs dependent on fatty acids for mitochondrial metabolism within the hypoxic tumor. Indeed, inhibition of lipid oxidation enhances the survival of mice with glioma. Interestingly, HIF-1α-deficient-Treg mice exhibit significantly enhanced animal survival in a murine model of glioma, due to their stymied migratory capacity, explaining their reduced abundance in tumor-bearing mice. Thus HIF-1α acts as a metabolic switch for Tregs between glycolytic-driven migration and oxidative phosphorylation-driven immunosuppression.}, number={1}, journal={Cell Reports}, author={Miska, J. and Lee-Chang, C. and Rashidi, A. and Muroski, M.E. and Chang, A.L. and Lopez-Rosas, A. and Zhang, P. and Panek, W.K. and Cordero, A. and Han, Y. and et al.}, year={2019}, pages={226–237.e4} }
 @article{panek_pituch_miska_kim_rashidi_kanojia_lopez-rosas_han_yu_chang_et al._2019, title={Local Application of Autologous Platelet-Rich Fibrin Patch (PRF-P) Suppresses Regulatory T Cell Recruitment in a Murine Glioma Model}, volume={56}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85056826280&partnerID=MN8TOARS}, DOI={10.1007/s12035-018-1430-0}, abstractNote={The immunosuppressive microenvironment is one of the major factors promoting the growth of glioblastoma multiforme (GBM). Infiltration of CD4+CD25+Foxp3+ regulatory T cells (Tregs) into the tumor microenvironment plays a significant role in the suppression of the anti-tumor immunity and portends a dismal prognosis for patients. Glioma-mediated secretion of chemo-attractant C-C motif ligand 2 and 22 (CCL2/22) has previously been shown by our group to promote Treg migration in vitro. In this study, we show that a local implantation of platelet-rich fibrin patch (PRF-P) into the brain of GL261 glioma-bearing mice prolonged the survival of affected animals by 42.85% (p = 0.0011). Analysis performed on brain tumor tissue harvested from PRF-P-treated mice revealed a specific decrease in intra-tumoral lymphocytes with a preferential depletion of immunosuppressive Tregs. Importantly, co-culture of GL261 or chemo-attractants (CCL2/22) with PRF-P abrogated Treg migration. Pharmacological blockade of the CCL2/22 interaction with their receptors potentiated the inhibitory effect of PRF-P on Tregs recruitment in culture. Moreover, our findings revealed the soluble CD40 ligand (sCD40L) as a major Treg inhibitory player produced by activated platelets entrapped within the fibrin matrix of the PRF-P. Blockade of sCD40L restored the migratory capacity of Tregs, emphasizing the role of PRF-P in preventing the Treg migration to glioma tissue. Our findings highlight autologous PRF-P as a personalized, Treg-selective suppression platform that can potentially supplement and enhance the efficacy of glioma therapies.}, number={7}, journal={Molecular Neurobiology}, author={Panek, W.K. and Pituch, K.C. and Miska, J. and Kim, J.W. and Rashidi, A. and Kanojia, D. and Lopez-Rosas, A. and Han, Y. and Yu, D. and Chang, C.L. and et al.}, year={2019}, pages={5032–5040} }
 @article{zhang_miska_lee-chang_rashidi_panek_an_zannikou_lopez-rosas_han_xiao_et al._2019, title={Therapeutic targeting of tumor-associated myeloid cells synergizes with radiation therapy for glioblastoma}, volume={116}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85075254734&partnerID=MN8TOARS}, DOI={10.1073/pnas.1906346116}, abstractNote={Significance}, number={47}, journal={Proceedings of the National Academy of Sciences of the United States of America}, author={Zhang, P. and Miska, J. and Lee-Chang, C. and Rashidi, A. and Panek, W.K. and An, S. and Zannikou, M. and Lopez-Rosas, A. and Han, Y. and Xiao, T. and et al.}, year={2019}, pages={23714–23723} }
 @article{kim_kane_panek_young_rashidi_yu_kanojia_hasan_miska_gómez-lim_et al._2018, title={A Dendritic Cell-Targeted Adenoviral Vector Facilitates Adaptive Immune Response Against Human Glioma Antigen (CMV-IE) and Prolongs Survival in a Human Glioma Tumor Model}, volume={15}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85050333576&partnerID=MN8TOARS}, DOI={10.1007/s13311-018-0650-3}, abstractNote={Antitumor immunotherapeutic strategies represent an especially promising set of approaches with rapid translational potential considering the dismal clinical context of high-grade gliomas. Dendritic cells (DCs) are the body's most professional antigen-presenting cells, able to recruit and activate T cells to stimulate an adaptive immune response. In this regard, specific loading of tumor-specific antigen onto dendritic cells potentially represents one of the most advanced strategies to achieve effective antitumor immunization. In this study, we developed a DC-specific adenoviral (Ad) vector, named Ad5scFvDEC205FF, targeting the DC surface receptor, DEC205. In vitro analysis shows that 60% of DCs was infected by this vector while the infectivity of other control adenoviral vectors was less than 10%, demonstrating superior infectivity on DCs. Moreover, an average of 14% of DCs were infected by Ad5scFvDEC205FF-GFP, while less than 3% of non-DCs were infected following in vivo administration, demonstrating highly selective in vivo DC infection. Importantly, vaccination with this vehicle expressing human glioma-specific antigen, Ad5scFvDEC205FF-CMV-IE, shows a prolonged survival benefit in GL261CMV-IE-implanted murine glioma models (p < 0.0007). Furthermore, when rechallenged, cancerous cells were completely rejected. In conclusion, our novel, viral-mediated, DC-based immunization approach has the significant therapeutic potential for patients with high-grade gliomas.}, number={4}, journal={Neurotherapeutics}, author={Kim, J.W. and Kane, J.R. and Panek, W.K. and Young, J.S. and Rashidi, A. and Yu, D. and Kanojia, D. and Hasan, T. and Miska, J. and Gómez-Lim, M.A. and et al.}, year={2018}, pages={1127–1138} }
 @article{pituch_miska_krenciute_panek_li_rodriguez-cruz_wu_han_lesniak_gottschalk_et al._2018, title={Adoptive Transfer of IL13Rα2-Specific Chimeric Antigen Receptor T Cells Creates a Pro-inflammatory Environment in Glioblastoma}, volume={26}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85042609548&partnerID=MN8TOARS}, DOI={10.1016/j.ymthe.2018.02.001}, abstractNote={In order to fully harness the potential of immunotherapy with chimeric antigen receptor (CAR)-modified T cells, pre-clinical studies must be conducted in immunocompetent animal models that closely mimic the immunosuppressive malignant glioma (MG) microenvironment. Thus, the goal of this project was to study the in vivo fate of T cells expressing CARs specific for the MG antigen IL13Rα2 (IL13Rα2-CARs) in immunocompetent MG models. Murine T cells expressing IL13Rα2-CARs with a CD28.ζ (IL13Rα2-CAR.CD28.ζ) or truncated signaling domain (IL13Rα2-CAR.Δ) were generated by retroviral transduction, and their effector function was evaluated both in vitro and in vivo. IL13Rα2-CAR.CD28.ζ T cells’ specificity toward IL13Rα2 was confirmed through cytokine production and cytolytic activity. In vivo, a single intratumoral injection of IL13Rα2-CAR.CD28.ζ T cells significantly extended the survival of IL13Rα2-expressing GL261 and SMA560 glioma-bearing mice; long-term survivors were resistant to re-challenge with IL13Rα2-negative and IL13Rα2-positive tumors. IL13Rα2-CAR.CD28.ζ T cells proliferated, produced cytokines (IFNγ, TNF-α), and promoted a phenotypically pro-inflammatory glioma microenvironment by inducing a significant increase in the number of CD4+ and CD8+ T cells and CD8α+ dendritic cells and a decrease in Ly6G+ myeloid-derived suppressor cells (MDSCs). Our data underline the significance of CAR T cell studies in immunocompetent hosts and further validate IL13Rα2-CAR T cells as an efficacious therapeutic strategy for MG. In order to fully harness the potential of immunotherapy with chimeric antigen receptor (CAR)-modified T cells, pre-clinical studies must be conducted in immunocompetent animal models that closely mimic the immunosuppressive malignant glioma (MG) microenvironment. Thus, the goal of this project was to study the in vivo fate of T cells expressing CARs specific for the MG antigen IL13Rα2 (IL13Rα2-CARs) in immunocompetent MG models. Murine T cells expressing IL13Rα2-CARs with a CD28.ζ (IL13Rα2-CAR.CD28.ζ) or truncated signaling domain (IL13Rα2-CAR.Δ) were generated by retroviral transduction, and their effector function was evaluated both in vitro and in vivo. IL13Rα2-CAR.CD28.ζ T cells’ specificity toward IL13Rα2 was confirmed through cytokine production and cytolytic activity. In vivo, a single intratumoral injection of IL13Rα2-CAR.CD28.ζ T cells significantly extended the survival of IL13Rα2-expressing GL261 and SMA560 glioma-bearing mice; long-term survivors were resistant to re-challenge with IL13Rα2-negative and IL13Rα2-positive tumors. IL13Rα2-CAR.CD28.ζ T cells proliferated, produced cytokines (IFNγ, TNF-α), and promoted a phenotypically pro-inflammatory glioma microenvironment by inducing a significant increase in the number of CD4+ and CD8+ T cells and CD8α+ dendritic cells and a decrease in Ly6G+ myeloid-derived suppressor cells (MDSCs). Our data underline the significance of CAR T cell studies in immunocompetent hosts and further validate IL13Rα2-CAR T cells as an efficacious therapeutic strategy for MG.}, number={4}, journal={Molecular Therapy}, author={Pituch, K.C. and Miska, J. and Krenciute, G. and Panek, W.K. and Li, G. and Rodriguez-Cruz, T. and Wu, M. and Han, Y. and Lesniak, M.S. and Gottschalk, S. and et al.}, year={2018}, pages={986–995} }
