tbuckley/cabot-search huggingface dataset:
QOL-01. LONGITUDINAL COMPARISON OF NEUROCOGNITIVE TRAJECTORIES IN PEDIATRIC MEDULLOBLASTOMA PATIENTS TREATED WITH PROTON VERSUS PHOTON RADIOTHERAPY
Authors: Lisa Kahalley, Rachel Peterson, M Douglas Ris, Laura Janzen, M Fatih Okcu, David Grosshans, Vijay Ramaswamy, Arnold Paulino, David Hodgson, Anita Mahajan, Derek Tsang, Normand Laperriere, William Whitehead, Robert Dauser, Michael Taylor, Heather Conklin, Eric Bouffet, Murali Chintagumpala, Donald Mabbott
Journal: Neuro-Oncology (2020)

Abstract PURPOSE By reducing dose to normal brain tissue, proton radiotherapy (PRT) may lessen neurocognitive risk traditionally associated with photon radiotherapy (XRT). We examined change in neurocognitive scores over time in pediatric medulloblastoma patients treated with PRT versus XRT. METHODS Neurocognitive scores from 79 patients (37 PRT, 42 XRT) were examined. Patients were treated between 2007–2018 on the same treatment protocols that differed only by craniospinal modality (PRT versus XRT). Change in scores over time since diagnosis were compared between groups. RESULTS Groups were similar on most demographic/clinical variables: sex (67.1% male), age at diagnosis (mean 8.6 years), CSI dose (median 23.4 Gy), length of follow-up (mean 4.3 years), and parental education (mean 14.3 years). Boost dose (p&amp;lt;0.001) and margin (p=0.001) differed between groups. Adjusting for covariates, the PRT group exhibited superior outcomes in global IQ, perceptual reasoning, and working memory versus the XRT group (all p&amp;lt;0.05). The XRT group exhibited significant decline in global IQ, working memory, and processing speed (all p&amp;lt;0.05). The PRT group exhibited stable scores in all domains except processing speed (p=0.003). Posterior fossa syndrome imparted risk independent of modality. CONCLUSION This is the first study comparing neurocognitive trajectories between pediatric patients treated for medulloblastoma with PRT versus XRT on comparable, contemporary protocols. PRT was associated with more favorable neurocognitive outcomes in most domains compared to XRT, although processing speed emerged as vulnerable in both groups. This is the strongest evidence to date of an intellectual sparing advantage with PRT in the treatment of pediatric medulloblastoma.
NCMP-06. METASTATIC CENTRAL NERVOUS SYSTEM DISEASE SECONDARY TO BURKITT LYMPHOMA IN A PATIENT WITH PRIOR HISTORY OF MELANOMA
Authors: Uju Momah, Jennifer Brewer, Anthony Tran, David Shapiro
Journal: Neuro-Oncology (2020)

Abstract Sporadic Burkitt’s Lymphoma accounts for only 1–2% of Non Hodgkin’s Lymphoma, and metastasizes to the central nervous system (CNS) is uncommon, occurring in about 13–17% of adult patients. 1 Melanoma is far more likely to metastasize to the CNS, occurring in about 37% of adult patients.2 Here we present the case of a 69 year old Gambian female with a prior medical history of plantar melanoma. She initially presented to her primary care provider with back pain and adenopathy, and was referred to surgical consultation for diagnosis and concern for recurrent melanoma. Her workup revealed metastatic Burkitt’s Lymphoma with disease in the abdomen, lungs and likely CNS involvement. This report chronicles her disease course and approach to management.
