tbuckley/cabot-search huggingface dataset:
Abstract 2904: Induction of autophagy reveals a cytoprotective mechanism by which DNA polymerase gamma (pol-γ) prevents UVB-induced skin cancer
Authors: Sanjit K. Dhar, Vasu Bakthavachalu, Tadahide Izumi, Jing Chen, Haining Zhu, Daret K. St. Clair
Journal: Cancer Research (2015)

Abstract DNA polymerase γ (polγ), a major mitochondrial DNA repair enzyme, is essential for replication and repair of the mitochondrial genome. It is well-established that mitochondrial genomic stability is important for healthy cell survival; however, whether and how polγ plays a role in autophagic response remain unknown. Our previous studies demonstrated that polγ is inactivated upon exposure to ultraviolet B (UVB) irradiation by a peroxynitrite-mediated mechanism. In this study, we identified tyrosine 964, which is near the active site of polγ, as the target of nitration-induced inactivation by the use of LC/MS/MS mass spectroscopy coupled to immunoprecipitation, Western blotting and a 3` to 5` exonuclease activity assay. Treatment of mouse skin epithelial cells with UVB radiation validated the presence of polγ nitration and reduction of its enzymatic activity in vivo. To determine the effect of UVB in autophagic responses, mouse skin epithelial (JB6) cells were transfected with GFP-labeled LC-3 cDNA and exposed to UVB radiation, or wild-type C57BL/6 mice were exposed to UVB radiation and examined for LC-3 cleavage products. UVB radiation of JB6 cells and mouse skin increased LC-3 cleavage products and beclin levels, suggesting increased autophagic response to UVB treatment both in vitro and in vivo. To elucidate the role of Polγ in autophagic responses, the expression of polγ in JB6 cells was inhibited by siRNA for polγ. Consistent with the role of polγ in preventing UVB-induced autophagy, knockdown of polγ led to an increase LC-3 cleavage products. Knockdown of polγ induced prosurvival autophagic responses via the mTOR-signaling-complex-1(mTORC1) and complex-2(mTORC2). Interestingly, the mTORC2 complex plays a prominent role in the prosurvival autophagy responses based on the bromodeoxyuridine uptake assay, following knockdown and overexpression approaches. Importantly, suppression of polγ alone leads to transformation and invasion ofJB6 cells, which are increased following UVB treatment. The results reveal a unique role of Polγ in autophagy and support the role of Polγ in the suppression of prosurvival autophagic response to UVB- mediated carcinogenesis. Citation Format: Sanjit K. Dhar, Vasu Bakthavachalu, Tadahide Izumi, Jing Chen, Haining Zhu, Daret K. St. Clair. Induction of autophagy reveals a cytoprotective mechanism by which DNA polymerase gamma (pol-γ) prevents UVB-induced skin cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2904. doi:10.1158/1538-7445.AM2015-2904
Abstract 3441: Proteomic profiling identifies PTK2/FAK as a targetable marker of radioresistance in head and neck cancer
Authors: Heath D. Skinner, Uma Giri, John S. Yordy, Michael D. Story, Jing Wang, Lauren A. Byers, Michelle D. Williams, Adel K. El-Naggar, Sang H. Woo, Liang P. Yang, You Fan, Curtis R. Pickering, Jeffrey N. Myers, John V. Heymach
Journal: Cancer Research (2015)