 @inbook{kim_pituch_xiao_young_panek_muroski_rashidi_kane_kanojia_lesniak_2018, title={Gene/Viral Treatment Approaches for Malignant Brain Cancer}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85054675259&partnerID=MN8TOARS}, DOI={10.1016/B978-0-12-812100-9.00015-2}, abstractNote={Gene therapy is a rapidly developing treatment modality that functions on its ability to deliver genes directly to the tumor site in order to yield antitumoral effects and thus prolong patient survival. The delivery of any gene(s) requires a delivery system that either involves the direct delivery of therapeutic gene(s) to the tumor site via viral or nonviral vectors, or through carriers that express the gene(s) in the tumor site via neural stem cells, mesenchymal stem cells, or other carriers. Four basic categories of gene therapy are currently being investigated for the treatment of brain tumors: (i) prodrug activation and suicide gene therapy; (ii) immunomodulatory and cytokine-based gene therapy; (iii) brain tumor hallmark targeting therapy; and (iv) oncolytic virotherapy. Preclinical studies of gene therapy for brain tumors have led to an array of human clinical trials, demonstrated to be remarkably safe and well tolerated with encouraging therapeutic results.}, booktitle={Handbook of Brain Tumor Chemotherapy, Molecular Therapeutics, and Immunotherapy: Second Edition}, author={Kim, J.W. and Pituch, K.C. and Xiao, A. and Young, J.S. and Panek, W.K. and Muroski, M.E. and Rashidi, A. and Kane, J.R. and Kanojia, D. and Lesniak, M.S.}, year={2018}, pages={211–227} }
 @article{kim_miska_young_rashidi_kane_panek_kanojia_han_balyasnikova_lesniak_2017, title={A Comparative Study of Replication-Incompetent and -Competent Adenoviral Therapy-Mediated Immune Response in a Murine Glioma Model}, volume={5}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85020708999&partnerID=MN8TOARS}, DOI={10.1016/j.omto.2017.05.001}, abstractNote={Oncolytic virotherapy is a treatment approach with increasing clinical relevance, as indicated by the marked survival benefit seen in animal models and its current exploration in human patients with cancer. The use of an adenovirus vector for this therapeutic modality is common, has significant clinical benefit in animals, and its efficacy has recently been linked to an anti-tumor immune response that occurs following tumor antigen presentation. Here, we analyzed the adaptive immune system's response following viral infection by comparing replication-incompetent and replication-competent adenoviral vectors. Our findings suggest that cell death caused by replication-competent adenoviral vectors is required to induce a significant anti-tumor immune response and survival benefits in immunocompetent mice bearing intracranial glioma. We observed significant changes in the repertoire of immune cells in the brain and draining lymph nodes and significant recruitment of CD103+ dendritic cells (DCs) in response to oncolytic adenoviral therapy, suggesting the active role of the immune system in anti-tumor response. Our data suggest that the response to oncolytic virotherapy is accompanied by local and systemic immune responses and should be taken in consideration in the future design of the clinical studies evaluating oncolytic virotherapy in patients with glioblastoma multiforme (GBM).}, journal={Molecular Therapy - Oncolytics}, author={Kim, J.W. and Miska, J. and Young, J.S. and Rashidi, A. and Kane, J.R. and Panek, W.K. and Kanojia, D. and Han, Y. and Balyasnikova, I.V. and Lesniak, M.S.}, year={2017}, pages={97–104} }
 @article{panek_kane_young_rashidi_kim_kanojia_lesniak_2017, title={Hitting the nail on the head: Combining oncolytic adenovirusmediated virotherapy and immunomodulation for the treatment of glioma}, volume={8}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85031935138&partnerID=MN8TOARS}, DOI={10.18632/oncotarget.20810}, abstractNote={Glioblastoma is a highly aggressive malignant brain tumor with a poor prognosis and the median survival 14.6 months. Immunomodulatory proteins and oncolytic viruses represent two treatment approaches that have recently been developed for patients with glioblastoma that could extend patient survival and result in better treatment outcomes for patients with this disease. Together, these approaches could potentially augment the treatment efficacy and strength of these anti-tumor therapies. In addition to oncolytic activities, this combinatory approach introduces immunomodulation locally only where cancerous