2008 Thomas W. Smith Memorial Lecture—Protein Kinase C α as a Novel Therapeutic Target for Treating Heart Failure
Authors: Jeffrey Molkentin
Journal: Circulation (2008)

We have shown that protein kinase C (PKC) α functions as a proximal regulator of Ca 2+ handling in cardiac myocytes (Braz et al, Nat. Med. 10:248, 2004). Deletion of PKC α in the mouse resulted in augmented sarcoplasmic reticulum Ca 2+ loading, enhanced Ca 2+ transients, and augmented contractility, whereas overexpression of PKCα in the heart blunted contractility. Mechanistically, PKCα regulates Ca 2+ handling by altering inhibitor-1 phosphorylation, which suppresses protein phosphatase-1 activity, thus modulating phospholamban activity and sarcoplasmic reticulum Ca 2+ AT-Pase 2 (SERCA2). Acute inhibition of PKCα with the pharmacologic agents Ro-32-0432 or Ro-31-8220 significantly augmented cardiac contractility in vivo or in an isolated work performing heart preparation in wild-type mice, but not in PKC α-deficient mice. Ro-32-0432 also acutely increased cardiac contractility in two different models of heart failure in vivo. Moreover, acute or chronic treatment with Ro-32-8220 in a mouse model of heart failure, due to deletion of the muscle lim protein (MLP) gene, significantly augmented cardiac contractility and restored normal pump function. Adenoviral-mediated gene therapy with a dominant negative PKCα cDNA rescued heart failure in a chronic rat model of postinfarction cardiomyopathy. Moreover, expression of dominant-negative PKCα in cardiac myocytes using a cardiac-specific transgenic system (tetracycline-regulated) also enhanced cardiac contractility and antagonized heart failure due to myocardial infarction injury. Finally, another PKCα/β inhibitor, ruboxistaurin (LY333531), antagonized heart failure after long-term pressure overload in mice. PKCα is the dominant conventional PKC isoform expressed in the adult human heart, providing potential relevance of these findings to human pathophysiology. Indeed, pharmacological inhibition of PKCα may serve as a novel therapeutic strategy for either enhancing cardiac contractility in the setting of severe functional deterioration or as a long-term treatment option to prevent worsening of heart failure in earlier stages.
<i>Tripterygium wilfordii</i>: An inspiring resource for rheumatoid arthritis treatment
Authors: Yanqiong Zhang, Xia Mao, Weijie Li, Wenjia Chen, Xiaoyue Wang, Zhaochen Ma, Na Lin
Journal: Medicinal Research Reviews (2020)

Abstract Tripterygium wilfordii Hook F ( Tw HF)‐based therapy is among the most efficient and crucial therapeutics for the treatment of rheumatoid arthritis (RA), which indicates that Tw HF is a potential source of novel anti‐RA drugs. However, accumulating studies have observed that Tw HF‐based therapy induces multi‐organ toxicity, which prevents the wide use of this herb in clinical practice, although several recent studies have attempted to reduce the toxicity of Tw HF. Notably, our research group developed a “Clinical Practice Guideline for Tripterygium Glycosides/ Tripterygium wilfordii Tablets in the Treatment of Rheumatoid Arthritis” (No. T/CACM 1337‐2020) approved by the China Association of Chinese Medicine to standardize the clinical application of Tw HF‐based therapy and thus avoid adverse effects. Although great strides have been made toward the characterization of Tw HF‐based therapy and revealing its underlying pharmacological and toxicological mechanisms, several crucial gaps in knowledge remain as potential barriers to enhance its therapeutic effects on the premise of safety assurance. This review offers a global view of Tw HF, ranging from its chemical constituents, quality control, clinical observations, and underlying pharmacological mechanisms to toxic manifestations and mechanisms. We focus on the important and emerging aspects of this field and highlight the major challenges and strategies for using novel techniques and approaches to gain new insights into unresolved questions. We hope that this review will improve the understanding of Tw HF application and draw increasing interdisciplinary attention from clinicians that practice both Chinese and Western medicine, basic researchers, and computer scientists.
GCT-60. DEVELOPMENT OF MICROBLEEDING AFTER PROTON THERAPY FOR PATIENTS WITH GERM CELL TUMOR
Authors: Hidehiro Kohzuki, Ai Muroi, Masashi Mizumoto, Hideaki Sakurai, Eiichi Ishikawa, Akira Matsumura
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Proton therapy has been increasingly used to treat pediatric brain tumor. However, there were few reports about radiation-induced cerebral microbleeds(CMBs) and cavernous malformation among these patients. Here we evaluate the incidence and risk factor of CMBs with MR imaging. MATERIAL AND METHOD We retrospectively identified patients with germ cell tumor treated with whole ventricle irradiation of 30.6 Gy using proton therapy at the Tsukuba University Hospital between 2004 and 2017. CMBs were characterized by examination of MR imaging scan including susceptibility-weighted imaging and T2* weighed gradient-recalled echo sequence. RESULT The mean age at the time of proton therapy was 14.5 years. The median follow-up duration was 62.3 months. Three patients were treated by local boost in addition to whole ventricle irradiation. CMBs were found in 78% at 5 years, and 88% at 10 years from irradiation. Over 80% of CMBs occurred in area of the brain exposed to 30 Gy. CONCLUSION This study indicated over 30 Gy irradiation may become a risk factor for development of CMBs. Although the correlation between development of CMBs and cognitive function, proton therapy might have an advantage to reduce late sequelae with decreasing irradiating dose to surrounding normal brain tissue.
