tbuckley/cabot-search huggingface dataset:
MEDU-32. ADVANCING PRECLINICAL MODELING OF HIGH RISK MEDULLOBLASTOMA BY PERFORMING CLINICALLY-RELEVANT RADIOTHERAPY ON PATIENT-DERIVED XENOGRAFTS
Authors: Stephanie Smith, Christopher Tinkle, Brandon Bianski, Brent Orr, Giles Robinson, Birgit Nimmervoll, Victoria Morel, Richard Gilbertson, Amar Gajjar, Thomas Merchant, Martine Roussel
Journal: Neuro-Oncology (2017)

Medulloblastoma (MB) is the most common malignant pediatric brain tumor that comprises four major subgroups. Group 3 (MBGrp3) that overexpress MYC and Sonic hedgehog (MBSHH) with MYCN amplification and TP53 loss of function have a particularly poor prognosis. MBs are treated with surgical resection, craniospinal irradiation (CSI), and chemotherapy with or without targeted agents. Radiation therapy is a core component of the current MB treatment regimen. Despite this aggressive approach, a significant number of patients, particularly in the high-risk groups, will ultimately fail primary therapy. To improve preclinical trials that more faithfully recapitulate aspects of the disease and therapeutic interventions, we established and molecularly characterized patient-derived xenografts (PDXs) of the high-risk MB Grp3 and MBSHH subgroups. Initial preclinical delivery of two dimensional whole brain radiotherapy significantly increased overall survival of mice bearing MB Grp3 or MBSHH PDX tumors. However, control and radiation-treated mice developed metastases in the spine and brain regions shielded from the radiation. Therefore, we developed a more sophisticated protocol that accurately and reproducibly delivers CSI to mice using the image-guided Small Animal Radiation Research Platform. We have successfully treated mice orthotopically implanted with high-risk MBGrp3 tumors up to 36 Gy (2Gy per day, 5 days on 2 days off) and have observed significantly improved survival. We are now poised to deliver fully fractionated irradiation to the complete neuraxis of PDX-bearing mice and are beginning to systematically test CSI in combination with targeted pharmacologic agents to identify potential synergy that results in a therapeutic advantage.
Economic Evaluation of Quality Improvement Interventions Designed to Prevent Hospital Readmission
Authors: Teryl K. Nuckols, Emmett Keeler, Sally Morton, Laura Anderson, Brian J. Doyle, Joshua Pevnick, Marika Booth, Roberta Shanman, Aziza Arifkhanova, Paul Shekelle
Journal: JAMA Internal Medicine (2017)

<h3>Importance</h3> Quality improvement (QI) interventions can reduce hospital readmission, but little is known about their economic value. <h3>Objective</h3> To systematically review economic evaluations of QI interventions designed to reduce readmissions. <h3>Data Sources</h3> Databases searched included PubMed, Econlit, the Centre for Reviews &amp; Dissemination Economic Evaluations, New York Academy of Medicine's Grey Literature Report, and Worldcat (January 2004 to July 2016). <h3>Study Selection</h3> Dual reviewers selected English-language studies from high-income countries that evaluated organizational or structural changes to reduce hospital readmission, and that reported program and readmission-related costs. <h3>Data Extraction and Synthesis</h3> Dual reviewers extracted intervention characteristics, study design, clinical effectiveness, study quality, economic perspective, and costs. We calculated the risk difference and net costs to the health system in 2015 US dollars. Weighted least-squares regression analyses tested predictors of the risk difference and net costs. <h3>Main Outcomes and Measures</h3> Main outcomes measures included the risk difference in readmission rates and incremental net cost. This systematic review and data analysis is reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. <h3>Results</h3> Of 5205 articles, 50 unique studies were eligible, including 25 studies in populations limited to heart failure (HF) that included 5768 patients, 21 in general populations that included 10 445 patients, and 4 in unique populations. Fifteen studies lasted up to 30 days while most others lasted 6 to 24 months. Based on regression analyses, readmissions declined by an average of 12.1% among patients with HF (95% CI, 8.3%-15.9%;<i>P</i> &lt; .001; based on 22 studies with complete data) and by 6.3% among general populations (95% CI, 4.0%-8.7%;<i>P</i> &lt; .001; 18 studies). The mean net savings to the health system per patient was $972 among patients with HF (95% CI, −$642 to $2586;<i>P</i> = .23; 24 studies), and the mean net loss was $169 among general populations (95% CI, −$2610 to $2949;<i>P</i> = .90; 21 studies), reflecting nonsignificant differences. Among general populations, interventions that engaged patients and caregivers were associated with greater net savings ($1714 vs −$6568;<i>P</i> = .006). <h3>Conclusions and Relevance</h3> Multicomponent QI interventions can be effective at reducing readmissions relative to the status quo, but net costs vary. Interventions that engage general populations of patients and their caregivers may offer greater value to the health system, but the implications for patients and caregivers are unknown.
Abstract 219: Cardiac Angiogenic Imbalance Leads to Peripartum Cardiomyopathy
Authors: Zolt Arany, Ian Patten, Sarosh Rana, Sajid Shahul, Glenn Rowe, Cholsoon Jang, Laura Liu, Michele Hacker, Julie Rhee, John Mitchell, Feroze Mahmood, Phil Hess, Caitlin Farrell, Nicole Koulisis, Eliyahu Khankin, Suzanne Burke, Igor Tudorache, Johann Bauersachs, Federica del Monte, Denise Hilfiker-Kleiner, Ananth Karumanchi
Journal: Circulation Research (2012)

