tbuckley/cabot-search huggingface dataset:
Ultra-small pH-responsive Nd-doped NaDyF<sub>4</sub> Nanoagents for Enhanced Cancer Theranostic by <i>in situ</i> Aggregation
Authors: Yuxin Liu, Huimin Fan, Quanwei Guo, Anqi Jiang, Xiaoxia Du, Jing Zhou
Journal: Theranostics (2017)

To achieve accurate tumor location and highly efficient cancer therapy effect, the properties of cancer theranostic agents should be optimized and enhanced.In this work, ultra-small Nd doped NaDyF4 were firstly reported as novel contrast agents for near-infrared second window downconversion luminescence (NIR II DCL) and magnetic resonance imaging.Based on the optimization strategy, gallic acid-Fe(III) complex modified NaDyF4:10%Nd (NaDyF4:10%Nd-GA-Fe) was selected as the optimal agent with high transversal relaxivity, strong NIR II DCL, high photothermal conversion efficiency, and low toxicity.In vitro experiment found that it can be aggregated rapidly in low pH condition, leading to the particle size increasing.Due to the theranostic properties coupled in NaDyF4:10%Nd-GA-Fe are size dependent, properties enhancement was observed within the pH responsive aggregation progress.Further study in small animal model bearing tumor demonstrated the enhanced cancer theranostic by in situ aggregation.The optimized nanoagents have potential applications in medical and also provide a novel strategy for future study of cancer theranostic enhancement.
Recurrent ubiquitin B silencing in gynecological cancers establishes dependence on ubiquitin C
Authors: Alexia T. Kedves, Scott Gleim, Xiaoyou Liang, Dennis M. Bonal, Frederic Sigoillot, Fred Harbinski, Sneha Sanghavi, Christina Benander, Elizabeth George, Prafulla C. Gokhale, Quang-De Nguyen, Paul T. Kirschmeier, Robert J. Distel, Jeremy Jenkins, Michael S. Goldberg, William C. Forrester
Journal: Journal of Clinical Investigation (2017)

Transcriptional repression of ubiquitin B (UBB) is a cancer-subtype-specific alteration that occurs in a substantial population of patients with cancers of the female reproductive tract. UBB is 1 of 2 genes encoding for ubiquitin as a polyprotein consisting of multiple copies of ubiquitin monomers. Silencing of UBB reduces cellular UBB levels and results in an exquisite dependence on ubiquitin C (UBC), the second polyubiquitin gene. UBB is repressed in approximately 30% of high-grade serous ovarian cancer (HGSOC) patients and is a recurrent lesion in uterine carcinosarcoma and endometrial carcinoma. We identified ovarian tumor cell lines that retain UBB in a repressed state, used these cell lines to establish orthotopic ovarian tumors, and found that inducible expression of a UBC-targeting shRNA led to tumor regression, and substantial long-term survival benefit. Thus, we describe a recurrent cancer-specific lesion at the level of ubiquitin production. Moreover, these observations reveal the prognostic value of UBB repression and establish UBC as a promising therapeutic target for ovarian cancer patients with recurrent UBB silencing.
CMET-05. HEALTH-ECONOMIC ANALYSES OF RADIOTHERAPY FOR PATIENTS WITH BRAIN METASTASES: CAN ECONOMICS GUIDE THE ESTABLISHMENT OF PATIENT CARE PATHWAYS?
Authors: Nebras Warsi, Laureen Hachem, Farshad Nassiri, Alireza Mansouri
Journal: Neuro-Oncology (2017)

