tbuckley/cabot-search huggingface dataset:
IMMU-14. IMPLICATIONS FOR T-CELL IMMUNOTHERAPY: CELL SURFACE ANTIGEN AND HLA class I EXPRESSION IN PEDIATRIC BRAIN TUMORS ARE HETEROGENOUS
Authors: Haley Houke, Suzanne J Baker, Martine F Roussel, Stephen Gottschalk, Giedre Krenciute
Journal: Neuro-Oncology (2019)

BACKGROUND: T cells immunotherapy holds the promise to improve outcomes for pediatric brain tumor patients. We have an interest in cell therapy with T cells expressing chimeric antigen receptors (CARs). CAR T cells recognize cell surface antigens. One goal of our study is to evaluate the cell surface expression of five potential CAR targets: IL13Ra2, HER2, EphA2, B7-H3, and GD2 in pediatric brain tumors. In addition, we wanted to determine HLA class I expression, to evaluate the possibility of targeting pediatric brain tumors with conventional T cells that require HLA class I expression for tumor cell recognition. METHODS: We established a flow cytometry-based method to profile CAR targets, and HLA class I expression from frozen pediatric patient derived xenograft (PDX) samples, which had never been cultured in vitro. We validated our method, antibodies and gating rules on established brain tumor cell lines before analyzing PDX samples. RESULTS: We have profiled 39 pediatric brain tumor PDX samples: 17 medulloblastomas, 5 ependymomas, 5 ATRT, 2 embryonal tumors, 6 HGG and 4 DIPG samples. We found that antigen expression has high intra- and inter-PDX sample variability with B7-H3 and IL13Ra2 being most consistently expressed. HLA class I was present on the cell surface of HGG and DIPG samples, however significantly down-regulated in 20 out of 29 other brain tumor types. CONCLUSION: To our knowledge this is the largest collection of pediatric brain tumor PDX samples that have been systematically analyzed for the expression of targetable cell surface antigens. Our results indicate that more than one antigen needs to be targeted to prevent the emergence of antigen loss variants. In addition, variable expression of HLA class I in the majority of pediatric brain tumors suggest that pediatric brain tumors have developed immune evasion strategies to prevent recognition by conventional T cells.
Radioluminescent nanoparticles for radiation-controlled release of drugs
Authors: Rahul Misra, Kaustabh Sarkar, Jaewon Lee, Vincenzo J. Pizzuti, Deborah S. Lee, Melanie P. Currie, Sandra E. Torregrosa-Allen, David E. Long, Gregory A. Durm, Mark P. Langer, Bennett D. Elzey, You-Yeon Won
Journal: Journal of Controlled Release (2019)
GENE-03. CASE REPORT: CHOROID PLEXUS CARCINOMA TREATED WITH STEREOTACTIC RADIOSURGERY IN 2-YEAR-OLD WITH LI FRAUMENI SYNDROME
Authors: Eva Galvan, Richard Crownover
Journal: Neuro-Oncology (2019)

CASE REPORT: The child was diagnosed with choroid plexus carcinoma (CPC) at age 8 months. The tumor was positive for TP53 genomic alteration. Germline genetic test sent at age 10 months returned positive for heterozygous TP53 pathogenic mutation. She underwent surgical resection, chemotherapy, and repeat resection at 13 months. At 31 months, she had three small nodules concerning for recurrent disease surrounding the large surgical cavity. Repeat surgical resection was declined by her family. She therefore underwent stereotactic radiosurgery (SRS) to each lesion to a dose of 24 Gy in 1 fraction. Anesthesia was required at the time of planning CT simulation and at the time of treatment. At one year since the procedure, she has demonstrated no further recurrent disease and no evidence of secondary malignancy at this time. DISCUSSION: Retrospective studies approximate rates of p53 mutations in children with CPC at 40%. Radiation is avoided—unless absolutely necessary—in children less than 3 years old because of the risks of neurocognitive delay, endocrine and growth toxicities, and the risk of secondary malignancies. Patients with Li Fraumeni syndrome have further dramatic increase in rates of developing secondary malignancies after exposure to ionizing radiation. SRS provides dose escalation while minimizing ionizing radiation dose to normal surrounding tissue. CONCLUSIONS: Any child diagnosed with CPC should undergo genetic testing for p53 germline mutation because of high pre-test probability. In selected cases, SRS provides an alternative to surgery as local control for limited CPC. SRS minimizes the dose of ionizing radiation delivered to normal tissues in patients with p53 mutation, or in young patients in whom less-focused radiation techniques may cause increased negative neurocognitive effects. Because of the short treatment course, SRS also minimizes the number of days under anesthesia required for young patients, thereby minimizing risk incurred by repeated anesthetic requirements.
Confronting My Bias
Authors: Megan B. Richie
Journal: JAMA Neurology (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Neurology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Neurology journal
IMMU-12. NOVEL APPROACH FOR THE TREATMENT OF PEDIATRIC HIGH-GRADE GLIOMAS WITH THE COMBINATION OF ONCOLYTIC ADENOVIRUSES AND GENE THERAPY ENCODING A BiTE DIRECTED TO THE EphA2 TUMOR ANTIGEN.
Authors: Claudia Manuela Arnone, Tamascia Belardinilli, Angela Mastronuzzi, Vinicia Polito, Antonella Cacchione, Andrea Carai, Francesca Diomedi Camassei, Marco Scarsella, Concetta Quintarelli, Biagio De Angelis, Franco Locatelli, Ignazio Caruana, Francesca Del Bufalo
Journal: Neuro-Oncology (2019)