Peri-partum cardiomyopathy (PPCM) is a frequently fatal disease that affects women near delivery, and occurs more frequently in women with pre-eclampsia and/or multiple gestation. The etiology of PPCM, or why it associates with pre-eclampsia, remains unknown. We show here that PPCM is associated with a systemic angiogenic imbalance, accentuated by pre-eclampsia. Mice that lack cardiac PGC-1α, a powerful regulator of angiogenesis, develop profound PPCM. Importantly, the PPCM is entirely rescued by pro-angiogenic therapies. In humans, the placenta in late gestation secretes VEGF inhibitors like soluble Flt1 (sFlt1), and this is accentuated by multiple gestation and pre-eclampsia. This anti-angiogenic environment is accompanied by sub-clinical cardiac dysfunction, the extent of which correlates with circulating levels of sFlt1. Exogenous sFlt1 alone caused diastolic dysfunction in wildtype mice, and profound systolic dysfunction in mice lacking cardiac PGC-1α. Finally, plasma samples from women with PPCM contained abnormally high levels of sFlt1. These data strongly suggest that PPCM is in large part a vascular disease, caused by excess anti-angiogenic signaling in the peri-partum period. The data also explain how late pregnancy poses a threat to cardiac homeostasis, and why pre-eclampsia and multiple gestation are important risk factors for the development of PPCM.
Statins for primary prevention in older people do not cut mortality or CHD events, study finds
Authors: Susan Mayor
Journal: BMJ (2017)

Treating older people who have moderate hyperlipidaemia and hypertension with statins for primary prevention of cardiovascular disease does not reduce mortality or coronary heart disease events, results from a post-hoc analysis of a large randomised trial have shown.1

Many older patients take statins for primary cardiovascular disease prevention. Although some evidence shows benefits from statins for secondary prevention in older people with cardiovascular diseases, limited data are available on the risks and benefits for primary prevention in this age group.

Researchers carried out a post-hoc analysis of data …
IMMU-01. CYTOTOXIC AND SUPPRESSIVE IMMUNE CELL TRAFFICKING TO PEDIATRIC BRAIN TUMORS: A BALANCING ACT
Authors: Nicole Lieberman, Kristen Haberthur, Amira Davis, Harrison Chinn, Jeffrey Stevens, Conrad Winter, Gail Deutsch, Sarah Leary, Courtney Crane
Journal: Neuro-Oncology (2017)

BACKGROUND: Because of the potential to specifically eliminate tumor cells while leaving healthy tissue intact, immunotherapy is a particularly appealing treatment option for children with brain tumors. However, little is known about the tumor microenvironment (TME) in pediatric brain tumors, and its effect on the immune system is unclear. We have previously shown that in contrast to adult glioblastoma (GBM), which have extensive accumulation of a variety of suppressive immune cells, such as tumor-associated macrophages (TAMs), aggressive pediatric brain tumors such as medulloblastomas and high grade gliomas (HGG) do not have a similar accumulation of immune cells in the TME. We hypothesize that pediatric brain tumors escape recognition by the immune system as a result of defects in immune trafficking to the TME and/or failure to recognize the tumor. METHODS: Quantitative PCR for immunosuppressive factors was performed on pediatric brain tissue (non-tumor brain, pilocytic astrocytoma, or GBM, n=5 per group). Chemokine concentration in plasma (n=77) obtained at the time of diagnosis or during follow-up treatment was measured by bioplex analysis. Surface protein expression on patient leukocytes (n=40) was evaluated by flow cytometry. RESULTS: Pediatric brain tumors do not exhibit high levels of immunosuppressive factors such as PD-L1 or M-CSF relative to normal brain. Plasma samples from pediatric brain tumor patients have decreased concentrations of chemokines that attract suppressive immune cells to the tumor site relative to control patients without tumor. Furthermore, we did not observe a change in chemokines that attract cytotoxic T and NK cells, supporting the hypothesis that immune cell trafficking and routine surveillance of transformed cells may be impaired in an immature immune system. CONCLUSIONS: These data suggest that in pediatric patients, designing cell therapy products that educate cytotoxic effectors and improve their homing to tumor may be more important than overcoming immunosuppression in the TME.
Insurance Coverage and Aid-in-Dying Medication Costs—Reply
Authors: Veena Shankaran, Richard J. LaFrance, Scott D. Ramsey
Journal: JAMA Oncology (2017)