Targeting of the Interleukin-7 Receptor Alpha-Chain (IL-7Rα) Blocks B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) Development and Reduces Leukemic Infiltration to the Central Nervous System (CNS)
Authors: Ameera Alsadeq, Anila George Vadakumchery, Ali Almasri, Hend Abdelrasoul, Markus Werner, Lennart Lenk, Felix Seyfried, Klaus-Michael Debatin, Lueder-Hinrich Myer, Gunnar Cario, Martin Schrappe, Denis Martin Schewe, Hassan Jumaa
Journal: Blood (2017)
Antigen-driven clonal selection shapes the persistence of HIV-1–infected CD4+ T cells in vivo
Authors: Francesco R. Simonetti, Hao Zhang, Garshasb P. Soroosh, Jiayi Duan, Kyle Rhodehouse, Alison L. Hill, Subul A. Beg, Kevin McCormick, Hayley E. Raymond, Christopher L. Nobles, John K. Everett, Kyungyoon J. Kwon, Jennifer A. White, Jun Lai, Joseph B. Margolick, Rebecca Hoh, Steven G. Deeks, Frederic D. Bushman, Janet D. Siliciano, Robert F. Siliciano
Journal: Journal of Clinical Investigation (2020)

Clonal expansion of infected CD4+ T cells is a major mechanism of HIV-1 persistence and a barrier to achieving a cure. Potential causes are homeostatic proliferation, effects of HIV-1 integration, and interaction with antigens. Here, we show that it is possible to link antigen responsiveness, the full proviral sequence, the integration site, and the T cell receptor β-chain (TCRβ) sequence to examine the role of recurrent antigenic exposure in maintaining the HIV-1 reservoir. We isolated CMV- and Gag-responding CD4+ T cells from 10 treated individuals. Proviral populations in CMV-responding cells were dominated by large clones, including clones harboring replication-competent proviruses. TCRβ repertoires showed high clonality driven by converging adaptive responses. Although some proviruses were in genes linked to HIV-1 persistence (BACH2, STAT5B, MKL1), the proliferation of infected cells under antigenic stimulation occurred regardless of the site of integration. Paired TCRβ and integration site analysis showed that infection could occur early or late in the course of a clone's response to antigen and could generate infected cell populations too large to be explained solely by homeostatic proliferation. Together, these findings implicate antigen-driven clonal selection as a major factor in HIV-1 persistence, a finding that will be a difficult challenge to eradication efforts.
EPID-09. THE INCIDENCE OF PRIMARY BRAIN TUMORS IN CHILDREN IN JAPAN BASED ON 2016 NATIONAL CANCER REGISTRY IN JAPAN
Authors: Yuko Watanabe, Yoshitaka Narita, Takamasa Kayama
Journal: Neuro-Oncology (2020)

Abstract The national cancer registries began in January 2016 and the actual number of cancer patients in 2016 including primary brain tumors in Japan was released as a preliminary report in January 2019. According to the report, 667 incidence of pediatric brain tumors were reported in aged 0–14 years (boy: 382; girl: 285), of them 537 patients underwent surgery, chemotherapy, or radiation therapy (diagnosis: 516, undiagnosed: 21), and 130 patients were followed up without any treatments. The breakdown of tumor types was 279 Neuroepithelial tumors, 73 Embryonal tumors (61 Medulloblastomas), and 63 Germ Cell Tumors (GCTs). The crude rate per 100,000 population in 2016 was 4.23 for all pediatric brain tumors, 1.77 for Neuroepithelial tumor, 0.39 for Medulloblastoma, and 0.40 for GCTs. In comparison, the United States CBTRUS2019 (2012–2016) reported that the age-adjusted incidence rates per 100,000 population in the United States was 5.74 for all pediatric brain tumors, 4.15 for Neuroepithelial tumors, 0.48 for Medulloblastoma, and 0.22 for GCTs. The age-adjusted incidence in Japan based on the US population in 2000 was 4.21 for all pediatric brain tumors, Neuroepithelial tumor 1.77, Medulloblastoma 0.39, and GCTs 0.39, suggesting that the incidence of Neuroepithelial tumor and Medulloblastoma is lower whereas that of GCTs is approximately twice comparing to the US. By taking advantage of the national cancer registry data, which was publicly opened to researchers in 2019, we report the incidence of primary brain tumors and its comparison worldwide based on the re-classification criteria of primary brain tumors including benign tumor.
