tbuckley/cabot-search huggingface dataset:
Immune adjuvant activity of Barrogen, a novel immunomodulatory protein
Authors: Charles F. Aylsworth, David Juckett, Barnett Rosenberg
Journal: Cancer Research (2006)

3883  The recombinant immunomodulatory Eimeria antigen (EA) protein (Barrogen) has demonstrated remarkable immunotherapeutic activity against experimental transplantable tumors and appears to be a potent stimulator of the innate immune system (Rosenberg et. al., Int. J. Cancer 114:756-765, 2005). Nearly 100% cure rates are observed in mice treated with ng doses of Barrogen immediately following tumor transplantation. In addition, elevated systemic levels of IL-12p70 and other pro-inflammatory cytokines are associated with Barrogen treatment both in vivo and in vitro. The cellular mechanism of action of Barrogen is thought to be mediated through the activation of dendritic cells, which are central to the induction of both innate and adaptive immune responses. To examine the activity of Barrogen in the induction of adaptive immune responses in vivo we examined the effect of Barrogen treatment in conjunction with a tumor vaccine prior to the transplantation of a lethal dose of tumor (S180) cells. Male Balb/c mice were treated as follows: (1) Sham injected with vehicle controls; (2) Injected (ip) with an S180 tumor vaccine in the form of a whole tumor cell homogenate (TuAg) 19 days prior to S180 tumor cell transplantation; (3) Injected (ip) with Barrogen alone (10ng per mouse) 19, 16, 12 and 9 days prior to S180 tumor cell transplantation; (4) Injected with both TuAg 19 days prior to and Barrogen (10 ng per mouse) 19, 16, 12 and 9 days prior to S180 tumor cell transplantation. Survival rates were observed for 90 days following tumor cell transplantation. Sham injected mice or mice treated with Barrogen alone had 0% survival. 25% of the mice treated with the TuAg alone survived. However, 75% of the mice treated with both TuAg and Barrogen survived suggesting that Barrogen in conjunction with a tumor vaccine can result in effective protection against a lethal tumor challenge by enhancement of the adaptive immune system. There was a 2-fold increase in spleen weights in mice treated with both TuAg and Barrogen when compared with mice treated with TuAg or Barrogen alone. In a separate experiment, large granular lymphocytes (LGLs) were isolated from the spleens of mice treated as described above. LGLs were co-cultured with S180 tumor cells in an in vitro assay to assess cell-mediated cytotoxicity against S180 cells. A significant increase in the number and percentage of S180-specific cytolytic lymphocytes was observed in LGLs isolated from the spleens of mice treated with the combination of Barrogen and TuAg compared with mice treated with TuAg or Barrogen alone. These results indicated that in addition to previous reports describing Barrogen-induced activation of the innate immune system, Barrogen can also stimulate adaptive immune responses, suggesting that Barrogen may be useful as an effective adjuvant to stimulate adaptive immune responses against cancer cells.
Variants in STAT4 Associated With Cure of Chronic HBV Infection in HBeAg-positive Patients Treated With Pegylated Interferon-alpha
Authors: Haitao Chen, Jian Sun, Bin Zhou, Qing Xie, Xier Liang, Rong Fan, Carly Conran, Jianfeng Xu, Yuan Ji, Xinxin Zhang, Li Sun, Jidong Jia, Guiqiang Wang, Jinlin Hou, De-Ke Jiang
Journal: Clinical Gastroenterology and Hepatology (2019)
Malawi launches first malaria vaccination programme for children
Authors: Elisabeth Mahase
Journal: BMJ (2019)

The Malawi government has launched a pilot programme for the world’s first malaria vaccine.1

The programme, which will also include Ghana and Kenya in the next few weeks, aims to vaccinate 360 000 children under two years old annually across the three countries. It will focus on areas with moderate to high malaria transmission.

Malaria kills 435 000 people a year globally, over 250 000 …
Abstract 21007: Role of Thick Fibrotic Tissue in the Left Atrium on the Outcome of Atrial Fibrillation Ablation
Authors: Mobin Kheirkhahan, Alex Baher, Johannes Siebermair, Gagandeep Kaur, Benjamin A Steinberg, Frederick T Han, Mihail G Chelu, Nassir F Marrouche
Journal: Circulation (2017)