Abstract One of the primary treatments for head and neck squamous cell carcinoma (HNSCC) is radiotherapy. Despite decades of study, few if any targetable biomarkers for resistance to this modality. To systematically evaluate resistance to radiotherapy in HNSCC, we evaluated 50 HNSCC cell lines using reverse phase protein array (RPPA). Utilizing this method we identified 11 protein markers with altered expression in radioresistant HNSCC cell lines (FDR 1%), including PTK2/FAK. Both PTK2/Fak gene expression and copy number were highly correlated to PTK2/Fak protein expression and both were associated with radioresistance in these cell lines. Additionally, in clinical samples from the TCGA, PTK2/Fak copy number was highly associated with gene expression, with high expression levels in HNSCC tumors. To validate the association between PTK2/Fak and clinical radioresistance in HNSCC, we examined PTK2/FAK copy number in two separate cohorts of HNSCC patients treated uniformly with radiotherapy (n = 39 and n = 44). In both cohorts, PTK2/Fak amplification was associated with treatment failure following radiotherapy (p = 0.04 and p = 0.03 respectively and p = 0.004 for the combined population). Additionally, in a separate cohort of HNSCC patients treated with radiotherapy, high levels of PTK2/Fak gene expression were associated with failure following radiotherapy (p = 0.02). Additionally, in vitro pharmacologic inhibition of PTK2/FAK function led to radiosensitization in multiple HNSCC cell lines, primarily via induction of G2/M arrest, with minimal apoptosis observed. Taken together, these data identify a validated, targetable biomarker of radioresistance in HNSCC. Citation Format: Heath D. Skinner, Uma Giri, John S. Yordy, Michael D. Story, Jing Wang, Lauren A. Byers, Michelle D. Williams, Adel K. El-Naggar, Sang H. Woo, Liang P. Yang, You Fan, Curtis R. Pickering, Jeffrey N. Myers,, John V. Heymach. Proteomic profiling identifies PTK2/FAK as a targetable marker of radioresistance in head and neck cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3441. doi:10.1158/1538-7445.AM2015-3441
NK Cell Proliferation and Cytolytic Function Are Compromised In the Hypoxic Tumor Microenvironment
Authors: Sonny Ang, Maria Lima Da Silva, Margaret Dawson, Matthew Figliola, Sourindra Maiti, Helen Huls, Elizabeth J. Shpall, Richard Champlin, Dean A. Lee, Lucia Silla, Laurence J.N. Cooper
Journal: Blood (2010)
Abstract LB-269: Nutritional effect on CD44 in head and neck cancer
Authors: Turki M. Almuhaimid, Faisal F. Alotaibi, Erika Rearegue, William Goodwin, Elizabeth Franzmann
Journal: Cancer Research (2015)

Abstract Head and neck (HN) cancer incidence accounts for more than 550,000 cases annually worldwide, with an estimated of 55,000 Americans developing head and neck cancer each year. There are multiple risk factors associated with HN cancer including smoking, alcohol consumption, human papillomavirus (HPV) infection, genetic predisposition, poor oral hygiene, periodontal disease and poor diet. According to World Health Organization (WHO), 35 - 55% of human cancers and approximately 15% of oropharyngeal cancers can be attributed to dietary deficiencies or imbalances. There is convincing evidence that we can reduce the risk of cancer, including that of oral cancer through improved nutrition. CD44 is a cancer stem cell marker associated with HN cancer and poor prognosis. Protein levels in saliva are also associated with HN cancer risk. This study will investigate the relationship between nutritional effect of a balanced diet which includes fruits and vegetables and levels of CD44 and salivary protein. 150 participants diagnosed with HN cancer and 150 controls were frequency matched for tobacco use, alcohol, age, gender, race and socioeconomic status. Participants completed a lifestyle questionnaire which included questions about fruit and vegetable consumption. Oral rinse CD44 and protein levels were measured in both groups. We did a preliminary investigation on the number of servings of juice, salad, fruits, carrots, potato and other vegetables within the cancer case and control groups to determine whether there was an association between these dietary variables and CD44 and protein levels. HN cancer cases who ate salad one or more times per week were found to have significantly lower CD44 levels than those who ate salad less frequently (4.22ng/ml verses 7.09 ng/ml p = 0. 004). Since high CD44 levels are associated with worse prognosis, these findings suggest that dietary factors such as greater salad intake may be associated with better HN cancer prognosis. Citation Format: Turki M. Almuhaimid, Faisal F. Alotaibi, Erika Rearegue, William Goodwin, Elizabeth Franzmann. Nutritional effect on CD44 in head and neck cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-269. doi:10.1158/1538-7445.AM2015-LB-269
287. Improved Outcomes Following Drug-Resistant Immunotherapy in a Human Xenograft Model of Temozolomide-Resistant Glioblastoma Multiforme
Authors: Harold T. Spencer, Larisa Pereboeva, George Y. Gillespie, Anindya Dasgupta, Kathryn S. Sutton, Lawrence S. Lamb
Journal: Molecular Therapy (2015)