Functionalized nanogel for treating activated astrocytes in spinal cord injury
Authors: Simonetta Papa, Valeria Veneruso, Emanuele Mauri, Giada Cremonesi, Xhuljana Mingaj, Alessandro Mariani, Massimiliano De Paola, Arianna Rossetti, Alessandro Sacchetti, Filippo Rossi, Gianluigi Forloni, Pietro Veglianese
Journal: Journal of Controlled Release (2020)
CSIG-05. S6K FEEDBACK REGULATION OF THE RECEPTOR TYROSINE KINASE AXL IN PTEN-DEFICIENT GLIOBLASTOMA
Authors: Pranjal Sarma, Kelli N Ennis, Collin Wetzel, David R Plas
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma multiforme (GBM), the most aggressive type of malignant brain cancer in adults, harbors frequent mutations and/or deletions in the tumor suppressor gene PTEN leading to therapeutic resistance. In PTEN-deficient GBM, mTOR complex 1 (mTORC1) and the S6 kinases (S6Ks) mediate increased metabolism and apoptosis resistance. Previously we established that combining the LY-2584702 inhibitor of S6K1 with the BMS-777607 inhibitor of the AXL receptor tyrosine kinase (RTK) was selectively cytotoxic for PTEN-deficient GBM. Here we determined the impact of these inhibitors on S6K1 and S6K2 signal transduction and tumor cell metabolism. While combination of LY-2584702 with BMS-777607 was sufficient to prevent S6K phosphorylation of ribosomal protein S6 (rpS6), treatment with either drug as a single agent was not sufficient to suppress rpS6 phosphorylation. Genetic inactivation of S6Ks revealed that inactivation of S6K2 cooperated with LY-2584702 to prevent S6K substrate phosphorylation. Similarly, persistent S6K signaling in BMS777607-treated GBM cells was significantly reduced when S6K2 was targeted. These results indicate that S6K2 integrates signal transduction inputs from both PTEN-regulated and AXL-regulated pathways. Metabolomic analysis revealed combination effects of S6K and AXL inhibitors in reducing nucleotide precursor metabolic flux. We therefore propose that combination inhibition of S6K and AXL signaling compromises S6K-dependent nucleotide synthesis in PTEN-deficient GBM.
DDEL-05. BLOOD-BRAIN BARRIER DISRUPTION AND ENHANCED RADIOSENSITIZERS EXTRAVASATION UPON FOCUSED ULTRASOUND FOR TREATMENT OF DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Elvin ‘t Hart, Marc Derieppe, Maaike Bruin, Helena Besse, Rianne Haumann, Eelco Hoving, Alwin Huitema, Mario Ries, Dannis van Vuurden
Journal: Neuro-Oncology (2020)

Abstract Poor prognosis of diffuse midline glioma, including diffuse intrinsic pontine glioma (DIPG), reflects the low efficacy of current treatment strategies, mainly due to (1) a largely intact blood-brain barrier (BBB) and (2) the proficiency of tumour tissues to upregulate multiple DNA repair genes, resulting into radio-resistance. In vitro studies showed therapeutic benefit by combining radiotherapy and radiosensitizers, while pre-clinical and clinical studies evidenced safe and transient opening of the BBB using microbubble mediated focused ultrasound (FUS). Previously, we demonstrated the enhanced extravasation of olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor in the mouse pons. Local drug delivery was applied using an in-house built X-ray image-guided FUS system with a 1 MHz mono-element transducer delivering a tone-burst pulse with a mechanical index of 0.4. Tissue/blood drug concentrations were analysed by LC-MS/MS, 30 minutes after intraperitoneal injection of 10 mg/kg olaparib. The FUS system allowed for precise treatment of the pons, proven by local extravasation of Evans Blue-conjugated albumin. A significant 5.1 fold median increase was observed in absolute concentrations in the pons after FUS intervention compared to the control and a 4.9 fold increase of the median tissue-blood ratio (*p&amp;lt;0.05). No significant differences were detected in brain regions outside the ultrasound focus and other organs, confirming the local intervention. With this, the 299 nM equivalent olaparib concentration found in the pons will facilitate PARP inhibition in future murine patient-derived xenograft tumour models, thus leading to a greater therapeutic effect when in combination with radiotherapy treatment of DIPG.