Pediatric high-grade gliomas (pHGG) are amongst the most common malignant neoplasms of childhood, whose outcome remains dismal with conventional treatments. New therapeutic approaches are urgently needed. Immunotherapy based on Oncolytic Adenovirus(OA)is a promising strategy but its efficacy is suboptimal. We aimed at improving the antitumor efficacy by combining the OA and a gene-therapy with the Bibispecific T-cell Engager (BiTE) directed towards the erythropoietin-producing human hepatocellular carcinoma A2-receptor (EphA2),conveyed by a replication-incompetent adenoviral vector (EAd). We demonstrated, by immunohistochemistry and qPCR, the expression of EphA2 in 100% (16/16) of the pHGGs, its intensity correlating significantly with a worst outcome. We then tested the transgene amplification, after co-infection, on two HGG cell lines (U373, U87) by qPCR and Flow Cytometry (FACS) for the selectable marker ∆CD19, confirming a significantly enhanced production in OA+EAd vs EAd alone (p<0.01 and p<0.001, respectively). Notably, the FACS analysis of the infected tumor cells after 5 days of co-culture with T-cells showed a significantly increased apoptosis in the OA+EAd compared to the controls (p<0.001). To obtain the tumor eradication, we then fully activated the T-cells by including an anti-CD28 antibody (αCD28), revealing a further apoptosis enhancement. We then characterized the T-cell populations by FACS analysis showing a significant increase of activation and non-exhaustion markers and the addition of the αCD28 was able to induce a significantly higher production of interferon-γ in EAd or OA+EAd conditions. Finally, we established an orthotopic HGG mouse model and administered OA/Ead/OA+EAd and T cells intracranially. Preliminary data show that the treatment is well tolerated and that the EphA2-BiTE improves tumor control compared to the control groups. In conclusion, the combinatorial approach is able to amplify the production of the BiTE and to determine an effective tumor control in the presence of T-cells and αCD28, representing a promising innovative treatment.
Mechanisms involved in IL-15 superagonist enhancement of anti-PD-L1 therapy
Authors: Karin M. Knudson, Kristin C. Hicks, Sarah Alter, Jeffrey Schlom, Sofia R. Gameiro
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Immunotherapy targeting PD-1/PD-L1 fails to induce clinical responses in most patients with solid cancers. N-803, formerly ALT-803, is an IL-15 superagonist mutant and dimeric IL-15RαSushi-Fc fusion protein complex that enhances CD8<sup>+</sup> T and NK cell expansion and function and exhibits anti-tumor efficacy in preclinical models. Previous in vitro studies have shown that IL-15 increases PD-L1 expression, a negative regulator of CD8<sup>+</sup> T and NK cell function. Most reported preclinical studies administered N-803 intraperitoneally not subcutaneously, the current clinical route of administration. N-803 is now being evaluated clinically in combination with PD-1/PD-L1 inhibitors. However, the mechanism of action has not been fully elucidated. Here, we examined the anti­tumor efficacy and immunomodulatory effects of combining N-803 with an anti-PD-L1 antibody in preclinical models of solid carcinomas refractory to anti-PD-L1 or N-803. <h3>Methods</h3> Subcutaneous N-803 and an anti-PD-L1 monoclonal antibody were administered as monotherapy or in combination to 4T1 triple negative breast and MC38-CEA colon tumor-bearing mice. Anti-tumor efficacy was evaluated, and a comprehensive analysis of the immune-mediated effects of each therapy was performed on the primary tumor, lung as a site of metastasis, and spleen. <h3>Results</h3> We demonstrate that N-803 treatment increased PD-L1 expression on immune cells in vivo, supporting the combination of N-803 and anti-PD-L1. N-803 plus anti-PD-L1 was well-tolerated, reduced 4T1 lung metastasis and MC38-CEA tumor burden, and increased survival as compared to N-803 and anti-PD-L1 monotherapies. Efficacy of the combination therapy was dependent on both CD8<sup>+</sup> T and NK cells and was associated with increased numbers of these activated immune cells in the lung and spleen. Most alterations to NK and CD8<sup>+</sup> T cell phenotype and number were driven by N-803. However, the addition of anti-PD-L1 to N-803 significantly enhanced CD8<sup>+</sup> T cell effector function versus N-803 and anti-PD-L1 monotherapies, as indicated by increased Granzyme B and IFNγ production, at the site of metastasis and in the periphery. Increased CD8<sup>+</sup> T cell effector function correlated with higher serum IFNγ levels, without related toxicities, and enhanced anti-tumor efficacy of the N-803 plus anti-PD-L1 combination versus either monotherapy. <h3>Conclusions</h3> We provide novel insight into the mechanism of action of N-803 plus anti-PD-L1 combination and offer preclinical proof of concept supporting clinical use of N-803 in combination with checkpoint inhibitors, including for patients non- and/or minimally responsive to either monotherapy.
The short-chain fatty acid propionate increases glucagon and FABP4 production, impairing insulin action in mice and humans
Authors: Amir Tirosh, Ediz S. Calay, Gurol Tuncman, Kathryn C. Claiborn, Karen E. Inouye, Kosei Eguchi, Michael Alcala, Moran Rathaus, Kenneth S. Hollander, Idit Ron, Rinat Livne, Yoriko Heianza, Lu Qi, Iris Shai, Rajesh Garg, Gökhan S. Hotamisligil
Journal: Science Translational Medicine (2019)