cells are present. This thereby results in the change of the tumor microenvironment from immune-suppressive to immune-vulnerable via activation of cytotoxic T cells or through the removal of glioma cells immune-suppressive capability. This review discusses the strengths and weaknesses of adenoviral oncolytic therapy, and highlights the genetic modifications that result in more effective and targeted viral agents. Additionally, the mechanism of action of immune-activating agents is described and the results of previous clinical trials utilizing these treatments in other solid tumors are reviewed. The feasibility, synergy, and limitations for treatments that combine these two approaches are outlined and areas for which more work is needed are considered.}, number={51}, journal={Oncotarget}, author={Panek, W.K. and Kane, J.R. and Young, J.S. and Rashidi, A. and Kim, J.W. and Kanojia, D. and Lesniak, M.S.}, year={2017}, pages={89391–89405} }
 @article{yu_khan_suvà_dong_panek_xiao_wu_han_ahmed_balyasnikova_et al._2017, title={Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression}, volume={114}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85025680489&partnerID=MN8TOARS}, DOI={10.1073/pnas.1701911114}, abstractNote={Significance}, number={30}, journal={Proceedings of the National Academy of Sciences of the United States of America}, author={Yu, D. and Khan, O.F. and Suvà, M.L. and Dong, B. and Panek, W.K. and Xiao, T. and Wu, M. and Han, Y. and Ahmed, A.U. and Balyasnikova, I.V. and et al.}, year={2017}, pages={E6147–E6156} }
 @article{panek_khan_yu_lesniak_2017, title={Multiplexed nanomedicine for brain tumors: Nanosized Hercules to tame our Lernaean Hydra inside?}, volume={12}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85030650102&partnerID=MN8TOARS}, DOI={10.2217/nnm-2017-0260}, abstractNote={NanomedicineVol. 12, No. 20 EditorialFree AccessMultiplexed nanomedicine for brain tumors: nanosized Hercules to tame our Lernaean Hydra inside?Wojciech K Panek‡, Omar F Khan‡, Dou Yu & Maciej S LesniakWojciech K Panek‡ Department of Neurological Surgery, Brain Tumor Research Institute, The Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA‡Authors contributed equallySearch for more papers by this author, Omar F Khan‡ David H. Koch Institute for Integrative Cancer Research, Department of Chemical Engineering, Institute for Medical Engineering & Science, Harvard MIT Division of Health Science & Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA‡Authors contributed equallySearch for more papers by this author, Dou Yu Department of Neurological Surgery, Brain Tumor Research Institute, The Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USASearch for more papers by this author & Maciej S Lesniak*Author for correspondence: Tel.: +1 312 926 1094; Fax: +1 312 695 3294; E-mail Address: maciej.lesniak@northwestern.edu Department of Neurological Surgery, Brain Tumor Research Institute, The Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USASearch for more papers by this authorPublished Online:3 Oct 2017https://doi.org/10.2217/nnm-2017-0260AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit Keywords: GBMnanoparticlenanomedicinebrain tumorsiRNAconvection enhanced deliveryBTIC/brain tumor initiating cellsstem cell transcription factorFirst draft submitted: 17 August 2017; Accepted for publication: 30 August 2017; Published online: 3 October 2017A vivid embodiment of human fear is the gruesome monster Lernaean Hydra from Greek and Roman mythology, which is depicted as a multiheaded serpent guarding the entry to the underworld with nightmarish regenerative powers: for every chopped off head, replacements would multiply and the surging demonic ferocity would ensue (Figure 1). Similar motifs of such hopeless terror scatter across cultures, and the Greco-Roman fable teaches that divine intervention and the incredible might of the legendary Hercules were needed to kill the beast. A remarkable parallel can be drawn with our continuing, capricious combat against one of the deadliest human diseases to date: glioblastoma (GBM). With merely 14 months of average life expectancy despite maximal combination therapy of surgical resection, radiation and chemotherapy, GBM is the Hydra inside marked by persistent therapy resistance and unstoppable recurrence. Brain tumor-initiating cells (BTICs) are analogous to the regenerative venomous Hydra heads, in that existing therapeutic stress from classic therapy modalities only emboldens the aggressive progression of the disease, driven by these adaptive cell types in GBM. An obvious question is: where is our rescuer, Hercules? The evolution of nanotechnologies