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Alternative Evolutionary Paths to Bacterial Antibiotic Resistance Cause Distinct Collateral Effects
Authors: Camilo Barbosa, Vincent Trebosc, Christian Kemmer, Philip Rosenstiel, Robert Beardmore, Hinrich Schulenburg, Gunther Jansen
Journal: Molecular Biology and Evolution (2017)

When bacteria evolve resistance against a particular antibiotic, they may simultaneously gain increased sensitivity against a second one. Such collateral sensitivity may be exploited to develop novel, sustainable antibiotic treatment strategies aimed at containing the current, dramatic spread of drug resistance. To date, the presence and molecular basis of collateral sensitivity has only been studied in few bacterial species and is unknown for opportunistic human pathogens such as Pseudomonas aeruginosa. In the present study, we assessed patterns of collateral effects by experimentally evolving 160 independent populations of P. aeruginosa to high levels of resistance against eight commonly used antibiotics. The bacteria evolved resistance rapidly and expressed both collateral sensitivity and cross-resistance. The pattern of such collateral effects differed to those previously reported for other bacterial species, suggesting interspecific differences in the underlying evolutionary trade-offs. Intriguingly, we also identified contrasting patterns of collateral sensitivity and cross-resistance among the replicate populations adapted to the same drug. Whole-genome sequencing of 81 independently evolved populations revealed distinct evolutionary paths of resistance to the selective drug, which determined whether bacteria became cross-resistant or collaterally sensitive towards others. Based on genomic and functional genetic analysis, we demonstrate that collateral sensitivity can result from resistance mutations in regulatory genes such as nalC or mexZ, which mediate aminoglycoside sensitivity in β-lactam-adapted populations, or the two-component regulatory system gene pmrB, which enhances penicillin sensitivity in gentamicin-resistant populations. Our findings highlight substantial variation in the evolved collateral effects among replicates, which in turn determine their potential in antibiotic therapy.
Flexible nanofilms coated with aligned piezoelectric microfibers preserve the contractility of cardiomyocytes
Authors: P. José Gouveia, S. Rosa, L. Ricotti, B. Abecasis, H.V. Almeida, L. Monteiro, J. Nunes, F. Sofia Carvalho, M. Serra, S. Luchkin, A. Leonidovitch Kholkin, P. Marques Alves, P. Jorge Oliveira, R. Carvalho, A. Menciassi, R. Pires das Neves, L. Silva Ferreira
Journal: Biomaterials (2017)

The use of engineered cardiac tissue for high-throughput drug screening/toxicology assessment remains largely unexplored. Here we propose a scaffold that mimics aspects of cardiac extracellular matrix while preserving the contractility of cardiomyocytes. The scaffold is based on a poly(caprolactone) (PCL) nanofilm with magnetic properties (MNF, standing for magnetic nanofilm) coated with a layer of piezoelectric (PIEZO) microfibers of poly(vinylidene fluoride–trifluoroethylene) (MNF+PIEZO). The nanofilm creates a flexible support for cell contraction and the aligned PIEZO microfibers deposited on top of the nanofilm creates conditions for cell alignment and electrical stimulation of the seeded cells. Our results indicate that MNF+PIEZO scaffold promotes rat and human cardiac cell attachment and alignment, maintains the ratio of cell populations overtime, promotes cell-cell communication and metabolic maturation, and preserves cardiomyocyte (CM) contractility for at least 12 days. The engineered cardiac construct showed high toxicity against doxorubicin, a cardiotoxic molecule, and responded to compounds that modulate CM contraction such as epinephrine, propranolol and heptanol.
Persistence of EpCAM-positive disseminated tumor cells after platinum-based chemotherapy in the bone marrow of patients with primary ovarian cancer
Authors: P. Wimberger, M. Heubner, R. Kimmig, M. E. Scheulen, S. Kasimir-Bauer
Journal: Journal of Clinical Oncology (2007)