INTRODUCTION: Conventional treatment strategies for Temozolomide (TMZ)-resistant high-grade gliomas have been uniformly dismal. We have shown that TMZ-resistant tumors up-regulate stress-associated NKG2D ligands (NKG2DL) during the first hours after exposure to TMZ, thereby creating an opportunity for NKG2DL-directed cell therapies. We report improved survival using a combination of TMZ chemotherapy and gene modified TMZ-resistant γΔ T cells which we term Drug Resistant Immunotherapy (DRI). TMZ resistance is conferred by lentivector transfer of methylguanine methyltransferase (MGMT) enabling cytotoxic lymphocyte function during high-dose chemotherapy. METHODS: Tumor NKG2DL expression and DRI cytotoxicity were assessed by flow cytometry. Intracranial (IC) glioma xenografts were established on Day 0 with either unmodified (P) or a TMZ resistant clone (T) of human primary GBM-X12 passaged exclusively in immunodeficient mice. Tumor-bearing mice were treated with intraperitoneal TMZ 60mg/kg on days 6, 8,13, and 15 followed by IC injection of 1.5 × 106 DRI 4h after each TMZ dose × 2 weeks. Control mice received non-modified cells, TMZ, or no therapy. Survival was assessed using Kaplan-Meier analysis. RESULTS: Both GBM-X12P and X12T express NKG2DL MIC-A, MIC-B, and ULBP-4. DRI cells killed both tumors in vitro at approximately 80% at an effector: target ratio of 20:1 with no toxicity against cultured human astrocytes. Cell therapy alone did not improve survival beyond that of untreated mice. For the parent tumor X12P (Figure 1), TMZ therapy significantly improved median survival over untreated controls (29 vs. 59 days, p < 0.0001), and addition of DRI increased median survival to 120 days with 80% long term survivors. For the TMZ-resistant X12T (Figure 2), TMZ alone did not improve survival over untreated controls (22 vs. 27 days p = 0.4827). Addition of DRI significantly increased median survival from 22 days to 38 days (p = 0.0004) with 10% of animals surviving to day +119. CONCLUSIONS: This is the first report of combined TMZ chemotherapy and drug-resistance modified γΔ T cell therapy resulting in a significant increase in time to progression and improvement in median and overall survival in immunodeficient mice bearing otherwise impervious human primary xenograft tumors using a strategy is readily adaptable to the clinical setting
Abstract 4417: Vatalanib targets ABCG2-overexpressing multidrug resistant colon cancer cells under hypoxia
Authors: Kenneth K. To, Daniel C. Poon, Yuming Wei, Fang Wang, Ge Lin, Li-wu Fu
Journal: Cancer Research (2015)

Abstract Cancer microenvironment is characterized by significantly lower oxygen concentration. This hypoxic condition is known to reduce drug responsiveness to cancer chemotherapy via multiple mechanisms, among which the upregulation of an efflux transporter ABCG2 confers resistance to a wide variety of structurally unrelated anticancer drugs. Vatalanib (PTK787) is a multitargeted tyrosine kinase inhibitor for VEGFR2, Flt and c-Kit, which exhibit potent anticancer activity in vitro and in vivo. We investigated the potentiation effect of vatalanib on the anticancer activity of conventional cytotoxic drugs in colon cancer cell lines under both normoxic and hypoxic growth conditions. More significant synergistic anticancer activity was observed under hypoxic condition. Mechanistically, vatalanib was found to inhibit ABCG2 and P-gp efflux activity, probably by acting as an uncompetitive inhibitor and interfering with their ATPase activity. Under hypoxic growth condition, ABCG2-overexpressing cells sorted out by FACS technique as side population cells (SP) were found to be significantly more responsive to irinotecan (an ABCG2 substrate anticancer drug) in the presence of vatalanib. The colony formation capactiy of these SP cells was remarkably reduced upon treatment with a combination of irinotecan and vatalanib, compared to irinotecan alone. However, vatalanib, at concentrations that produced the circumvention of ABCG2-mediated resistance, did not appreciably alter ABCG2 mRNA or protein expression levels or the phosphorylation of Akt and extracellular signal-regulated kinase 1/2 (ERK1/2). Vatalanib was also evaluated for potential interference with the cytochrome P450 metabolic enzymes by a rapid N-in-one in vitro interaction screening assay. The result indicates that vatalanib is only a mild inhibitor of both CYP34A and CYP2D, two major drug-metabolizing P450 enzymes, which presumably may avoid the undesirable drug-drug interactions in combination therapy. Our study thus advocates the further investigation of vatalanib for use in combination chemotherapy to circumvent hypoxia-mediated drug resistance. Citation Format: Kenneth K. To, Daniel C. Poon, Yuming Wei, Fang Wang, Ge Lin, Li-wu Fu. Vatalanib targets ABCG2-overexpressing multidrug resistant colon cancer cells under hypoxia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4417. doi:10.1158/1538-7445.AM2015-4417
Cisplatin, epirubicin, capecitabine, and gemcitabine (PEXG) as first-line treatment in metastatic or unresectable pancreatic cancer: Active and well tolerated?
Authors: Gareth Rivalland, Benjamin James Lawrence, Soizick Jeanne Lynette Mesnage, Jane Reeve, Michael P. N. Findlay
Journal: Journal of Clinical Oncology (2014)