offers hope to formulate a nanosized Hercules to attack BTICs at the core, the labor that inspired us to devote this editorial to elaborate the implications.Figure 1. Hercules, by John Singer Sargent (1921), depicting the epic battle with the Lernaean Hydra.Museum of Fine Arts, Boston, MA, USA. Wikimedia Commons.Evolving nano formulations of RNAi expand therapeutic potential for heterogeneous GBMRNAi via safe and efficacious delivery of siRNAs is on the rise at the clinical translation front. It can directly correct aberrant gene expressions that instigate malignant tumor growth in the CNS, which can be ‘undruggable’ when using small molecules and biologicals (e.g., antibodies). A variety of nanosized biomaterials have been formulated to carry out this repair mission with specific therapeutic targets identified by molecular and genetic probing of the cancer genome from patient-derived tissue samples. The formulation of nano vehicles for RNAi is critical for the clinical success. Early efforts focused on dendrimer inspired nano constructs and solid nanoparticles (NPs), followed by the biomimetic development of tumor derived exosome-based experimental therapeutics for brain delivery [1–19]. The engineering potential of cell type selectivity for these vehicles is limited. Further development of novel lipopolymeric nanoparticle (LPNP) platforms incorporates engineered polymers in the lipid bilayer outer shell, allowing for flexible cellular uptake properties [20–22]. The ability to easily modify the chemistry of the lipid NP surface was demonstrated by recent advancements [9,23]. In the latest article by Yu et al. [23], BTIC specific uptake of LPNPs was observed, which opens the opportunity to fine tune the tumor targeting selectivity of LPNPs, thereby enhancing therapeutic potency while minimizing off-targeting or healthy tissue toxicity.Multi-targeting capacity is vital for nanoRNAi formulations against patient specific GBMThe evolution of nano carriers for siRNAs started with single core solid nano constructs based on classic materials such as gold [24], iron oxide, chitosan [5,17], porous silica [8], sugar [15], solid lipids [3,4,6,9] and an array of dendrimer inspired NPs [12]. Some of these applications showed early promise in effective RNAi of key GBM growth-promoting genes: Jensen et al. demonstrated that gold NP mediated siRNA knockdown of the oncoprotein Bcl2Like12 (Bcl2L12) reduced tumor growth [24]; Costa et al. demonstrated effective GBM inhibition using anti-miR-21 oligonucleotides, a different approach for tumor promoting miR-21 silencing [4]; and Danhier et al. also showed combined benefits of TMZ/chemo with chitosan based nano RNAi against Galectin and EGFR [5]. However, the most exciting potential of the latest multiplexed nano RNAi therapy against BTIC is the ability to customize the therapeutic targeting based on patient tissue features and the capacity to co-deliver synergistic multi-targeting siRNAs. Using a flexible LPNP nano carrier system, Yu et al. demonstrated sustained therapeutic benefit by incorporating four distinct siRNA constructs directed at four key master transcription factors, namely SOX2, OLIG2, SALL2 and POU3F2, in tumor growth driving BTICs [23]. The implication of this new advancement is that a variety of multiplexed RNAi therapy schemes are now possible based on an individual patient's tumor genetic profile, and efficacious personalized therapeutic outcomes are achievable even with increased evidence of intratumoral heterogeneity and post-therapy tumor metabolic adaptation. Given that diverse genetic drivers are continuously uncovered based on GBM BTIC characterization [25–27], therapeutic strategies targeting a singular genetic/epigenetic abnormality in GBM are insufficient to subdue the ‘multiheaded monster’.Essential considerations for chemical engineering designs of nanoRNAi systemsThe journey towards efficacious nanomedicine for complex GBM starts with careful considerations of the nano construct design. For any nanoscale carrier delivering a therapeutic payload, form follows function. Drugs that are extremely hydrophobic are difficult to administer due to their low solubility and concomitant low bioavailability. For such payloads, a solid lipid NP or carbon nanotube construction can be advantageous. Their insoluble cores can partition the drug, and an outer hydrophilic layer, at times built using a surfactant, is used to promote cell membrane permeability. By contrast, RNAs, including siRNAs, are soluble and polyanionic. However, solubility does not mean greater bioavailability for RNA; the immune system responds to foreign RNAs as pathogenic, readily degrading