Introduction: Left Atrial (LA) Fibrosis may serve as a substrate for Atrial Fibrillation (AF) and the total percentage of LA fibrosis affects the outcome of ablation therapy. But the role of “thick” (transmural or near transmural) fibrotic tissue, as opposed to superficial fibrosis, in the AF prognosis is not well studied. We assess the amount of LA wall fibrosis thickness on AF ablation outcome. Methods and Results: Patients’ parameters were obtained from DECAAF trial. LA fibrosis was quantified with Late Gadolinium Enhancement MRI (LGE-MRI) and when within LA myocardium, 3 or more voxels (each voxel = 0.625mm) were enhanced that area was considered as thick fibrotic tissue. First Cox regression was devised to measure the impact of thick fibrosis on the outcome of AF ablation. Then patients were divided into 2 groups: First group with more than 3.89% of thick LA fibrosis and the second group with less than that. This cut-off was achieved through Receiver Operation Curve analysis of our cohort. Patients were 58.9 ± 10.9 of age and their amount of thick LA fibrosis was 3.5% ± 2.4%. The result of Cox regression showed: 1% increase in the extent of thick LA fibrosis, the recurrence rate of AF increases by 20% after ablation. (HR = 1.2, CI 95% = 1.1 - 1.3, P &lt; 0.0001). The first and second group matched in terms of age, gender, LA volume, and co-morbidities. The first group were 2.9 times more at risk for AF recurrence after the ablation (CI95% = 1.9 - 4.5, P &lt; 0.001) and they had a significantly lower chance of remaining AF free after ablation (0.385 vs 0.621, P &lt; 0.0001) Conclusions: We found the percentage of LA wall fibrosis thickness to correlate with a worse AF ablation outcome and an increased risk of AF recurrence. Therefore assessing percentage of thick fibrotic tissue within LA wall may be of a greater interest than assessing total percentage of fibrosis.
Abstract 16990: Impact of 2013 ACC/AHA Cholesterol Management Guidelines on Statins Use Among Nationally Representative Adult Populations in United States: Medical Expenditure Panel Survey (2010-2015)
Authors: Joseph A Salami, Anshul Saxena, Haider Warraich, Rohan Khera, Victor Okunrintemi, Javier Valero-Elizondo, Michael J Blaha, Ron Blankstein, Salim S Virani, Emir Veledar, Harlan M Krumholz, Khurram Nasir
Journal: Circulation (2018)

Background: The 2013 American College of Cardiology/American Heart Association (ACC/AHA) Cholesterol Management Guidelines recommended statin as the first-line lipid-lowering therapy (LLT) for primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD). We aim to examine the impact of the guidelineson statin use in the US. Methods: Using the2010-2015 Medical Expenditure Panel Survey (MEPS) data, we estimated trends in statin utilization in adults age 40-75 years in 4 defined groups: (1) All adults, adults with: (2) established ASCVD, (3) diabetes mellitus [DM] and no ASCVD and, (4) estimated 10-year risk &gt;=7.5% in absence of ASCVD and DM. Joint-point regression (JPR) analysis was used to examine changes in statin use trend around the period of the guideline’s publication. Results: We found no statistically significant change in statin use. (Figure) The use of any statin therapy in 2010-2012 ranged from 24.6 to 25.1%, and 24.6 to 25.1% in 2014-2015 among all adults. Statin use among those with ASCVD ranged from 58.8 to 56.6% (2010-2012) and 56.7-57.8% (2014-2015). Similar trends were noted in our two other study groups. However, a significantly higher proportion of statin users among established ASCVD patients reported use of high intensity doses: 34.3 to 38.1% post- versus 29.6 to 31.6% pre-guideline publication with an average annual percentage change (AAPC) of 4.9 (95% CI: 2.9-6.9). (Figure) Joint point regression showed no statistically significant inflection in the trend line of all and high-intensity statin use in any of the study groups after guideline publication. Conclusion: There was a mild increase in high-intensity statin use after the 2013 ACC/AHA guidelines release, but no impact on overall statin use in US two years after publication. Barriers to guideline adoption and opportunities to increase the impact of guidelines on clinical practice need to be investigated.
Single-Agent Ibrutinib Versus Chlorambucil-Obinutuzumab As First-Line Treatment in Patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (CLL/SLL): Results of a Cross-Trial Comparison
Authors: Alessandra Tedeschi, Richard Greil, Fatih Demirkan, Tadeusz Robak, Carol Moreno, Paul Barr, Bertrand Anz, David Simpson, Gianluca Gaidano, Osnat Bairey, Don Stevens, Devinder Gill, Ian W. Flinn, Thomas J. Kipps, Jan A. Burger, Jennifer Lin, Thomas Webb, Viktor Fedorov, Lori Styles, John G. Gribben
Journal: Blood (2018)
A review of bispecific antibodies and antibody constructs in oncology and clinical challenges
Authors: Frans V. Suurs, Marjolijn N. Lub-de Hooge, Elisabeth G.E. de Vries, Derk Jan A. de Groot
Journal: Pharmacology & Therapeutics (2019)