Propionate activates the insulin counter-regulatory hormonal response in mice, resulting in insulin resistance and weight gain.
THER-09. EVALUATION OF PROTEIN KINASE INHIBITORS WITH PLK4 CROSS-OVER POTENTIAL IN PEDIATRIC EMBRYONAL BRAIN TUMORS
Authors: Anders Bailey, Amreena Suri, Maurício Tavares, Saktimayee Roy, Tadanori Tomita, Alan Kosikowski, Daniel Watterson, Simone Sredni
Journal: Neuro-Oncology (2019)

BACKGROUND: In previous work we established that PLK4 is overexpressed and essential for proliferation and survival of pediatric embryonal brain tumors. PLK4 is a cell cycle-regulated protein recruited at the centrosome in dividing cells. Its overexpression triggers centrosome amplification, which is associated with genetic instability and carcinogenesis. We demonstrated that PLK4 inhibition exerts a potent cytostatic effect in EBT. We also established the synergism of the PLK4 inhibitor CFI-400945 with cytotoxic drugs and other signal transduction modulators. METHODS: We studied protein kinase inhibitors (PKI) with PLK4 cross-over potential (CFI-400945, CFI-400437, centrinone, centrinone-B, R-1530, axitinib, alisertib and KW-2449) by assessing their chemical profiles through docking simulations over PLK4 (PDB entry: 3COK) using Gold 5.4 software; evaluating their potential to penetrate the BBB (via logBB calculation by Clark equation), performing LanthaScreen EU Kinase Binding assays (ThermoFisher Scientific) and cell based studies (viability and proliferation) in multiple embryonal tumor cell lines (MON, BT-12, BT-16, DAOY, D283). RESULTS: Kinase binding assays and cell based studies showed that CFI-400437 was the most effective compound, yielding an IC50 <5nM in the binding assay and requiring <100nM of drug to significantly inhibit proliferation in multiple cell lines. However, docking simulations using the PLK4 catalytic cavity and each of the various PKIs demonstrated that all of the inhibitors tested exhibit similar interactions within the binding cavity, engaging in H-bonding with backbone residues Glu-89 and Cys-91. Additional polar and hydrophobic (π-stacking) interactions were also identified for each of the PKIs. LogBB calculations revealed that compound R-1530 has the greatest likelihood to enter the brain (LogBB+0.130). CONCLUSION: Although CFI-400945 is the most effective PLK4 inhibitor among those assayed, it has low potential for BBB exposure. Molecular docking results indicate the potential to develop new chemical entities with higher BBB exposure potential using a similar binding mode to that of CFI-400945.
Role of urine immunofixation in the complete response assessment of MM patients other than light-chain-only disease
Authors: Juan-José Lahuerta, Ana Jiménez-Ubieto, Bruno Paiva, Joaquín Martínez-López, José González-Medina, Lucía López-Anglada, María-Teresa Cedena, Noemi Puig, Albert Oriol, María-Jesús Blanchard, Rafael Ríos, Jesús Martin, Rafael Martínez, Anna Sureda, Miguel Teodoro Hernández, Javier de la Rubia, Isabel Krsnik, Valentín Cabañas, Luis Palomera, Joan Bargay, María-Victoria Mateos, Laura Rosiñol, Jesús F. San Miguel, Joan Blade
Journal: Blood (2019)
Tamoxifen restores extracellular trap formation in neutrophils from patients with chronic granulomatous disease in a reactive oxygen species–independent manner
Authors: Atul Sharma, Katelyn McCann, Jitendra Kumar Tripathi, Pooja Chauhan, Christa Zerbe, Bibhuti B. Mishra, Steven M. Holland, Jyotika Sharma
Journal: Journal of Allergy and Clinical Immunology (2019)
Abstract 20203: Relationship Between the Lesion Gap Assessed by DE-MRI and the Re-conduction Site in 2nd AF Ablation Procedure
Authors: Kunihiko Kiuchi, Koji Fukuzawa, Shumpei Mori, Kiyohiro Hyogo, Hiroshi Imada, Jun Kurose, Tomomi Akita, Hideya Suehiro, Yu-ichi Nagamatsu, Yasusyo Taniguchi, ken-ichi Hirata, Yoshiaki Watanabe, Shinsuke Shimoyama, Noriyuki Negi, Katsusuke Kyotani
Journal: Circulation (2017)