Treatment options for brain metastases include whole-brain radiation therapy (WBRT), stereotaxic radiosurgery (SRS), and surgical resection followed by adjuvant therapy. Although SRS provides similar survival benefits and poses less morbidity-related costs than WBRT, it may predispose patients to higher recurrence risk and later utilization of salvage therapies. In today’s limited spending climate, it is critical to find the most medically sound and economical uses for these therapies. We conducted a critical literature review, searching the MEDLINE, EMBASE, Cochrane, CRD, and EconLit databases using keywords pertaining to brain metastases, radiotherapy, and health economic evaluations, without limits on publication date or language. 12 studies were identified (nine American, one German, one Vietnamese, and one Taiwanese). Six used modelling but only one applied discounting. Survival with SRS was at least equivalent to surgical resection and WBRT. SRS – even with salvage therapy and routine MRI surveillance – was more cost-effective than surgical resection and WBRT. For patients expected to survive longer, between 12–24 months, SRS combined with hippocampal-sparing WBRT (ICER $80,253) or hippocampal-sparing WBRT alone (ICER $24,701) were cost-effective compared to surgical resection and WBRT. For tumors not amenable to SRS, surgical resection with intra-operative brachytherapy was more cost-effective than surgery followed by SRS ($19,271/QALY vs. $44,219/QALY). Though further modelling work is needed, we propose the following cost-effective pathway: tumors smaller than 3cm may be managed by SRS with MRI surveillance every three months and salvage therapy (SRS or WBRT) on evidence of recurrence. Hippocampal-sparing WBRT could serve as a valuable adjuvant therapy in patients surviving longer than 12 months. Tumors larger than 3cm or not amenable to SRS could be surgically resected with intraoperative brachytherapy or cavity SRS, followed by routine MRI surveillance every three months and additional salvage therapy (SRS or WBRT) on evidence of recurrence.
P2.01-014 ABOUND.PS2: Safety and Efficacy of Nab-Paclitaxel–Based Therapy in Patients with NSCLC and ECOG PS 2
Authors: A. Gajra, N. Abdel Karim, D. Mulford, M. Matrana, H. Ali, E. Santos, T.J. Ong, A. Sanford, K. Amiri, D. Spigel
Journal: Journal of Thoracic Oncology (2017)
IMMU-41. H3.3K27M MUTATION-DERIVED NOVEL NEOANTIGEN – CHARACTERIZATION OF THE HLA-A2-BINDING EPITOPE AND A SPECIFIC T CELL RECEPTOR FOR DEVELOPMENT OF T CELL-BASED IMMUNOTHERAPY
Authors: Zinal Chheda, Gary Kohanbash, Kaori Okada, Naznin Jahan, John Sidney, Matteo Pecoraro, Diego Carrera, Shruti Shrivastav, Shuming Liu, Kira Downey, Pavlina Chuntova, Payal Watchmaker, Sabine Mueller, Ian Pollack, Raja Rajalingam, Angel Montero Carcaboso, Matthias Mann, Alessandro Sette, Yafei Hou, Hideho Okada
Journal: Neuro-Oncology (2017)

The median overall survival for children with diffuse intrinsic pontine glioma (DIPG) is less than a year. The majority of diffuse midline gliomas, including over 70% of DIPG, harbor an amino-acid substitution from lysine (K) to methionine (M) at position 27 of histone 3 variant 3.3. As predicted by the NetMHC3.4 peptide binding algorithm, a competitive binding inhibition assay demonstrated that 10-mer peptide encompassing the K27M mutation (H3.3K27M peptide hereafter), but not the corresponding non-mutant peptide, has an excellent binding affinity to human leukocyte antigen (HLA)-A2. Importantly, mass spectrometry analysis of H3.3K27M+ glioma cells demonstrated that the H3.3K27M peptide is naturally processed and presented by HLA class I. H3.3K27M-specific CD8+ T cell responses were detected in patients´ peripheral blood mononuclear cells by interferon-γ ELISPOT assay. Repeated stimulation of HLAA2+ CD8+ T cells with the H3.3K27M peptide led to establishment of H3.3K27M-reactive CD8+ T-cell clones. From one clone with excellent binding to the HLA-A2-H3.3K27M tetramer, cDNA for T cell receptor (TCR) α and β chains were cloned into a retroviral vector. Human HLA-A2+ T-cells transduced with the TCR efficiently killed HLA-A2+ H3.3K27M+ glioma cells in an antigen- and HLA-specific manner. Adoptive transfer of TCR-transduced T-cells significantly suppressed the progression of orthotopic xenografts in mice. Furthermore, alanine-scanning assays demonstrated that there are no known human proteins that share the set of key amino acid residues required for recognition by the TCR, strongly suggesting that the TCR could be safely used in patients without causing off-target toxicity. These data provide us with a strong basis for developing novel immunotherapy strategies targeting this epitope. We have initiated a pilot study evaluating the safety and preliminary clinical activities of the H3.3K27M peptide vaccine in HLAA2+ pediatric patients with H3.3K27M+ glioma though Pacific Pediatric Neuro-Oncology Consortium (PNOC-007).
P1.02-017 Freely Floating Cancer Cells in Lymph Node Sinuses of Hilar Lymph Node Positive Lung Cancer Patients
Authors: Y. Nakamura, M. Mukai, S. Hiraiwa, K. Kishima, T. Sugiyama, T. Tajiri, S. Yamada, M. Iwazaki
Journal: Journal of Thoracic Oncology (2017)
GENE-19. TIE2-MEDIATED EPIGENETIC MODIFICATIONS REGULATE RADIORESISTANCE OF GLIOBLASTOMA
Authors: Mohammad Hossain, Rehnuma Shifat, Yisel Rivera-Molina, Francisco Puerta-Martinez, Hong Jiang, Debora Kim, David Johnson, Mark Bedford, Erik Sulman, Frederick Lang, Juan Fueyo, Candelaria Gomez-Manzano
Journal: Neuro-Oncology (2017)

Glioblastomas invariably recur after therapy due to the presence of cells exhibiting a multidrug-resistance phenotype. The development of new therapeutic strategies requires the identification of key molecular pathways regulating this resistant phenotype. Our group has made several seminal contributions on the role of the tyrosine kinase receptor TIE2 in gliomas. We have reported the expression of TIE2 in human surgical glioma specimens in relation to malignancy, specifically in brain tumor stem cells. Recently, we have identified that the unexpected membrane-to-nuclear trafficking of TIE2 is related with radioresistance of brain tumor stem cells, acting as a genotoxic stress sensor to activate DNA repair machinery. Interestingly, TIE2 binds, upon IR stress, to DNA/protein complexes. The work presented here shows the unexpected TIE2-mediated tyrosine phosphorylation of several core histones. Specifically, we discovered two new histone marks (H4pY51 and H2BpY40). We screened for pY-Readers using a SH2 domain array for phospho-tyrosine ligand analysis. From this study, we found that H4pY51 and H2pY40 modifications are read by the proto-oncogenes ABL1 and CRK, respectively. Our data also showed that TIE2/H4pY54/ABL1 complex binds to DNA repair proteins, activating a NHEJ DNA repair mechanism. In an effort to find the molecular mechanisms underlying TIE2 nuclear translocation, we identified that TIE2 binds and directly phosphorylates CAV1 at Tyr14 residue in vitro and in vivo, an essential modification for the translocation of both TIE2 and CAV1 to the nucleus. Our results summarize that upon IR stress TIE2 localizes to the nucleus where is involved in key cellular functions by directly phosphorylating core histones, and recruiting SH2 domain proteins to the DNA damage sites, complexing to the DNA repair machinery. Our discovery might be of high significance to understand the resistance of cancer to DNA-damage inducers, which eventually might result in the design of TIE2-targeting combinational therapies for patients with glioblastomas.
EXTH-36. DEVELOPMENT OF STABLE AND BRAIN-PENETRATING DISULFIRAM NANOPARTICLES, CHARACTERIZATION AND EFFICACY IN GLIOMA CELL CULTURE AND XENOGRAFT MODELS
Authors: Hanumantha Rao Madala, Surendra Reddy Punganuru, Kalkunte Srivenugopal, Francis Ali-Osman
Journal: Neuro-Oncology (2017)

Blood brain-barrier entry, tumor heterogeneity, need to eliminate the tumorigenic stem cells and inhibit the DNA repair protein MGMT are all essential considerations in glioma treatment. Previously, we showed that alcohol aversion drug disulfiram (DSF) shares all these properties [Carcinogenesis 35, 692, 2014; Oncotarget 4,502, 2013]. DSF was shown to inhibit the MGMT activity in the same way as ALDH by conjugating with the active-site cysteine 145 and sensitize brain tumors to alkylating agents. Although DSF exerts significant anticancer effects in vitro, the drug undergoes rapid decomposition and metabolism. To overcome this problem, we engineered DSF nanoparticles by encapsulating the drug in PEG: PLGA polymer by solvent evaporation method. The formulation was optimized for various process formulation variables. The optimized nano-formulation (NP) ranged from 70–80 nm in particle size as confirmed using dynamic light scattering. Transition electron microscopy and scanning electron microscopy revealed their shape and surface. Drug loading, encapsulation efficiency and in vitro release were also. The time course of internalization of particles using a cyanine dye (HITC-1) showed a lysosomal accumulation followed by mitochondria. Live animal imaging after IV injections of HITC-labeled DSF-NPs revealed a selective accumulation in the brain and subcutaneous tumors. Further, the cytotoxicity elicited by DSFNPs against various brain tumor cells was extended and greater than obtained with the free drug. The DSFNPs also induced significant degradation of MGMT in a concentration-dependent manner in glioma cells. ROS induction by the encapsulated drug was confirmed through DCF-DA and DHE staining of live cells; co-staining these cells with the mitochondrial membrane potential markers DiOC6 and DHE confirmed the altered mitochondrial integrity. GSTP1 inhibition and ROS induction by DSFNPs led to an activation of JNK/MAPK pathway, culminating in autophagy and apoptosis as verified by western blotting, FACS and immunofluorescence of appropriate markers.
Extending Ethical Strides: From Tribal IRBs to the Bronx Community Research Review Board
Authors: Phoebe Friesen, Lisa Kearns, Barbara K. Redman, Arthur L. Caplan
Journal: The American Journal of Bioethics (2017)

We are grateful to Hull and Wilson (2017) for expanding on our brief discussion of the necessity of recognizing harms to communities that can occur within research, and for making space for further...
P3.01-012 Symptom Impact of First-Line Dacomitinib versus Gefitinib in EGFR-Positive NSCLC: Results from a Randomized Phase 3 Study
Authors: M.R. Migliorino, T. Mok, Y. Wu, X. Zhou, K.H. Lee, K. Nakagawa, S. Niho, F. Tsuji, R. Linke, R. Rosell, J. Corral, A. Pluzanski, E. Sbar, R. Sandin, A. Reisman, T. Wang, J.L. White, Y. Cheng
Journal: Journal of Thoracic Oncology (2017)
Strong and frequent T‐cell responses to the minor allergen Phl p 12 in Spanish patients IgE‐sensitized to Profilins
Authors: G. Lund, S. Brand, T. Ramos, L. Jimeno, P. Boissy, F. Vega, M. Arina, L. H. Christensen, I. Hoof, K. H. Meno, D. Barber, C. Blanco, P. A. Würtzen, P. S. Andersen
Journal: Allergy (2017)

Profilins are dominant pan-allergens known to cause cross-sensitization, leading to clinical symptoms such as pollen-food syndrome. This study aimed to determine the T-cell response to Phl p 12 in profilin-sensitized patients, by measuring the prevalence, strength and cross-reactivity to clinically relevant profilins.The release of Phl p allergens from pollen was determined by mass spectrometry and immunochemistry. T-cell responses, epitope mapping and cross-reactivity to profilins (Phl p 12, Ole e 2, Bet v 2 and Mal d 4) were measured in vitro using PBMCs from 26 Spanish grass-allergic donors IgE-sensitized to profilin. Cross-reactivity was addressed in vivo using 2 different mouse strains (BALB/c and C3H).Phl p 12 and Phl p 1 are released from pollen simultaneously and in similar amounts. Both T-cell response frequency (17/26 donors) and strength were comparable between Phl p 12 and Phl p 1. T-cell cross-reactivity to other profilins correlated with overall sequence homology, and 2 immunodominant epitope regions of Phl p 12 were identified. Data from mice immunized with Phl p 12 showed that cross-reactivity to Bet v 2 was mediated by conserved epitopes and further influenced by additional genetic factors, likely to be MHC II.The strength, prevalence and cross-reactivity of T-cell responses towards Phl p 12 are comparable to the major allergen Phl p 1, which supports the hypothesis that T cells to Phl p 12 can play an important role in development of allergic symptoms, such as those associated with pollen-food syndrome.
NIMG-45. CRT MOLECULAR PROBE TARGETING TRANSFERRIN RECEPTOR 1 IN GLIOMA ANIMAL MODEL
Authors: Yi-ying Zhao, Hai-ping Cai, Yin-sheng Che, Jing Wang, Fu-rong Chen, Zhong-ping Chen
Journal: Neuro-Oncology (2017)

Glioma is the most frequent primary tumor in the central nervous system. The current imaging assessments are inadequate in the therapeutic process. A newly discovered cyclic peptide CRTIGPSVC (abbreviated as CRT) through the blood-brain barrier and home in glioma cells by transferrin receptor 1 (TfR1) mediated endocytosis. The expression of TfR1 was upregulated in a variety of tumors including glioma. This study intends to design Near Infrared probe Cy5-CRT and validate the specificity of the CRT-Cy5 peptide in glioma animal model and provide the experimental basis for clinical application. The human glioma cell line U87 was transfected with lentivirus H113 to obtain U87-MG H113 that stably expressing luciferase. The U87-MG H113 cells were injected into the caudate nucleus of mice. Three weeks later, the signal of luciferase was detected by small animal imaging instrument after the intraperitoneal injection of luciferin. PBS, Cy5-CRT, and Cy5-CG7C were intravenously injected into the mice of each group respectively. The Cy5 signal was detected at 24 h, 36 h, 48 h post-injection. we successfully established stably expressing luciferase cell line, which luciferin intensity was positively correlated with cell number. Three weeks later, 12 of glioma orthotopic animals were divided into PBS, Cy5-CRT, Cy5-CG7C group. Signal analysis showed an 8-times increase of Cy5 signal intensity in Cy5-CRT group than other two groups. Our results showed that Cy5-CRT optical probe targeting transferrin receptor is sensitive and specific for detection of gliomas, and could be further investigation for its clinical application. Keywords: Molecular probe, Transferrin receptor, Glioma; Orthotopic animal model
Deletion Variants of CFHR1 and CFHR3 Associate with Mesangial Immune Deposits but Not with Progression of IgA Nephropathy
Authors: Perrine Jullien, Blandine Laurent, Guillaume Claisse, Ingrid Masson, Miriana Dinic, Damien Thibaudin, Francois Berthoux, Eric Alamartine, Christophe Mariat, Nicolas Maillard
Journal: Journal of the American Society of Nephrology (2017)

Export Activation of complement through the alternative pathway has a key role in the pathogenesis of IgA nephropathy (IgAN). Large, international, genome-wide association studies have shown that deletion of complement factor H–related genes 1 and 3 (CFHR3,1Δ) is associated with a reduced risk of developing IgAN, although the prognostic value of these deletions in IgAN remains unknown. Here, we compared the renal outcomes of patients with IgAN according to their CFHR3,1Δ genotype. This retrospective, monocentric cohort study included 639 white patients with biopsy-proven IgAN since 1979 (mean age at diagnosis, 40.1 years; median follow-up, 132 months). We determined the number of CFHR3 and CFHR1 gene copies by quantitative PCR and collected clinical and biologic data by reviewing the patients' medical records. In all, 30.5% of the patients were heterozygous and 4% were homozygous for CFHR3,1Δ. We did not detect an association between CFHR3,1Δ and age, eGFR, urinary protein excretion rate, or the presence of hypertension or hematuria at the time of diagnosis. The mean intensities of immune IgA, IgG, and C3 deposits were lower in the group with heterozygous or homozygous gene deletions than in those with no deletion. However, CFHR3,1Δ did not associate with progression to stage 3 CKD or renal death. In conclusion, the CFHR3,1Δ genotype did not associate with progression toward CKD stages 3 and 5 in our white population of patients with IgAN, although it did associate with a reduced level of glomerular immune deposits.
Clonal replacement and expansion among invasive meningococcal isolates of serogroup W in France
Authors: Eva Hong, Anne-Sophie Barret, Aude Terrade, Mélanie Denizon, Denise Antona, Myriam Aouiti-Trabelsi, Ala-Eddine Deghmane, Isabelle Parent du Châtelet, Daniel Levy-Bruhl, Muhamed-Kheir Taha
Journal: Journal of Infection (2017)
IMMU-58. IDH1 MUTATION REGULATES MYELOID CELLS MEDIATED IMMUNOSUPPRESSION IN GLIOMA
Authors: Mahmoud S Alghamri, Neha Kamran, Felipe J Nunez, Pedro R Lowenstein, Maria G Castro
Journal: Neuro-Oncology (2017)

the Cancer Genome Atlas network (TCGA).CD317 protein expression was assayed by immunohistochemistry in a human tissue microarray (TMA).In vitro, we assessed CD317 mRNA expression by RT-PCR and CD317 protein levels by flow cytometry in 13 human glioblastoma cell lines.A cytotoxicity assay after treatment with HM1.24-ETA' immunotoxin was performed in human glioblastoma cell lines.Finally, HM1.24-ETA' was evaluated in the intracranial human LN-229 glioma xenograft nude mouse model.RESULTS: Interrogations from the TCGA database showed increased CD317 mRNA expression in human glioblastoma compared to lower grade gliomas.In the group of glioblastoma patients enhanced CD317 mRNA expression was associated with decreased probability of survival (p<0.001).CD317 protein levels correlated directly with the tumor grade of astrocytic gliomas in the TMA.CD317 was expressed heterogeneously on mRNA and protein levels in the tested cell-lines.HM1.24-ETA' induced cytotoxicity in CD317-positive glioblastoma cells in a concentration-dependent manner.HM1.24-ETA' prolonged survival compared to the control-toxin (anti-kappa-ETA') in the LN-229 xenograft nude mouse model (median survival: 39 days compared to 19 days; p=0.017).CONCLUSION: These data underline CD317 as a valuable target for immunotherapy by HM1.24-ETA' for glioblastoma patients.
P2.03-051 The Impact of EGFR Mutations. Treatment with ITKs in Non-Small Cell Lung Cancer Patients
Authors: T. García Manrique, O. Saavedra, N. Palazón Carrión, C. Pérez Gago, J. Calvete, R. Carrillo, F.J. Valdivia García, D. Vicente Baz
Journal: Journal of Thoracic Oncology (2017)
ACTR-33. A PHASE I DOSE ESCALATION AND CENTRAL NERVOUS SYSTEM (CNS) PHARMACOKINETIC STUDY OF PULSATILE AFATINIB IN PATIENTS WITH BRAIN CANCER
Authors: Tiffany Juarez, Najee Boucher, Annie Heng, Jaya Gill, Minhdan Nguyen, Judy Truong, Marlon Saria, Achal Achrol, Garni Barkhoudarian, Daniel Kelly, Santosh Kesari
Journal: Neuro-Oncology (2017)

Patients with primary brain cancer or brain metastases represent a population with a large unmet medical need. The critical premise behind our investigation into pulse dosing of growth factor inhibitors for brain cancer is that current treatment is limited by drug penetration into the central nervous system (CNS). In general, CNS concentrations and exposure is expected to increase with increasing drug doses; however, safety limitations of daily dosing and systemic drug accumulation often preclude high enough levels of drug to penetrate the CNS. Pulse dosing could allow for much higher doses of drug administration to reach adequate therapeutic levels in the brain while also allowing a recovery period to mitigate toxicities. Afatinib is a small molecule, selective and irreversible ErbB family blocker selected for investigation of this strategy. This is a Phase I open-label, single-center, ‘3 + 3’ dose-escalation study (NCT02423525) to determine the safety and tolerability of pulsatile afatinib in patients with brain cancer and to define a recommended phase 2 dose. The study will also assess the exposure of afatinib in cerebrospinal fluid and serum, objective tumor response according to RANO criteria, progression-free survival and overall survival, and will explore the association between molecular phenotypes and patient response. Eligibility criteria include age >18 years, histologically confirmed brain cancer of any kind having failed prior therapy or having no available standard therapies, Karnofsky Performance Score of ≥ 60%, no interstitial lung disease, no history of poorly controlled gastrointestinal disorders, and no prior participation in a blinded afatinib clinical study. Afatinib is administered orally every four days (q4d) in escalating cohorts of 80mg, 120mg, 180mg, and 200mg until disease progression or unacceptable toxicity. Enrollment to two dose cohorts (80, 120mg q4d) is complete with no dose-limiting toxicities. The study is open to enrollment and results will be presented using descriptive statistics.