RADT-46. SYSTEMATIC REVIEW OF RADIOSENSITIZERS FOR MALIGNANT BRAIN TUMORS: POTENTIAL FOR LEARNING FROM PAST FAILURES
Authors: Usman Beg, Brianna Snyder, Sarosh Madhani, Nima Hamidi, Alireza Mansouri
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Radiation therapy (RT) is the cornerstone of management of malignant CNS tumors but its efficacy is limited in hypoxic tumors. Although numerous radiosensitizer compounds have been developed to enhance the effect of RT, progress has been stagnant. Through this systematic review of the literature on radiosensitizers for malignant CNS tumors, we have sought to provide an overview of radiosensitizers developed to date, summarize their safety and efficacy, and evaluate areas for possible improvement. METHODS PUBMED, EMBASE, Cochrane, and Web of Science were searched using terminology pertaining to radiosensitizers for brain tumor RT according to PRISMA guidelines. Publications reporting clinical evidence of non-antineoplastic radiosensitizers with RT for malignant CNS tumors were included. Pre-specified variables were extracted. Outcomes of interest were overall survival, progression-free survival, adverse events, and quality-of-life outcomes. RESULTS Forty-eight publications were identified which included 20 unique non-antineoplastic radiosensitizing agents. Only 2/20 agents, fluosol with oxygen, and efaproxiral, showed improvement in outcomes in patients with glioblastoma and brain metastasis, respectively. A larger study was not able to confirm the latter. While molecular similarities between these two agents were not identifiable, the effective mechanism of action allowed them to modulate hypoxia from within blood vessels, without crossing blood-brain barrier. Nine agents required dose modification, change of schedule, or complete discontinuation due to toxicities. CONCLUSION Despite decades of research, progress in the field of radiosensitizers for malignant CNS tumors has been limited. Available data demonstrates the lack of progress in identifying effective radiosensitizers for brain tumors. Of the many non-antineoplastic radiosensitizers that have been tested, only two have showed (limited) efficacy by targeting tumor oxygenation. Alternative strategies such as synthetic drug design, based on a mechanism of action that is independent of crossing the blood-brain barrier, may be necessary. Such studies are currently underway.
Model-informed machine learning for multi-component<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" altimg="si1.svg"><mml:msub><mml:mi>T</mml:mi><mml:mn>2</mml:mn></mml:msub></mml:math>relaxometry
Authors: Thomas Yu, Erick Jorge Canales-Rodríguez, Marco Pizzolato, Gian Franco Piredda, Tom Hilbert, Elda Fischi-Gomez, Matthias Weigel, Muhamed Barakovic, Meritxell Bach Cuadra, Cristina Granziera, Tobias Kober, Jean-Philippe Thiran
Journal: Medical Image Analysis (2020)

Recovering the T2 distribution from multi-echo T2 magnetic resonance (MR) signals is challenging but has high potential as it provides biomarkers characterizing the tissue micro-structure, such as the myelin water fraction (MWF). In this work, we propose to combine machine learning and aspects of parametric (fitting from the MRI signal using biophysical models) and non-parametric (model-free fitting of the T2 distribution from the signal) approaches to T2 relaxometry in brain tissue by using a multi-layer perceptron (MLP) for the distribution reconstruction. For training our network, we construct an extensive synthetic dataset derived from biophysical models in order to constrain the outputs with a priori knowledge of in vivo distributions. The proposed approach, called Model-Informed Machine Learning (MIML), takes as input the MR signal and directly outputs the associated T2 distribution. We evaluate MIML in comparison to a Gaussian Mixture Fitting (parametric) and Regularized Non-Negative Least Squares algorithms (non-parametric) on synthetic data, an ex vivo scan, and high-resolution scans of healthy subjects and a subject with Multiple Sclerosis. In synthetic data, MIML provides more accurate and noise-robust distributions. In real data, MWF maps derived from MIML exhibit the greatest conformity to anatomical scans, have the highest correlation to a histological map of myelin volume, and the best unambiguous lesion visualization and localization, with superior contrast between lesions and normal appearing tissue. In whole-brain analysis, MIML is 22 to 4980 times faster than the non-parametric and parametric methods, respectively.