Bispecific antibodies (bsAbs) are antibodies that bind two distinct epitopes to cancer.. For use in oncology, one bsAb has been approved and 57 bsAbs are in clinical trials, none of which has reached phase 3. These bsAbs show great variability in design and mechanism of action. The various designs are often linked to the mechanisms of actions. The majority of bsAbs engage immune cells to destroy tumor cells. However, some bsAbs are also used to deliver payloads to tumors or to block tumor signaling pathways. This review provides insight into the choice of construct for bsAbs, summarizes the clinical development of bsAbs in oncology and identifies subsequent challenges.
Ethical Criteria for Health-Promoting Nudges: A Case-by-Case Analysis
Authors: Bart Engelen
Journal: The American Journal of Bioethics (2019)

Health-promoting nudges have been put into practice by different agents, in different contexts and with different aims. This article formulates a set of criteria that enables a thorough ethical evaluation of such nudges. As such, it bridges the gap between the abstract, theoretical debates among academics and the actual behavioral interventions being implemented in practice. The criteria are derived from arguments against nudges, which allegedly disrespect nudgees, as these would impose values on nudgees and/or violate their rationality and autonomy. Instead of interpreting these objections as knock-down arguments, I take them as expressing legitimate worries that can often be addressed. I analyze six prototypical nudge cases, such as Google's rearrangement of fridges and the use of defaults in organ donation registration. I show how the ethical criteria listed are satisfied by most-but not all-nudges in most-but not all-circumstances.
HGG-27. CLINICAL ANALYSIS OF CHOROID PLEXUS TUMORS
Authors: Yoshiko Nakano, Ryuta Saito, Masahiro Kanamori, Atsushi Kawamura, Taishi Nakamura, Yuko Watanabe, Yasuhiro Matsusaka, Noritsugu Kunihiro, Keiko Okada, Junichi Hara, Hiroaki Sakamoto, Koichi Ichimura
Journal: Neuro-Oncology (2019)

BACKGROUND: Choroid plexus tumors (CPT) includes choroid plexus papilloma (CPP), atypical choroid plexus papilloma (aCPP), and choroid plexus carcinoma (CPC). Because of its rarity, limited data are available on the current status of treatment and outcomes for pediatric CPTs. METHOD: Clinical data on patients with CPT aged between 0 and 30 years at diagnosis treated in 4 institutions in Japan were retrospectively reviewed. RESULTS: Twenty-seven pts were pathologically diagnosed with CPT. One individual who was initially diagnosed with CPC developed a rhabdoid tumor of the kidney, and the diagnosis was changed to AT/RT. The remaining 26 pts were further analyzed. Median age at diagnosis was 1 year (0 to 25). The mean follow-up period was 8.1 years (range: 0.2 to 24 years). All pts with CPP (n=11) underwent gross-total resection without adjuvant therapy, and none of them experienced relapse. Of the 7 pts with aCPP, 3 experienced relapse. Two pts with local relapse were alive after salvage surgery, while one pt died of the disseminated disease. Regarding pts with CPC (n=8), 7 pts received surgery followed by adjuvant chemotherapy and radiotherapy. Two pts survived without evidence of disease. Six pts relapsed, three of whom died with disseminated disease and the other three achieved remission without dissemination. OS and EFS of CPC pts at 10 years were 58% and 15%, respectively. Two patients were diagnosed with Li-Fraumeni syndrome (LFS). One LFS patient with CPC was alive with a follow-up of three years and the other was died of medulloblastoma after complete remission of aCPP. CONCLUSION: Compared with the excellent prognosis of CPP, the survival rates for CPC and aCPP are unsatisfactory. Molecular analysis to correlate with clinical data is underway. IMMUNOLOGY/IMMUNOTHERAPY
THER-19. MACHINE LEARNING APPROACH TO TUMOR DIAGNOSIS USING SMALL DATASETS: PROOF OF PRINCIPLE USING PEDIATRIC ADAMANTINOMATOUS CRANIOPHARYNGIOMA
Authors: Eric Prince, Ros Whelan, Trinka Vijmasi, Susan Staulcup, Paul Klimo, David Mirsky, Nicholas Stence, Todd Hankinson
Journal: Neuro-Oncology (2019)

Advances in Artificial Intelligence (AI) have rapidly become well known through the mainstream media, with myriad applications. Most commonly, AI has been leveraged for problems that possess vast amounts of sample data, as this enables AI models to better generalize patterns within the data. We hypothesized that novel computational methods could allow AI technologies to be applied to topics with more limited amounts of data, such as pediatric brain tumors. Craniopharyngioma, which has a frequency of approximately 2 in 1,000,000 children per year, requires very different treatment algorithms than other mass lesions that commonly present in the same anatomical region. As such, a prioriconfidence regarding the diagnosis of ACP would offer a distinct advantage to healthcare providers, patients, and caregivers. This makes ACP an idea model to test the application of novel AI methods. Through our collected multi-institutional dataset of CT and MRI comprising approximately 100 ACP patients controlled against 100 patients diagnosed with other suprasellar lesions, we demonstrate that state-of-the-art networks can correctly identify ACP with accuracy levels exceeding 88%, which we demonstrate to be comparable or better than current diagnostic techniques. Using concepts such as data scaling, synthetic data expansion, image augmentation, transfer-learning, and fine-tuning, this preliminary work demonstrates the reliable application of AI models towards topics with restricted volumes of data.
THER-30. COMBINATION TOCA 511 &amp; 5-FC SIGNIFICANTLY EXTENDS SURVIVAL IN A MURINE ORTHOTOPIC MODEL OF INTRACEREBELLAR MEDULLOBLASTOMA
Authors: Angela Richardson, Sara Collins, Akhito Inagaki, Valerie Armstrong, Martine Roussel, David Robbins, Nagy Ayad, Douglas Jolly, Noriyuki Kasahara
Journal: Neuro-Oncology (2019)

Toca 511, a clinical-stage tumor-selective retroviral replicating vector (RRV) encoding an optimized yeast cytosine deaminase (CD) prodrug activator gene, in combination with Toca FC (extended-release 5-fluorocytosine (5-FC)), produces 5-fluorouracil (5-FU) within infected cancer cells, which in preclinical models has also been shown to kill immunosuppressive myeloid cells in the tumor microenvironment, leading to anti-cancer immune activation and long-term survival. This combination treatment is under evaluation in a registrational Phase 3 trial in patients with recurrent high-grade glioma. Here, we investigated the feasibility of applying Toca 511 & Toca FC to medulloblastoma, the most common malignant tumor of the pediatric nervous system. Established (HDMB03, DAOY) and primary (PDX10) human medulloblastoma cells were transduced with RRVs encoding either Emerald green fluorescent protein reporter (RRV-EMD) or the CD enzyme (RRV-CD, i.e. Toca 511). RRV replication in vitro, examined by flow cytometry for EMD fluorescence, showed spread to >90% of cells in culture by day 10 post-inoculation. In contrast to non-transduced or RRV-EMD-transduced controls, RRV-CD-transduced medulloblastoma cells exhibited significant dose-dependent reduction of viability upon exposure to 5-FC, as measured by MTS assay. In vivo, stereotactic intracerebellar implantation of HDMB03 cells into nude mice without treatment resulted in cell dose-dependent median survival time and eventual 100% lethality at all cell doses tested, with median survival of 28 days after implantation of 1x10^5 tumor cells. In this orthotopic medulloblastoma model, mice with RRV-CD-transduced intracerebellar HDMB03 tumors exhibited long-term survival upon 5-FC treatment, as compared to mice treated with PBS or implanted with non-transduced cells (p=0.00007). No deaths occurred in these mice with RRV-CD-transduced HDMB03 tumors while on sequential cycles of 5-FC prodrug, until prodrug treatment was stopped, after which 25% long-term survival was observed (median survival 110 days). The results of this proof-of-concept study support further preclinical investigation of RRV-CD-mediated prodrug activator gene therapy for this pediatric malignancy.
Positron Emission Tomography Detects <i>In Vivo</i> Expression of Disialoganglioside GD2 in Mouse Models of Primary and Metastatic Osteosarcoma
Authors: Elizabeth R. Butch, Paul E. Mead, Victor Amador Diaz, Heather Tillman, Elizabeth Stewart, Jitendra K. Mishra, Jieun Kim, Armita Bahrami, Jason L.J. Dearling, Alan B. Packard, Shana V. Stoddard, Amy L. Vāvere, Yuanyuan Han, Barry L. Shulkin, Scott E. Snyder
Journal: Cancer Research (2019)

The cell membrane glycolipid GD2 is expressed by multiple solid tumors, including 88% of osteosarcomas and 98% of neuroblastomas. However, osteosarcomas are highly heterogeneous, with many tumors exhibiting GD2 expression on <50% of the individual cells, while some tumors are essentially GD2-negative. Anti-GD2 immunotherapy is the current standard of care for high-risk neuroblastoma, but its application to recurrent osteosarcomas, for which no effective therapies exist, has been extremely limited. This is, in part, because the standard assays to measure GD2 expression in these heterogeneous tumors are not quantitative and are subject to tissue availability and sampling bias. To address these limitations, we evaluated a novel, sensitive radiotracer [64Cu]Cu-Bn-NOTA-hu14.18K322A to detect GD2 expression in osteosarcomas (six patient-derived xenografts and one cell line) in vivo using positron emission tomography (PET). Tumor uptake of the radiolabeled, humanized anti-GD2 antibody [64Cu]Cu-Bn-NOTA-hu14.18K322A was 7-fold higher in modestly GD2-expressing osteosarcomas (32% GD2-positive cells) than in a GD2-negative tumor (9.8% vs. 1.3% of the injected dose per cc, respectively). This radiotracer also identified lesions as small as 29 mm3 in a 34% GD2-positive model of metastatic osteosarcoma of the lung. Radiolabeled antibody accumulation in patient-derived xenografts correlated with GD2 expression as measured by flow cytometry (Pearson r = 0.88, P = 0.01), distinguishing moderately GD2-expressing osteosarcomas (32%-69% GD2-positive cells) from high GD2 expressors (>99%, P < 0.05). These results support the utility of GD2 imaging with PET to measure GD2 expression in osteosarcoma and thus maximize the clinical impact of anti-GD2 immunotherapy. SIGNIFICANCE: In situ assessment of all GD2-positive osteosarcoma sites with a novel PET radiotracer could significantly impact anti-GD2 immunotherapy patient selection and enable noninvasive probing of correlations between target expression and therapeutic response.
TMOD-20. THE PEDIATRIC BRAIN TUMOR ATLAS: AN INITIATIVE BY THE CHILDREN’S BRAIN TUMOR TISSUE CONSORTIUM AND PACIFIC PEDIATRIC NEUROONCOLOGY CONSORTIUM
Authors: Yuankun Zhu, Yiran Guo, Allison Heath, Pichai Raman, Elizabeth Appert, Jennifer Mason, Bo Zhang, Karthik Kalletla, Miguel Brown, Natasha Singh, Bailey Farrow, Alex Felmeister, Parimala Killada, Meen Chul Kim, Jena Lilly, Mateusz Koptyra, Rishi Lulla, Sabine Mueller, Michael Prados, Adam Resnick, Javad Nazarian, Phillip Storm, Angela Waanders
Journal: Neuro-Oncology (2019)

The Pediatric Brain Tumor Atlas (PBTA), created as a multi-center effort by the Children’s Brain Tumor Tissue Consortium (CBTTC) and Pacific Pediatric Neuro-Oncology Consortium (PNOC) and supported by the Gabriella Miller Kids First Data Resource Center (DRC), has the initial goal of comprehensively characterizing over 1,600 clinically annotated pediatric brain tumor samples and making the data publicly available to cancer researchers worldwide in near real time and without embargo. PBTA comprises comprehensive clinical data in addition to whole exome sequencing, whole genome sequencing (WGS), RNA sequencing (RNASeq), miRNA sequencing, and proteomics. To address the need to inform novel discovery and clinical implementation of genomic approaches for diagnostic/therapeutic purposes, PBTA utilizes the cloud-based research environment of the Gabriella Miller Kids First DRC to provide near real-time integration, dissemination, processing, and sharing of associated petabyte-scale harmonized data. The PBTA initiative leverages the DRC platform’s users to access their dbGAP approved use of TARGET and other pediatric cancer datasets hosted by NCI’s Cancer Genomics’ Cloud and Genomic Data Commons, allowing for cross-disease studies. Processed annotations is further enabled for the PBTA via PedcBioPortal, a data visualization/analysis application further integrating additional public and deposited datasets. In its first data release are over 30 different types of pediatric brain tumors representing over 1,000 subjects. This data is available on the Kids First DRC Portal and PedcBioPortal and users can seamlessly move between applications. Data types include those for matched tumor/normal samples, such as WGS, RNASeq, proteomics, longitudinal clinical data, imaging data (MRIs and radiology reports), histology slide images, and pathology reports. CBTTC/PNOC promote real-time data release and collaborative discovery via shared resources. The combination of cloud-based analytic platforms with data from both genomics and clinical practice serves to define a new paradigm for accelerated pediatric cancer translational research.