them. Nucleotide chemical modifications can help prevent an immune response and degradation. Modified RNA can thus be attached to the surface of solid NPs. For example, gold particles with modified surface chemistries can enable covalent or electrostatic attachment. Charged materials do have trade-offs though, as materials with permanent charges can be more readily opsonized or toxic. Forgoing the NP paradigm and directly conjugating modified RNA to targeting moieties is another potential solution, though endosomal escape after uptake can potentially be compromised. Thus, the form of the nanoscale delivery carrier must solve these many RNA-specific challenges.Advantages of lipopolymeric nanoRNAi formulationsLPNPs are a promising solution. Flexible chemical synthesis means charge can be controlled. Ionizable materials, such as those containing amines, are temporarily switched to a cationic state to condense the polyanionic RNA and then returned to a neutral state. Thus, toxicity challenges caused by permanent charges are avoided. The ionizable feature is also leveraged for endosomal escape post-uptake through the proton sponge effect. Additionally, polymers can efficiently condense the RNA which, when combined with RNA chemical modification, can further prevent payload exposure and degradation. Moreover, ionizable amphiphilic polymers such as lipid polymers are both amenable to RNA payloads and NP self-assembly in aqueous environments, which obviates the need for organic solvents during production. Furthermore, NP stability can be influenced by the choice of polymer and lipid molecular weight. Even diameter can be affected, which directly impacts uptake in different tissues. Conversely, because polymer molecular weights can potentially alter the performance and characteristics of lipid polymeric NPs, their polydispersity must be carefully monitored and controlled during at-scale production.Engineering considerations for brain delivery of lipopolymeric nanoRNAi formulationsFor RNAi therapy in the brain, LPNPs offer an excellent balance of payload specificity, membrane permeability and toxicity, which can significantly boost their therapeutic index. Additionally, in terms of parenteral administration, direct injection further circumvents the challenge of crossing the blood–brain barrier after systemic delivery, which greatly focuses the therapy. However, with the large magnitude of lipid-polymer combinations possible by virtue of flexible, modular chemistry and extensive material screens may reveal new formulations that can traverse the barrier. Ionizable lipid polymeric NPs also contain and shield their RNA payloads, further avoiding localized charge-related material-induced effects and immune reactions in the brain. Another feature of lipid polymeric NPs is the RNA payload capacity. With higher ratios of RNA:lipid polymer, NPs can carry many copies of a siRNA or a multitude of different siRNAs. This type of multiplexing is tremendously advantageous because complex therapies requiring the silencing of multiple genes become possible. Moreover, one is not limited to equimolar mixes in siRNA in multiplexes. This means payloads can be proportioned to match the prevalence and duration of the target genes and gene products. Multiplexing may be useful in some screening applications as well. The multifunctional potential of the LPNP platform remains to be explored. Theoretically, the LPNP construct can be further customized for cell type selectivity given the differences in uptake dynamics observed for different brain cell types. Moreover, the cargo content can also include imaging reagents such as magnetic nanocore or quantum dots for in vivo and ex vivo biodistribution analysis after administration. Thus, the multimodal integration of functionality in LPNPs offers versatility and feasibility for clinical translation and real-time assessment in patients.Clinical prospects of nanomedicine for GBMClinical applications of nanomedicine for malignant brain tumors are rising. Several sophisticated nano formulations of RNAi or combination therapies are at the early clinical trial phases after promising preclinical proof of concept (Clinicaltrials.gov: NCT02766699, NCT01906385, NCT03020017, NCT00944801, NCT02340156, NCT02820454, NCT00470613 and NCT02022644) [28,29]. Although all current clinical trials focus on select therapeutic targets, it is yet to be seen whether multitargeting nano therapeutic strategies will translate and deliver superior antitumor efficacy. Beyond target selection, and despite the early indications of positive safety profiles for some of the nano therapeutics, there are additional factors of divergence between the various strategies that can potentially contribute to differences in therapeutic efficacy. The most important is the delivery route. Systemic delivery is a preferred route for experimental nanomedicine, because of the ostensible advantages of repeatability, minimal invasiveness and the supposedly unique blood–brain barrier penetrance capacity of most nano carriers. However, there is still a deep chasm between these perceived benefits and the actual ability to accumulate sufficient therapeutic dose at tumor sites after systemic injections to render meaningful therapeutic efficacy. With the demonstration of dose-dependent therapeutic benefits in experimental rodent models of GBM, Yu et al. confirmed recent evidence of intratumoral convection enhanced delivery (CED) using a subcutaneously implanted osmotic pump (Alzet™, Durect Corp., CA, USA). With increasing clinical interests for direct intratumoral delivery of GBM therapeutics via CED [30–35], this direction forgoes some of the perceptions of systemic delivery benefits and substitutes them with the potentially efficacious local accumulation of antitumor therapeutics. Clinical evaluation of CED based nano therapeutics for GBM is underway (NCT02022644). The potential for combinatorial clinical application with standard care (surgery, temozolomide and radiation) has yet to be tested and could be even greater than the multiplexed nanoRNAi alone. However, intratumoral delivery of nano therapeutics is an evolving strategy that requires continued technological innovations to reduce complications associated with the surgical implantation of catheters or other medical devices. Significant amelioration of the pain and inconvenience associated with the surgical implantation is needed for clinical translation.Challenges ahead for advancements in nanomedicine against GBMThe putative therapeutic potential of LPNP systems in rodent models of patient derived xenograft GBM has been demonstrated. Now, several engineering feats must be conquered to expedite clinical translation and expand the CNS applications of multiplexed LPNP therapies to other neurological disorders: The molecular mechanisms of LPNP uptake and endosomal escape need to be identified in order to enhance therapeutic efficacy of the LPNP system via engineering customization; brain delivery strategies and distribution plan must be refined to ensure full therapeutic coverage of the original and recurring GBM mass; methodologies must be established for dynamic sampling and therapeutic candidate adjustments based on tumor phenotype and genotype shift in response to therapy; enable therapeutic targeting of other brain tumor cellular compositions, such as immune cells and microenvironment, etc., to comprehensively purge the tumor promoting elements; the incorporation of more sophisticated genome engineering tools such as Clustered Regularly Interspersed Short Palindromic Repeats (CRISPR) technology; and enable non-invasive telemetry through, for example, live imaging modalities. With multidisciplinary collaborative efforts converging on the creation of multiplexed and multifunctional LPNP mediated nanomedicine strategies against BTICs, the prospect of a nanosized Hercules slaying the multiheaded Hydra inside our brain is bright and encouraging.Financial & competing interests disclosureThis work was supported by NIH R35CA197725 (MS Lesniak), Burroughs Wellcome Collaborative Travel Grant (D Yu), the Elsa U. Pardee Foundation Grant (D Yu). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.References1 Agrawal A, Min DH, Singh N et al. Functional delivery of siRNA in mice using dendriworms. ACS Nano 3(9), 2495–2504 (2009).Crossref, Medline, CAS, Google Scholar2 Bronisz A, Wang Y, Nowicki MO et al. 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Neuro Oncol. 17(Suppl. 2), ii3–ii8 (2015).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByThe Frontiers of Neurosurgery13 July 2019 Vol. 12, No. 20 Follow us on social media for the latest updates Metrics History Published online 3 October 2017 Published in print October 2017 Information© 2017 Future Medicine LtdKeywordsGBMnanoparticlenanomedicinebrain tumorsiRNAconvection enhanced deliveryBTIC/brain tumor initiating cellsstem cell transcription factorFinancial & competing interests disclosureThis work was supported by NIH R35CA197725 (MS Lesniak), Burroughs Wellcome Collaborative Travel Grant (D Yu), the Elsa U. Pardee Foundation Grant (D Yu). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download}, number={20}, journal={Nanomedicine}, author={Panek, W.K. and Khan, O.F. and Yu, D. and Lesniak, M.S.}, year={2017}, pages={2435–2439} }