16023 Background: The impact of chemotherapy on disseminated tumor cells (DTC) in ovarian cancer is still unknown. Therefore we evaluated in 30 patients with primary ovarian cancer, undergoing radical tumor debulking surgery, (1) the influence of first-line chemotherapy with carboplatinum and paclitaxel on DTC elimination in bone marrow (BM) and peripheral blood (PB), (2) the coexpression of the epitelial antigen EpCAM on DTC and (3) the impact on progression free survival (PFS). Methods: DTC were detected in PB (20ml) and bilateral BM aspirates (10ml) using density gradient centrifugation and immunocytochemistry, applying the anti-cytokeratin antibody A45-B/B3. EpCAM-positive DTC were analyzed by using the antibodies HEA-125-FITC and Ber-EP4-FITC. PFS was estimated using the Kaplan-Meier method and statistically evaluated using a two-sided log-rank test. A significant increase or decrease of DTC was assessed if the difference was = 2 DTC. Results: Before chemotherapy, we identified DTC in 16% of PB samples with a mean number of 2 cells (range 1–3) and in 50% of BM samples with a mean number of 3 cells/9x10E6 BM cells (range 1–8). After chemotherapy, DTC were detected in PB in only one patient but still in 50% of BM samples with a with a mean number of 17 cells/9x10E6 BM cells (range 1–100). In BM, chemotherapy completely eliminated DTC in 30% of the patients, no significant change was documented in 47% and a significant enhancement of DTC was shown in 33%, including 8 patients (27%) who had no DTC before chemotherapy. In case of significant increase of DTC, patients showed a trend for reduced PFS (12.8 months ± 0.7; mean PFS ± SEM) in comparison to patients with no increase (19.3 months ± 1.4) or decrease of DTC (p=0.07). DTC, persisting after chemotherapy, co-expressed EpCAM. Conclusions: It has to be considered, whether these patients with persisting EpCAM-positive DTC in BM might profit from an additive immunotherapy e.g. by the intraperitoneal application of a trifunctional antibody targeting EpCAM, CD3 and accessory cells. No significant financial relationships to disclose.
TMOD-04. A UNIQUE PEDIATRIC IDH1 MUTANT GLIOBLASTOMA IN VITRO AND IN VIVO MODEL
Authors: Dennis S. Metselaar, Michaël H. Meel, Piotr Waranecki, Kenn Zwaan, Pino J. Poddighe, Dannis G. van Vuurden, Gertjan L. Kaspers, Esther Hulleman
Journal: Neuro-Oncology (2017)

AbstractThe isocitrate dehydrogenase 1 (IDH1) mutation serves as a hallmark for secondary high-grade gliomas, occurring in approximately 80% of all secondary glioblastomas (GBM) in adults. IDH1 mutations in pediatric high-grade gliomas are much rarer, and its role is still largely unknown. The lack of biologically representative in vitro and in vivo IDH1 mutant models makes it difficult to study this malignancy. Here we describe the establishment of a pediatric endogenous IDH1 mutant GBM primary cell line (VUMC-HGG-09) derived from an 11 year old female patient. We effectively cultured the VUMC-HGG-09 cells both as neurospheres in a serum-free environment, and as an adherent monolayer in serum enriched medium. VUMC-HGG-09 cells were orthotopically injected into brains of athymic nude mice, which caused successful engraftment and aggressively growing tumors in all the animals. Hematoxylin and vimentin staining showed a diffuse GBM like growth pattern through the whole brain. Furthermore, presence of the human R132H IDH1 mutation was confirmed by immunohistochemistry of the resected mouse brains. Shallow sequencing, whole chromosome painting FISH, and SNP-array were used to map chromosomal aberrations. These data revealed a rarely found chromothripsis like pattern within chromosome 7 and several minor deletions and translocations among other chromosomes. The VUMC-HGG-09 is a unique model that to our knowledge represents the first in vitro and in vivo pediatric IDH1 mutant glioma model. A growing body of evidence suggests the IDH1 mutation to play a vital role in the process of tumorigenesis as well as its value as a clinical prognostic marker. Therefore, VUMC-HGG-09 could serve both as a unique pediatric GBM model, as well as a pivotal in vitro and in vivo model to study IDH1 mutant tumors in both pediatric and adult neuro-oncology.
IMMU-18. HUMANIZED ANTI-CD47 ANTIBODY COMBINED WITH AN AGONIST ANTI-CD40 ANTIBODY IS AN EFFECTIVE TREATMENT FOR DIPG XENOGRAFTS WITH CRANIOSPINAL DISSEMINATION
Authors: Sharareh Gholamin, Suzana Kahn, Rogelio Esparza, Irving Weissman, Siddhartha Mitra, Samuel Cheshier
Journal: Neuro-Oncology (2017)

INTRODUCTION: DIPG is the most common malignant brainstem tumor in children. The resistance of DIPG to standard treatments along with inoperability of this tumor because of the anatomical location leave DIPG patients with dismal prognosis. Multiple studies revealed that DIPG patients have only a few months of survival after detection of cranio-spinal metastasis. Our previous work showed that a humanized anti-CD47 antibody (anti-huCD47 mAb), an immune-modulatory drug that increases phagocytic activity of macrophages against cancer cells, has a therapeutic effect on DIPG xenografts. However, the efficacy of anti-CD47 therapy was reduced with tumor size and presence of metastasis at the onset of treatment. Therefore, we tested the synergistic effect of anti-huCD47 mAb combined with anti-msCD40 mAb, another immuno-modulatory antibody that increases the recruitment of macrophages to the tumor site, on DIPG xenografts with cranio-spinal dissemination. METHODS: Human-derived DIPG cells were infected with GFP-luciferase expressing virus and injected to the pons of NOD scid gamma mice. The engraftment was verified via bioluminescent (BLI) imaging. The mice with positive signal in forebrain and spine were randomized for treatment with anti-huCD47 mAb alone, anti-msCD40 mAb alone, anti-huCD47 mAb coupled with anti-msCD40 mAb, and control. The efficacy of treatment was measured using follow-up BLI imaging and survival analysis. RESULTS: Follow-up BLI imaging revealed significant decline in the flux measures of mice receiving combined treatment (P< 0.05). BLI signals from the spinal and forebrain strongly diminished in the mice under combined treatment compared to the other groups. A significant extension in survival was seen in this group compared to the other three groups (P < 0.05). CONCLUSION: Combinatorial treatment with anti-CD47 Ab and anti-CD40 Ab is effective in the removal of not only DIPG from a primary site but also a cranio-spinal dissemination of the disease.
DIPG-41. ESTABLISHMENT AND CHARACTERISTICS OF TREATMENT-NAÏVE DIPG PRE-CLINICAL MODELS DERIVED FROM PATIENTS
Authors: Cheng Xu, Xiaoqing Liu, Yibo Geng, Qingran Bai, Changcun Pan, Yu Sun, Xin Chen, Hai Yu, Yuliang Wu, Qin Shen, Liwei Zhang
Journal: Neuro-Oncology (2017)

Diffuse intrinsic pontine glioma (DIPG) is a devastating pediatric brain tumor, which features the resistance of radiotherapy and chemotherapy. The majority of children are diagnosed between 5 and 10 years old, with the median survival less than 1 year. One of the main reasons why little progression has been made through several decades is the lack of DIPG pre-clinical models. Given the genetic and micro-environmental distinctions from supratentorial glioma, the specific DIPG pre-clinical model is urgently demanded. However, due to the enormous difficulties in the acquisition of DIPG specimens and the sophisticated technique required to perform brainstem orthotropic injection, the development of pre-clinical models for DIPG has fallen far behind supratentorial glioma models. Here we successfully established 8 DIPG primary cell lines derived from treatment-naïve surgery or biopsy specimens. These cell lines can be stably passaged and develop distinct morphologies with different growth rates and chromosome abnormalities. Besides, they have the identical genomic hallmarks with original tumors and can be stratified into three distinct subgroups by their mutation pattern in TP53 cell-cycle pathway: 1) H3F3A combined with TP53; 2) H3F3A combined with PPM1D mutation; 3) H3F3A with TP53/PPM1D double negative. Notably, remarkable expressions of several neural stem cell lineage markers, such as Nestin, Olig2, PDGFRα and GFAP have been seen in the primary cells, which may be the reason of cell self-renewal capacity and tumor heterogeneity. Moreover, three out of eight cells can generate subcutaneous and orthotopic xenografts in immunodeficient mice by the stereotactic injection, which largely resemble the characteristics of DIPG not only in MRI but also in tumor tissue staining. In conclusion, we successfully develop DIPG pre-clinical models including primary cell lines as well as subcutaneous and orthotopic xenografts resembling the specific features of human DIPG and can be used as proper tools to test potential therapeutic treatment.