Introduction: Delayed enhancement magnetic resonance imaging (DE-MRI) was reported to visualize the prior ablation lesion. However, the relationship between the lesion gap assessed by the DE-MRI and the re-conduction site has not been well discussed. We sought to investigate whether the DE-MRI could predict the re-condition site of pulmonary vein isolation (PVI) line. Methods: A total of 11 patients in 2nd AF procedure were enrolled in this study (mean age: 69 ±9 years old, mean left atrial diameter: 39 ±5 mm). The prior ablation was performed by a conventional catheter with radiofrequency (RF) energy and a point-by-point fashion. The DE-MRI was performed in all patients and the PVI lesion was three-dimensionally reconstructed and visualized by 3D work station (ZIO station or AZE virtual place). The lesion was assessed in a total of 176 segments around PV. The lesion gap was defined as a segment including no delayed enhancement site with a length of >4mm. Results: The lesion gaps could be visualized in 65...
Taking KLF9 to “Cort” for crimes against metabolism
Authors: David R. Sweet, Liyan Fan, Mukesh K. Jain
Journal: Journal of Clinical Investigation (2019)

Glucocorticoids (GCs) are essential for proper glycemic control, but in excess, can lead to hyperglycemia and diabetes. In this issue of the JCI, Cui et al. elucidate a mechanism by which GCs regulate gluconeogenesis utilizing the transcription factor Krüppel-like factor 9 (KLF9) in physiology and disease settings. They report that KLF9 is a GC-inducible factor that ultimately increases the transcription of proliferator-activated receptor γ coactivator 1 α (PGC1α), resulting in gluconeogenesis. Given the high incidence of GC-induced diabetes, identification of this signaling axis provides, not only critical scientific insight, but also a foundation for preventative therapies for patients receiving chronic GC treatment.
Low Dynamic Compliance May Indicate Expiratory Flow Limitation In Healthy Infants
Authors: D. Czovek, L. Willemse, B. Radics, G. Makan, A. Visagie, Z. Gingl, G. L. Hall, P. D. Sly, H. J. Zar, Z. Hantos, D. Gray
Journal: American Journal of Respiratory and Critical Care Medicine (2016)
Breast cancer metastasis suppressor 1 (BRMS1) expressing MDA-MB-435 cells have significantly reduced levels of phosphatidylinositol 4,5 bisphosphate (PtdIns(4,5)P2).
Authors: Danny R. Welch, Javad Torabinejad, Rajeev S. Samant, Nuray Erin, Derrick Johnston, Daryll B. Dewald
Journal: Cancer Research (2004)