e15217 Background: Cisplatin, epirubicin, 5-FU and gemcitabine (PEFG) improved PFS over gemcitabine in a phase III trial in advanced pancreatic ductal adenocarcinoma (PDA) (Reni, 2005). A dose-dense PEXG schedule (capecitabine substituted for 5-FU) showed similar efficacy (Reni, 2012) with a more acceptable toxicity profile. FOLFIRINOX is an active regimen, but has not been uniformly adopted at published doses due to concerns about toxicity. Many institutions therefore prefer the combination of gemcitabine and nab-paclitaxel (Von Hoff, 2012) which has a median overall survival (OS) of 8.5 months and response rate of 23%. Methods: A retrospective review of all patients (n= 28:13F) with unresectable or metastatic PDA treated first-line with PEXG in Auckland, New Zealand. PEXG was administered on a four-week cycle: cisplatin 30mg/m2; epirubicin 30mg/m2; gemcitabine 800 mg/m2 on days 1 and 14, and capecitabine 625mg/m2 BD continuously. Efficacy was evaluated using OS, progression-free survival (PFS), overall response rate (ORR) using RECIST v1.1 criteria, and toxicity using CTCAE v4.0. Minor responses were defined as a by 15-30% reduction in sum of the diameter of target lesions. Results: Median age 58 yrs (range 45–74 yrs); ECOG performance status 0-2; median number of cycles: 3.75; median OS 10.5 months; median PFS 6.2 months; ORR (CR+PR) 21.4%. Minor responses were seen in a further 17.9%. 53.6% of patients experienced only grade ≤2 toxicity. 28.6% of patients experienced asymptomatic grade ≥3 haematologic toxicity. Only 18%, 7% and 7% experienced grade 3 non-neutropenic infection, fatigue, and hand-foot syndrome respectively. There were no cases of neutropenic fever, peripheral neuropathy, or treatment-related death. No patient received growth factor support. Conclusions: In our experience PEXG shows similar median OS and response rate to that reported for gemcitabine-nab-paclitaxel. In those jurisdictions without funding for nab-paclitaxel PEXG offers a reasonable alternative. The modest toxicity profile in our series and in the original study suggests this treatment schedule may be a useful framework for incorporating newer agents.
356. High-Resolution X-Ray Fluorescence Microscopy (XFM) Indicates Enhanced Brain Copper Delivery in AAV9-Treated Menkes Disease Mice
Authors: Marie Reine Haddad, Martina Ralle, David J. Vine, Patricia M. Zerfas, Stephen G. Kaler
Journal: Molecular Therapy (2016)

Menkes disease is a lethal infantile neurodegenerative disorder caused by mutations in a copper transporter, ATP7A. The mottled-brindled (mo-br) mouse recapitulates the symptoms and early demise (14 days) of untreated human Menkes disease (3 years). We previously demonstrated that viral gene therapy using cerebrospinal fluid (CSF)-directed AAV9-ATP7A in combination with subcutaneous (sc) clinical grade copper histidinate enhanced survival, normalized growth, and improved biochemical and neurobehavioral outcomes in this model. In the current study, we examined copper biodistribution and concentration in specific brain regions for treated and untreated mutants compared to wild type mice, using X-ray fluorescence microscopy (XFM). XFM enables sensitive, quantitative measurement of the spatial distribution of biometals at image resolutions approaching the subcellular level. Ten days after rAAV9-ATP7A administration, copper levels in cerebral cortex, caudate and choroid plexus in the lateral ventricle in combination treated mice were all normal or slightly higher than normal compared to wild type mice and untreated mutants. Immunohistochemistry demonstrated robust ATP7A expression in choroid plexus epithelia as well as in neurons throughout the brain in the treated animals. These preliminary data support the hypothesis that choroid plexus is the major mediator of brain copper delivery by pumping copper into the CSF via ATP7A. Our findings provide further support for CSF-directed viral gene therapy in human subjects with Menkes disease.
Predictive factors of response to neoadjuvant chemotherapy (NAT) in triple negative breast (TNBC) cancer patients: a restrospective multicenter observational study
Authors: L. Iezzi, L. Mentuccia, P. Vici, C. Natoli, I. Sperduti, A. Astone, P. Marchetti, L. Pizzuti, A. Michelotti, V. Sini, A. Cassano, F. Ciancola, S. Quadrini, L. Moscetti, E. Landucci, E. Magnolfi, D. Sergi, T. Gamucci
Journal: Annals of Oncology (2015)
Abstract 3110: Urinary miR-1825 and miR-484: An oncogene and a tumor- suppressor gene among prostate cancer patients
Authors: Moemen Abdalla, Taha A. Haj-Ahmad, Yousef Haj-Ahmad
Journal: Cancer Research (2015)

Abstract MicroRNAs (miRNAs) are short, single-stranded RNA molecules with the ability of acting as post-transcriptional regulators of gene expression. MiRNAs regulate a number of important pathways, such as: cellular differentiation, proliferation, and apoptosis. MiRNA expression profiling patterns were demonstrated to have more potential than the common mRNA expression profiling for the characterization of poorly differentiated tumours. Studying miRNA expression profiles “signatures” will help in understanding the role of these miRNAs in the process of cancer development. The aim of this study was to profile the urinary miRNA expression signatures among prostate cancer patients in comparison to healthy male individuals. To identify the miRNA signatures specific for PCa, total RNA was isolated from 2.5mL of urine from all prostate cancer patients and from healthy males. RNA isolated from each group were pooled together and the differential expression analysis of miRNAs between the pooled samples was performed using MiRNA Microarray technology. Differential expression of two individual miRNAs, miR-1825 and miR-484, was observed between healthy males and prostate cancer patients. The relative expression of these two miRNAs were assessed among among the prostate cancer group and the healthy male group using RT-qPCR. MiR-1825 was up-regulated in seven out of eight PCa samples (88%), whereas miR-484 was down-regulated in six out of the eight PCa samples (75%). It has been found that the putative target for miR-1825 is member-1 of the Discoidin Domain family of Receptors (DDR1). The over-expression of DDR1 was reported to be a prognostic marker for the poor survival in several cancer types and therefore is proposed that miR-1825 might function as a tumor-suppressor by normally or in response to cancer, inhibiting DDR1's translation. As for miR-484, E3 ubiquitin-protein ligase (UBR5), which is thought to be involved with DNA repair, has been found to be the putative target for miR-484. It has be reported that the over-expression of a mutated version of UBR5 was found in breast and ovarian cancers where its deregulation was cited as a possible cause of malignant progression. It is therefore being proposed that miR-484 might function as a tumor- suppressor whereby its expression controls progression via the regulation of genes, such as UBR5, that have already been potentially associated with cancer progression. Citation Format: Moemen Abdalla, Taha A. Haj-Ahmad, Yousef Haj-Ahmad. Urinary miR-1825 and miR-484: An oncogene and a tumor- suppressor gene among prostate cancer patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3110. doi:10.1158/1538-7445.AM2015-3110
Abstract 4562: Slug knockdown suppresses malignant phenotype of nanomaterial-transformed human lung epithelial cells
Authors: Maria Voronkova, Sudjit Luanpitpong, Liying Wang, Yon Rojanasakul
Journal: Cancer Research (2015)

Abstract Nanomaterials have increasingly become part of modern everyday life, but their long-term health effects are largely unknown. Previous studies have shown that carbon nanotubes (CNTs), one of the most widely used nanomaterials in industry, can induce or promote tumor formation in animals, but the underlying mechanisms are unclear. We previously found that chronic exposure to CNTs induced malignant transformation of human lung epithelial cells, the primary cellular target of inhaled nanomaterials. The transformed cells exhibited aggressive cancer phenotypes, including increased cell migration, invasion and anchorage-independent cell growth. We hypothesized that such increased aggressiveness may be due to epithelial-mesenchymal transition (EMT). To test this hypothesis, cultured human lung epithelial BEAS-2B cells were continuously exposed to physiologically relevant concentration (0.02 μg/cm2 surface area dose) of single-walled CNT (SWCNT) for a period of 6 months. The cells were then analyzed for EMT markers and aggressive cellular behavior. Western blot analysis of EMT markers indicated an increased expression of mesenchymal markers and decreased epithelial markers, indicating the activation of EMT in the chronic SWCNT-exposed cells. Moreover, the cells exhibited a dramatic increase in one of the EMT master regulators, a transcription factor Slug (Snail2). We hypothesized that Slug upregulation may be responsible for the aggressive phenotype of the cells. We stably downregulated the Slug expression using lentiviral shRNA particles, and examined its effect on cell migration and invasion by Transwell® assays. Our results showed that knockdown of Slug attenuated cell migration and invasion without having any effect on cell proliferation. Together, our results indicated the activation of EMT by SWCNT and demonstrated its role in aggressive cancer phenotype. Slug plays a crucial role in this process and could serve as a potential biomarker for CNT-induced malignancies. Citation Format: Maria Voronkova, Sudjit Luanpitpong, Liying Wang, Yon Rojanasakul. Slug knockdown suppresses malignant phenotype of nanomaterial-transformed human lung epithelial cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4562. doi:10.1158/1538-7445.AM2015-4562