2433  BRMS1 suppresses metastasis of human (MDA-MB-435, MDA-MB-231, C8161) and murine cell lines (66cl4, 4T1) without suppressing tumorigenicity. The BRMS1 protein is physically associated with components of mSin3-histone deacetylase complexes and has been shown to alter transcription of some genes. Since transcriptional machinery is modulated in response to cellular signals, and since BRMS1-transfected cells show differential growth patterns (i.e., cells progressively proliferate in the mammary fat pad but do not proliferate in lungs), we hypothesized that some signaling pathways might be affected by BRMS1 restoration as well. In six independent experiments, MDA-MB-435 cells, vector-only transfectants and BRMS1 transfectants (435BRMS1) were labeled with myo-[3H]inositol and PtdIns head groups were analyzed by HPLC. Parental and vector-only transfectant patterns were virtually identical. However, 435BRMS1 cells showed a significant (
NHS reorganisation in 2013 led to fall in cervical screening uptake, study finds
Authors: Elisabeth Mahase
Journal: BMJ (2019)

England’s reorganisation of primary care trusts into clinical commissioning groups (CCGs) in 2013 led to a reduction in cervical screening uptake, a study has found.1

Areas that experienced more disruption from the introduction of the Health and Social Care Act 2012—for example, where CCGs were working with multiple local authorities rather than a single authority—had the biggest decline in cervical screening rates, found an …
ATRT-03. EFFICACY OF THE ONCOLYTIC ADENOVIRUS DELTA-24-RGD AS A THERAPEUTIC AGENT FOR THE TREATMENT OF PEDIATRIC EMBRYONAL BRAIN TUMORS
Authors: Marc Garcia-Moure, Marisol Gonzalez-Huarriz, Lucia Marrodan, Montserrat Puigdelloses, Ana Patiño-Garcia, Marta M Alonso
Journal: Neuro-Oncology (2019)

Atypical teratoid/rhabdoid tumors (ATRTs) and primitive neuroectodermal tumors (PNETs) are two rare primary embryonal brain tumors, which are among the most frequent solid brain tumors in infants under one year old. The outcome for these children remains dismal, especially in ATRTs which have a 2-year overall survival below 20%. Therefore, we need to find out new efficient and safe therapeutic options for these children. Delta-24-RGD (DNX-2401 in the clinic) is an oncolytic adenovirus that has already been tested in Phase I/II clinical trials in patients affected by recurrent glioblastoma (NCT00805376; NCT01956734), demonstrating anti-tumor effect without any evidence of severe side effect associated with viral administration. Of interest for pediatric brain tumors, an ongoing Phase I trial using Delta-24-RGD for the treatment of diffuse intrinsic pontine gliomas (NCT03178032) has also demonstrated a safe profile in these children. For these reasons, we propose to evaluate the anti-tumor effect of Delta-24-RGD in preclinical models of ATRT and PNET. The virus was able to infect and replicate in tumor cell cultures (three models of ATRT and four of PNET), inducing a potent cytotoxic effect. In addition, this cytotoxicity resulted in the released the immunogenic cell death markers Hsp70, Hsp90, HMGB1 and ATP, as well as an increased calreticulin exposure in the outer cell surface. Although not conclusive, the presence of these markers suggest the triggering of an anti-tumor immune response. Intratumoral administration of the virus extended significantly the overall survival of mice bearing ATRT or PNET xenografts, leading to up to 40% of long-term survivors. We are currently setting up an intraventricular model of disseminated disease, since most of patients with ATRT actually die due to the presence of metastases. In conclusion, these results demonstrate that Delta-24-RGD could be a feasible therapeutic option for children with PNETs and AT/RTs.
Abstract 15786: Deficiency of Axon-Guidance Molecule SLIT3 Attenuates Pressure Overload-Induced Left Ventricular Hypertrophy and Failure
Authors: Lianghui Gong, Shuyun Wang, Li Shen, Yifeng Yang, Dingding Xiong, Ming-Sing Si
Journal: Circulation (2018)

Introduction: The secreted axon-guidance molecule SLIT3 is important for heart development. SLIT3 has also been demonstrated to stimulate endothelial cells and angiogenesis and is widely expressed ...
Abstract 15740: Cardiac Magnetic Resonance Imaging Predictors of Ventricular Arrhythmia in Tetralogy of Fallot
Authors: Angela J Weingarten, Jonathan H Soslow, Larry W Markham
Journal: Circulation (2016)

Introduction: Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart defect. Surgical management has resulted in dramatic improvements in mortality; however, burden of both atrial a...
Additional Approaches to Treatment of Depression
Authors: Robert M. Carney
Journal: JAMA (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal